See Chapter 39 for Hepatocellular Carcinoma.
ESSENTIALS OF DIAGNOSIS
Prodrome of anorexia, nausea, vomiting, malaise, aversion to smoking.
Fever, enlarged and tender liver, jaundice.
Normal to low white cell count; markedly elevated aminotransferases.
Hepatitis can be caused by viruses, including the five hepatotropic viruses—A, B, C, D, and E—and many drugs and toxic agents; the clinical manifestations may be similar regardless of cause. Hepatitis A virus (HAV) is a 27-nm RNA hepatovirus (in the picornavirus family) that causes epidemics or sporadic cases of hepatitis. The virus is transmitted by the fecal-oral route, and its spread is favored by crowding and poor sanitation. Since introduction of the HAV vaccine in the United States in 1995, the incidence rate of HAV infection has declined from as much as 14 to 0.4 per 100,000 population, with a corresponding decline in the mortality rate from 0.1 to 0.02 death per 100,000 population and an increase in the mean age of death. In the United States, international travel has emerged as the leading risk factor, accounting for over 40% of cases, with another 18% of cases attributable to exposure to an international traveler. Common source outbreaks may still result from contaminated water or food, including inadequately cooked shellfish. In 2016, an outbreak in Virginia and neighboring states resulted from smoothies containing contaminated strawberries, and HAV has been described as a reemerging food-borne public health threat in Europe. Outbreaks among people who inject drugs or who are unvaccinated residents in institutions and cases among international adoptees and their contacts also have been reported.
The incubation period averages 30 days. HAV is excreted in feces for up to 2 weeks before clinical illness but rarely after the first week of illness. The mortality rate for hepatitis A is low, and fulminant hepatitis A is uncommon except for rare instances in which it occurs in a patient with concomitant chronic hepatitis C. There is no chronic carrier state. In the United States, about 30% of the population have serologic evidence of previous HAV infection.
Figure 16–1 shows the typical course of acute hepatitis A. Clinical illness is more severe in adults than in children, in whom it is usually asymptomatic. The onset may be abrupt or insidious, with malaise, myalgia, arthralgia, easy fatigability, upper respiratory symptoms, and anorexia. A distaste for smoking, paralleling anorexia, may occur early. Nausea and vomiting are frequent, and diarrhea or constipation may occur. Fever is generally present but is low-grade except in occasional cases in which systemic toxicity may occur. Defervescence and a fall in pulse rate often coincide with the onset of jaundice.
The typical course of acute type A hepatitis. (HAV, hepatitis A virus; anti-HAV, antibody to hepatitis A virus; ALT, alanine aminotransferase.) (Reprinted, with permission, from Koff RS. Acute viral hepatitis. In: Friedman LS, Keeffe EB [editors]. Handbook of Liver Disease, 3rd ed. Philadelphia: Saunders Elsevier, 2012.)
Abdominal pain is usually mild and constant in the right upper quadrant or epigastrium, often aggravated by jarring or exertion, and rarely may be severe enough to simulate cholecystitis.
Jaundice occurs after 5–10 days but may appear at the same time as the initial symptoms. In many patients, jaundice never develops. With the onset of jaundice, prodromal symptoms often worsen, followed by progressive clinical improvement. Stools may be acholic during this phase.
The acute illness usually subsides over 2–3 weeks with complete clinical and laboratory recovery by 9 weeks. In some cases, clinical, biochemical, and serologic recovery may be followed by one or two relapses, but recovery is the rule. A protracted course has been reported to be associated with HLA DRB1*1301. Acute cholecystitis occasionally complicates the course of acute hepatitis A.
Hepatomegaly—rarely marked—is present in over half of cases. Liver tenderness is usually present. Splenomegaly is reported in 15% of patients, and soft, enlarged lymph nodes—especially in the cervical or epitrochlear areas—may occur.
The white blood cell count is normal to low, especially in the preicteric phase. Large atypical lymphocytes may occasionally be seen. Mild proteinuria is common, and bilirubinuria often precedes the appearance of jaundice. Strikingly elevated ALT or AST levels occur early, followed by elevations of bilirubin and alkaline phosphatase; in a minority of patients, the latter persist after aminotransferase levels have normalized. Cholestasis is occasionally marked. Antibody to hepatitis A (anti-HAV) appears early in the course of the illness (Figure 16–1). Both IgM and IgG anti-HAV are detectable in serum soon after the onset. Peak titers of IgM anti-HAV occur during the first week of clinical disease and usually disappear within 3–6 months. Detection of IgM anti-HAV is an excellent test for diagnosing acute hepatitis A but is not recommended for the evaluation of asymptomatic persons with persistently elevated serum aminotransferase levels because false-positive results occur. False-negative results have been described in a patient receiving rituximab for rheumatoid arthritis. Titers of IgG anti-HAV rise after 1 month of the disease and may persist for years. IgG anti-HAV (in the absence of IgM anti-HAV) indicates previous exposure to HAV, noninfectivity, and immunity.
The differential diagnosis includes other viruses that cause hepatitis, particularly hepatitis B and C, and diseases such as infectious mononucleosis, cytomegalovirus infection, herpes simplex virus infection, Middle East respiratory syndrome, and infections caused by many other viruses, including influenza and Ebola virus; spirochetal diseases such as leptospirosis and secondary syphilis; brucellosis; rickettsial diseases such as Q fever; drug-induced liver injury; and ischemic hepatitis (shock liver). Occasionally, autoimmune hepatitis may have an acute onset mimicking acute viral hepatitis. Rarely, metastatic cancer of the liver, lymphoma, or leukemia may present as a hepatitis-like picture.
The prodromal phase of viral hepatitis must be distinguished from other infectious disease such as influenza, upper respiratory infections, and the prodromal stages of the exanthematous diseases. Cholestasis may mimic obstructive jaundice.
Strict isolation of patients is not necessary, but hand washing after bowel movements is required. Unvaccinated persons who are exposed to HAV are advised to receive postexposure prophylaxis with a single dose of HAV vaccine or immune globulin (0.02 mL/kg) as soon as possible. The vaccine is preferred in healthy persons aged 1 year to 40 years, whereas immune globulin is preferred in those who are younger than 1 year or older than 40 years, are immunocompromised, or have chronic liver disease.
Vaccination with one of two effective inactivated hepatitis A vaccines available in the United States provides long-term immunity and is recommended for persons living in or traveling to endemic areas (including military personnel), patients with chronic liver disease upon diagnosis after prescreening for immunity (although the cost-effectiveness of vaccinating all patients with concomitant chronic hepatitis C has been questioned), persons with clotting-factor disorders who are treated with concentrates, men who have sex with men, animal handlers, illicit drug users, sewage workers, food handlers, close personal contacts of international adoptees, and children and caregivers in day-care centers and institutions. For healthy travelers, a single dose of vaccine at any time before departure can provide adequate protection. Routine vaccination is advised for all children in states with an incidence of hepatitis A at least twice the national average and has been approved by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) for use in all children between ages 1 and 2 in the United States. HAV vaccine is also effective in the prevention of secondary spread to household contacts of primary cases. The recommended dose for adults is 1 mL (1440 ELISA units) of Havrix (GlaxoSmithKline) or 1 mL (50 units) of Vaqta (Merck) intramuscularly, followed by a booster dose at 6–18 months. A combined hepatitis A and B vaccine (Twinrix, GlaxoSmithKline) is available. HIV infection impairs the response to the HAV vaccine, especially in persons with a CD4 count less than 200/mcL.
Bed rest is recommended only if symptoms are marked. If nausea and vomiting are pronounced or if oral intake is substantially decreased, intravenous 10% glucose is indicated.
Dietary management consists of palatable meals as tolerated, without overfeeding; breakfast is usually tolerated best. Strenuous physical exertion, alcohol, and hepatotoxic agents should be avoided. Small doses of oxazepam are safe because metabolism is not hepatic; morphine sulfate should be avoided.
Corticosteroids have no benefit in patients with viral hepatitis, including those with fulminant disease.
In most patients, clinical recovery is generally complete within 3 months. Laboratory evidence of liver dysfunction may persist for a longer period, but most patients recover completely. Hepatitis A does not cause chronic liver disease, although it may persist for up to 1 year, and clinical and biochemical relapses may occur before full recovery. The mortality rate is less than 1.0%, with a higher rate in older adults than in younger persons.
et al. Hepatitis A hospitalizations in the United States, 2002–2011. Hepatology. 2015 Feb;61(2):481–5.
et al. Trends in disease and complications of hepatitis A virus infection in the United States, 1999–2011: a new concern for adults. J Infect Dis. 2015 Jul 15;212(2):176–82.
et al. Progress toward eliminating hepatitis A disease in the United States. MMWR Suppl. 2016 Feb 12;65(1):29–41.
et al. Persistence of seropositivity among persons vaccinated for hepatitis A during infancy by maternal antibody status: 15-year follow-up. Hepatology. 2016 Mar;63(3):703–11.
ESSENTIALS OF DIAGNOSIS
Prodrome of anorexia, nausea, vomiting, malaise, aversion to smoking.
Fever, enlarged and tender liver, jaundice.
Normal to low white blood cell count; markedly elevated aminotransferases early in the course.
Liver biopsy shows hepatocellular necrosis and mononuclear infiltrate but is rarely indicated.
Hepatitis B virus (HBV) is a 42-nm hepadnavirus with a partially double-stranded DNA genome, inner core protein (hepatitis B core antigen, HBcAg), and outer surface coat (hepatitis B surface antigen, HBsAg). There are eight different genotypes (A–H), which may influence the course of infection and responsiveness to antiviral therapy. The sodium-taurocholate cotransporting polypeptide, NTCP, is a strong candidate for the cellular receptor of HBV on hepatocytes. HBV is usually transmitted by inoculation of infected blood or blood products or by sexual contact and is present in saliva, semen, and vaginal secretions. HBsAg-positive mothers may transmit HBV at delivery; the risk of chronic infection in the infant is as high as 90%.
Since 1990, the incidence of HBV infection in the United States has decreased from 8.5 to 1.5 cases per 100,000 population. The prevalence is 0.27% in persons aged 6 or over. Because of universal vaccination since 1992, exposure to HBV is now very low among persons aged 18 or younger. HBV is prevalent in men who have sex with men and in people who inject drugs (about 7% of HIV-infected persons are coinfected with HBV), but the greatest number of cases result from heterosexual transmission. Other groups at risk include patients and staff at hemodialysis centers, physicians, dentists, nurses, and personnel working in clinical and pathology laboratories and blood banks. Half of all patients with acute hepatitis B in the United States have previously been incarcerated or treated for a sexually transmitted disease. The risk of HBV infection from a blood transfusion in the United States is no higher than 1 in 350,000 units transfused. Screening for HBV infection is recommended for high-risk groups by the US Preventive Services Task Force.
The incubation period of hepatitis B is 6 weeks to 6 months (average 12–14 weeks). The onset of hepatitis B is more insidious and the aminotransferase levels are higher on average than in HAV infection. Fulminant hepatitis occurs in less than 1%, with a mortality rate of up to 60%. Following acute hepatitis B, HBV infection persists in 1–2% of immunocompetent adults but in a higher percentage of children and immunocompromised adults. There are as many as 2.2 million persons (including an estimated 1.32 million foreign-born persons from endemic areas) with chronic hepatitis B in the United States and 248 million worldwide. Compared with the general population, the prevalence of chronic HBV infection is increased 2- to 3-fold in non-Hispanic blacks and 10-fold in Asians. Persons with chronic hepatitis B, particularly when HBV infection is acquired early in life and viral replication persists, are at substantial risk for cirrhosis and hepatocellular carcinoma (up to 25–40%); men are at greater risk than women.
The clinical picture of viral hepatitis is extremely variable, ranging from asymptomatic infection without jaundice to a fulminating disease and death in a few days. Figure 16–2 shows the typical course of acute HBV infection. The onset may be abrupt or insidious, and the clinical features are similar to those for acute hepatitis A (see earlier). Serum sickness may be seen early in acute hepatitis B. Fever is generally present and is low-grade. Defervescence and a fall in pulse rate often coincide with the onset of jaundice. Infection caused by HBV may be associated with glomerulonephritis and polyarteritis nodosa.
The typical course of acute type B hepatitis. (anti-HBs, antibody to HBsAg; HBeAg, hepatitis Be antigen; HBsAg, hepatitis B surface antigen; anti-HBe, antibody to HBeAg; anti-HBc, antibody to hepatitis B core antigen; ALT, alanine aminotransferase.) (Reprinted, with permission, from Koff RS. Acute viral hepatitis. In: Friedman LS, Keeffe EB [editors]. Handbook of Liver Disease, 3rd ed. Philadelphia: Saunders Elsevier, 2012.)
The acute illness usually subsides over 2–3 weeks with complete clinical and laboratory recovery by 16 weeks. In 5–10% of cases, the course may be more protracted, but less than 1% will have a fulminant course. Hepatitis B may become chronic.
The laboratory features are similar to those for acute hepatitis A, although serum aminotransferase levels are higher on average in acute hepatitis B, and marked cholestasis is not a feature. Marked prolongation of the prothrombin time in severe hepatitis correlates with increased mortality.
There are several antigens and antibodies as well as HBV DNA that relate to HBV infection and that are useful in diagnosis. Interpretation of common serologic patterns is shown in Table 16–5.
Table 16–5.Common serologic patterns in hepatitis B virus infection and their interpretation. |Favorite Table|Download (.pdf) Table 16–5. Common serologic patterns in hepatitis B virus infection and their interpretation.
|HBsAg ||Anti-HBs ||Anti-HBc ||HBeAg ||Anti-HBe ||Interpretation |
|+ ||– ||IgM ||+ ||– ||Acute hepatitis B |
|+ ||– ||IgG1 ||+ ||– ||Chronic hepatitis B with active viral replication |
|+ ||– ||IgG ||– ||+ ||Inactive HBV carrier state (low HBV DNA level) or HBeAg-negative chronic hepatitis B with active viral replication (high HBV DNA level) |
|+ ||+ ||IgG ||+ or – ||+ or – ||Chronic hepatitis B with heterotypic anti-HBs (about 10% of cases) |
|– ||– ||IgM ||+ or – ||– ||Acute hepatitis B |
|– ||+ ||IgG ||– ||+ or – ||Recovery from hepatitis B (immunity) |
|– ||+ ||– ||– ||– ||Vaccination (immunity) |
|– ||– ||IgG ||– ||– ||False-positive; less commonly, infection in remote past |
The appearance of HBsAg in serum is the first evidence of infection, appearing before biochemical evidence of liver disease, and persisting throughout the clinical illness. Persistence of HBsAg more than 6 months after the acute illness signifies chronic hepatitis B.
Specific antibody to HBsAg (anti-HBs) appears in most individuals after clearance of HBsAg and after successful vaccination against hepatitis B. Disappearance of HBsAg and the appearance of anti-HBs signal recovery from HBV infection, noninfectivity, and immunity.
IgM anti-HBc appears shortly after HBsAg is detected. (HBcAg alone does not appear in serum.) In the setting of acute hepatitis, IgM anti-HBc indicates a diagnosis of acute hepatitis B, and it fills the serologic gap in rare patients who have cleared HBsAg but do not yet have detectable anti-HBs. IgM anti-HBc can persist for 3–6 months, and sometimes longer. IgM anti-HBc may also reappear during flares of previously inactive chronic hepatitis B (see later). IgG anti-HBc also appears during acute hepatitis B but persists indefinitely, whether the patient recovers (with the appearance of anti-HBs in serum) or chronic hepatitis B develops (with persistence of HBsAg). In asymptomatic blood donors, an isolated anti-HBc with no other positive HBV serologic results may represent a falsely positive result or latent infection in which HBV DNA is detectable in serum only by polymerase chain reaction (PCR) testing.
HBeAg is a secretory form of HBcAg that appears in serum during the incubation period shortly after the detection of HBsAg. HBeAg indicates viral replication and infectivity. Persistence of HBeAg beyond 3 months indicates an increased likelihood of chronic hepatitis B. Its disappearance is often followed by the appearance of anti-HBe, generally signifying diminished viral replication and decreased infectivity.
The presence of HBV DNA in serum generally parallels the presence of HBeAg, although HBV DNA is a more sensitive and precise marker of viral replication and infectivity. Very low levels of HBV DNA, detectable only by PCR testing, may persist in serum and liver long after a patient has recovered from acute hepatitis B, but the HBV DNA in serum is bound to IgG and is rarely infectious. In some patients with chronic hepatitis B, HBV DNA is present at high levels without HBeAg in serum because of development of a mutation in the core promoter or precore region of the gene that codes HBcAg; these mutations prevent synthesis of HBeAg in infected hepatocytes. When additional mutations in the core gene are also present, the severity of HBV infection is enhanced and the risk of cirrhosis is increased (see later).
The differential diagnosis includes hepatitis A and the same disorders listed for the differential diagnosis of acute hepatitis A (see earlier). In addition, coinfection with HDV must be considered (see later).
Strict isolation of patients is not necessary. Thorough hand washing by medical staff who may contact contaminated utensils, bedding, or clothing is essential. Medical staff should handle disposable needles carefully and not recap them. Screening of donated blood for HBsAg, anti-HBc, and anti-HCV has reduced the risk of transfusion-associated hepatitis markedly. All pregnant women should undergo testing for HBsAg. HBV-infected persons should practice safe sex. Although cesarean section, in combination with immunoprophylaxis of the neonate, reduces the risk of perinatal transmission of HBV infection when the mother’s serum HBV DNA level is 200,000 international units/mL or higher (or the mother’s serum HBsAg level is above 4–4.5 log10 international units/mL), it is preferable to initiate antiviral treatment of the mother in the third trimester (see Chronic Hepatitis B & Chronic Hepatitis D). HBV-infected health care workers are not precluded from practicing medicine or dentistry if they follow CDC guidelines.
Hepatitis B immune globulin (HBIG) may be protective—or may attenuate the severity of illness—if given within 7 days after exposure (adult dose is 0.06 mL/kg body weight) followed by initiation of the HBV vaccine series. This approach is recommended for unvaccinated persons exposed to HBsAg-contaminated material via mucous membranes or through breaks in the skin and for individuals who have had sexual contact with a person with HBV infection (irrespective of the presence or absence of HBeAg in the source). HBIG is also indicated for newborn infants of HBsAg-positive mothers, followed by initiation of the vaccine series.
The CDC recommends HBV vaccination of all infants and children in the United States and all adults who are at risk for hepatitis B (including persons under age 60 with diabetes mellitus) or who request vaccination. Over 90% of recipients of the vaccine mount protective antibody to hepatitis B; immunocompromised persons, including patients receiving dialysis (especially those with diabetes mellitus), respond poorly (see Table 30–7). Reduced response to the vaccine may have a genetic basis in some cases and has also been associated with age over 40 years and celiac disease. The standard regimen for adults is 10–20 mcg (depending on the formulation) repeated again at 1 and 6 months, but alternative schedules have been approved, including accelerated schedules of 0, 1, 2, and 12 months and of 0, 7, and 21 days plus 12 months. For greatest reliability of absorption, the deltoid muscle is the preferred site of innoculation. Vaccine formulations free of the mercury-containing preservative thimerosal are given to infants under 6 months of age. When documentation of seroconversion is considered desirable, postimmunization anti-HBs titers may be checked. Protection appears to be excellent even if the titer wanes—at least for 20 years—and booster reimmunization is not routinely recommended but is advised for immunocompromised persons in whom anti-HBs titers fall below 10 milli-international units/mL. For vaccine nonresponders, three additional vaccine doses may elicit seroprotective anti-HBs levels in 30–50% of persons. Doubling of the standard dose may also be effective. Universal vaccination of neonates in countries endemic for HBV has reduced the incidence of hepatocellular carcinoma. Incomplete immunization is the most important predictor of liver disease among vaccinees.
Treatment of acute hepatitis B is the same as that for acute hepatitis A. Encephalopathy or severe coagulopathy indicates acute liver failure, and hospitalization at a liver transplant center is mandatory. Antiviral therapy is generally unnecessary in patients with acute hepatitis B but is usually prescribed in cases of fulminant hepatitis B as well as in spontaneous reactivation of chronic hepatitis B presenting as acute-on-chronic liver failure (see Acute Liver Failure).
In most patients, clinical recovery is complete in 3–6 months. Laboratory evidence of liver dysfunction may persist for a longer period, but most patients recover completely. The mortality rate for acute hepatitis B is 0.1–1% but is higher with superimposed hepatitis D.
Chronic hepatitis, characterized by elevated aminotransferase levels for more than 3–6 months, develops in 1–2% of immunocompetent adults with acute hepatitis B but in as many as 90% of infected neonates and infants and a substantial proportion of immunocompromised adults. Ultimately, cirrhosis develops in up to 40% of those with chronic hepatitis B; the risk of cirrhosis is even higher in HBV-infected patients coinfected with hepatitis C or HIV. Patients with cirrhosis are at risk for hepatocellular carcinoma at a rate of 3–5% per year. Even in the absence of cirrhosis, patients with chronic hepatitis B—particularly those with active viral replication—are at increased risk for hepatocellular carcinoma.
Refer patients with acute hepatitis who require liver biopsy for diagnosis.
et al. Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus. Hepatology. 2015 Aug;62(2):375–86.
et al. Cost-effectiveness of active-passive prophylaxis and antiviral prophylaxis during pregnancy to prevent perinatal hepatitis B virus infection. Hepatology. 2016 May;63(5):1471–80.
et al. World Gastroenterology Organisation Global Guideline Hepatitis B: September 2015. J Clin Gastroenterol. 2016 Oct;50(9):691–703.
TI (editor). Hepatitis B virus. Clin Liver Dis. 2016;20:607–749.
et al. Long-term immune response to hepatitis B virus vaccination regimens in adults with human immunodeficiency virus 1: secondary analysis of a randomized clinical trial. JAMA Intern Med. 2016 May 1;176(5):603–10.
et al. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Jul 1;161(1):58–66.
et al. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5). Lancet Infect Dis. 2016 May;16(5):606–17.
et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016 Jun 16;374(24):2324–34.
et al. Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988–2012. Hepatology. 2016 Feb;63(2):388–97.
et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015 Oct 17;386(10003):1546–55.
et al. Hepatitis B virus infection. Lancet. 2014 Dec 6;384(9959):2053–63.
et al. Managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up: position paper produced by Australian, UK and New Zealand key opinion leaders. Gut. 2016 Feb;65(2):340–50.
et al. Quantitative maternal hepatitis B surface antigen predicts maternally transmitted hepatitis B virus infection. Hepatology. 2016 Nov;64(5):1451–61.
et al. Telbivudine prevents vertical transmission of hepatitis B virus from women with high viral loads: a prospective long-term study. Clin Gastroenterol Hepatol. 2015 Jun;13(6):1170–6.
ACUTE HEPATITIS C & OTHER CAUSES OF ACUTE VIRAL HEPATITIS
Viruses other than HAV and HBV that can cause hepatitis are hepatitis C virus (HCV), hepatitis D virus (HDV) (delta agent), and hepatitis E virus (HEV) (an enterically transmitted hepatitis seen in epidemic form in Asia, the Middle East, and North Africa). Human pegivirus (formerly hepatitis G virus [HGV]) rarely, if ever, causes frank hepatitis. A related virus has been named human hepegivirus-1. A DNA virus designated the TT virus (TTV) has been identified in up to 7.5% of blood donors and found to be transmitted readily by blood transfusions, but an association between this virus and liver disease has not been established. A related virus known as SEN-V has been found in 2% of US blood donors, is transmitted by transfusion, and may account for some cases of transfusion-associated non-ABCDE hepatitis. In immunocompromised and rare immunocompetent persons, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus should be considered in the differential diagnosis of hepatitis. Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), Ebola virus infection, and influenza may be associated with marked serum aminotransferase elevations. Unidentified pathogens account for a small percentage of cases of acute viral hepatitis.
HCV is a single-stranded RNA virus (hepacivirus) with properties similar to those of flaviviruses. Seven major genotypes of HCV have been identified. In the past, HCV was responsible for over 90% of cases of posttransfusion hepatitis, yet only 4% of cases of hepatitis C were attributable to blood transfusions. Over 50% of cases are transmitted by injection drug use, and both reinfection and superinfection of HCV are common in people who actively inject drugs. Body piercing, tattoos, and hemodialysis are risk factors. The risk of sexual and maternal–neonatal transmission is low and may be greatest in a subset of patients with high circulating levels of HCV RNA. Having multiple sexual partners may increase the risk of HCV infection, and HIV coinfection, unprotected receptive anal intercourse with ejaculation, and sex while high on methamphetamine increase the risk of HCV transmission in men who have sex with men. Transmission via breastfeeding has not been documented. An outbreak of hepatitis C in patients with immune deficiencies has occurred in some recipients of intravenous immune globulin. Hospital- and outpatient facility–acquired transmission has occurred via multidose vials of saline used to flush Portacaths; through reuse of disposable syringes; through drug “diversion” and tampering with injectable opioids by an infected health care worker; through contamination of shared saline, radiopharmaceutical, and sclerosant vials; via inadequately disinfected endoscopy equipment; and between hospitalized patients on a liver unit. In the developing world, unsafe medical practices lead to a substantial number of cases of HCV infection. Covert transmission during bloody fisticuffs has even been reported, and incarceration in prison is a risk factor, with a frequency of 26% in the United States. In many patients, the source of infection is unknown. Coinfection with HCV is found in at least 30% of HIV-infected persons. HIV infection leads to an increased risk of acute liver failure and more rapid progression of chronic hepatitis C to cirrhosis; in addition, HCV increases the hepatotoxicity of antiretroviral therapy. The number of cases of chronic HCV infections in the United States is reported to have decreased from 3.2 million in 2001 to 2.3 million in 2013, although estimates of at least 4.6 million exposed and 3.5 million currently infected have also been reported. The incidence of new cases of acute, symptomatic hepatitis C declined from 1992 to 2005, but an increase was observed in persons aged 15 to 24 after 2002, as a result of injection drug use. Worldwide, 170 million people are infected with HCV, with the highest rates in central and east Asia, north Africa, and the Middle East.
Figure 16–3 shows the typical course of HCV infection. The incubation period for hepatitis C averages 6–7 weeks, and clinical illness is often mild, usually asymptomatic, and characterized by waxing and waning aminotransferase elevations and a high rate (greater than 80%) of chronic hepatitis. Spontaneous clearance of HCV following acute infection is more common (64%) in persons with the CC genotype of the IFNL3 (IL28B) gene (which encodes interferon lambda-3 on chromosome 19) than in those with the CT or TT genotype (24% and 6%, respectively). In persons with the CC genotype, jaundice is more likely to develop during the course of acute hepatitis C. Patients with the CC genotype and chronic hepatitis C are also more likely to respond to therapy with pegylated interferon (see Chronic Viral Hepatitis). Polymorphisms of genes encoding the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands (HLA-C1) and the interleukin-1 receptor-associated kinase 4 (IRAK4) are associated with spontaneous clearance and reduced clearance, respectively, of viremia following HCV exposure. In pregnant patients with chronic hepatitis C, serum aminotransferase levels frequently normalize despite persistence of viremia, only to increase again after delivery.
The typical course of acute and chronic hepatitis C. (ALT, alanine aminotransferase; Anti-HCV, antibody to hepatitis C virus by enzyme immunoassay; HCV RNA [PCR], hepatitis C viral RNA by polymerase chain reaction.)
Diagnosis of hepatitis C is based on an enzyme immunoassay (EIA) that detects antibodies to HCV. Anti-HCV is not protective, and in patients with acute or chronic hepatitis, its presence in serum generally signifies that HCV is the cause. Limitations of the EIA include moderate sensitivity (false-negatives) for the diagnosis of acute hepatitis C early in the course and low specificity (false-positives) in some persons with elevated gamma-globulin levels. In these situations, a diagnosis of hepatitis C may be confirmed by using an assay for HCV RNA. Occasional persons are found to have anti-HCV in serum, without HCV RNA in serum, suggesting recovery from HCV infection in the past.
HCV is a pathogenic factor in mixed cryoglobulinemia and membranoproliferative glomerulonephritis and may be related to lichen planus, autoimmune thyroiditis, lymphocytic sialadenitis, idiopathic pulmonary fibrosis, sporadic porphyria cutanea tarda, and monoclonal gammopathies. HCV infection confers a 20–30% or more increased risk of non-Hodgkin lymphoma. A previously reported association between HCV infection and insulin resistance and type 2 diabetes mellitus has been disproved. Hepatic steatosis is a particular feature of infection with HCV genotype 3 and may also occur in patients infected with other HCV genotypes who have risk factors for fatty liver. On the other hand, chronic HCV infection is associated with a decrease in serum cholesterol and low-density lipoprotein levels.
Testing donated blood for HCV has helped reduce the risk of transfusion-associated hepatitis C from 10% in 1990 to about 1 case per 2 million units in 2011. Birth cohort screening of persons born between 1945 and 1965 (“baby boomers”) for HCV infection has been recommended by the CDC and the US Preventive Services Task Force and could identify over 900,000 new cases. Universal one-time testing has been suggested as an alternative approach. HCV-infected persons should practice safe sex, but there is little evidence that HCV is spread easily by sexual contact or perinatally, and no specific preventive measures are recommended for persons in a monogamous relationship or for pregnant women. Vaccination against HAV (after prescreening for prior immunity) and HBV is recommended for patients with chronic hepatitis C, just as vaccination against HAV is recommended for patients with chronic hepatitis B, although the cost-effectiveness of vaccination has been questioned.
In the past, treatment of patients with acute hepatitis C with peginterferon (see later) for 6–24 weeks was shown to appreciably decrease the risk of chronic hepatitis. Because 20% of patients with acute hepatitis C, particularly those who are symptomatic, clear the virus without such treatment, reserving treatment for patients in whom serum HCV RNA levels failed to clear after 3 months was advised. Ribavirin was added if HCV RNA failed to clear after 3 months of peginterferon, but some authorities recommended using ribavirin with peginterferon from the start of therapy. Oral direct-acting agents have supplanted interferon-based therapy (see Chronic Viral Hepatitis).
In most patients, clinical recovery is complete in 3–6 months. Laboratory evidence of liver dysfunction may persist for a longer period. The overall mortality rate is less than 1%, but the rate is reportedly higher in older people. Fulminant hepatitis C is rare in the United States.
Chronic hepatitis, which progresses very slowly in many cases, develops in as many as 85% of all persons with acute hepatitis C. Ultimately, cirrhosis develops in up to 30% of those with chronic hepatitis C; the risk of cirrhosis and hepatic decompensation is higher in patients coinfected with both HCV and HBV or HIV. Patients with cirrhosis are at risk for hepatocellular carcinoma at a rate of 3–5% per year. Long-term morbidity and mortality in patients with chronic hepatitis C is lower in black than in white patients and lowest in those infected with HCV genotype 2 and highest in those with HCV genotype 3.
2. Hepatitis D (Delta Agent)
HDV is a defective RNA virus that causes hepatitis only in association with HBV infection and specifically only in the presence of HBsAg; it is cleared when the latter is cleared. Eight major genotypes (I-VIII) have been identified.
HDV may coinfect with HBV or may superinfect a person with chronic hepatitis B, usually by percutaneous exposure. When acute hepatitis D is coincident with acute HBV infection, the infection is generally similar in severity to acute hepatitis B alone. In chronic hepatitis B, superinfection by HDV appears to carry a worse short-term prognosis, often resulting in fulminant hepatitis or severe chronic hepatitis that progresses rapidly to cirrhosis.
In the 1970s and early 1980s, HDV was endemic in some areas, such as the Mediterranean countries (and later in Central and Eastern Europe), where up to 80% of HBV carriers were superinfected with HDV. In the United States, HDV occurred primarily among people who inject drugs. New cases of hepatitis D are now infrequent in the United States primarily because of the control of HBV infection (although rates of testing HBV carriers for HDV are inappropriately low), and cases seen today are usually from cohorts infected years ago who survived the initial impact of hepatitis D and now have cirrhosis. These patients are at risk for decompensation and have a threefold increased risk of hepatocellular carcinoma. New cases are seen primarily in immigrants from endemic areas, including Africa, central Asia, Eastern Europe, and the Amazon region of Brazil. More than 15 million people are infected worldwide. The diagnosis of hepatitis D is made by detection of antibody to hepatitis D antigen (anti-HDV) and, where available, hepatitis D antigen (HDAg) or HDV RNA in serum.
HEV is a 27- to 34-nm RNA hepevirus (in the Hepeviridae family) that is a major cause of acute hepatitis throughout Central and Southeast Asia, the Middle East, and North Africa, where it is responsible for waterborne hepatitis outbreaks. It is uncommon in the United States (although up to 20% of the population have antibodies to the virus) but should be considered in patients with acute hepatitis after a trip to an endemic area. In rare cases, hepatitis E can be mistaken for drug-induced liver injury. In industrialized countries, it may be spread by swine, and having a pet in the home and consuming undercooked organ meats or infected cow’s milk are risk factors. Illness generally is self-limited (no carrier state), but instances of chronic hepatitis with rapid progression to cirrhosis attributed to HEV have been reported in transplant recipients (particularly when tacrolimus rather than cyclosporine is used as the main immunosuppressant) and, rarely, in persons with HIV infection, preexisting liver disease, or cancer undergoing chemotherapy. The diagnosis of acute hepatitis E is made most readily by testing for IgM anti-HEV in serum, although available tests may not be reliable. Reported extrahepatic manifestations include arthritis; pancreatitis; monoclonal gammopathy; thrombocytopenia; a variety of neurologic complications, including Guillain-Barré syndrome, peripheral neuropathy, and hemophagocytic lymphohistiocytosis. In endemic regions, the mortality rate is high (15–25%) in pregnant women and correlates with high levels of HEV RNA in serum and gene mutations that lead to reduced expression of progesterone receptors. The risk of hepatic decompensation is increased in patients with underlying chronic liver disease. A 3-month course of treatment with oral ribavirin has been reported to induce sustained clearance of HEV RNA from the serum in 78% of patients. Improved public hygiene reduces the risk of HEV infection in endemic areas. Recombinant vaccines against HEV have shown promise in clinical trials, and one (Hecolin) is approved in China.
4. Human Pegivirus (Hepatitis G)
Human pegivirus is a flavivirus that is percutaneously transmitted and associated with chronic viremia lasting at least 10 years. It has been detected in 1.5% of blood donors, 50% of people who inject drugs, 30% of hemodialysis patients, 20% of hemophiliacs, and 15% of patients with chronic hepatitis B or C, but it does not appear to cause important liver disease or affect the response of patients with chronic hepatitis B or C to antiviral therapy. Human pegivirus coinfection may improve survival in patients with HIV infection and reduce the degree of liver fibrosis in patients with HCV-HIV coinfection. Diseases caused by human pegivirus 2, which is found in some patients with HCV infection, and human hepegivirus-1, which is related to HCV and pegivirus, have not yet been well characterized.
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et al. Chronic infection with camelid hepatitis E virus in a liver transplant recipient who regularly consumes camel meat and milk. Gastroenterology. 2016 Feb;150(2):355–7.
et al. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol. 2016 Oct;13(10):580–9.
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Acute liver failure may be fulminant or subfulminant. Fulminant hepatic failure is characterized by the development of hepatic encephalopathy within 8 weeks after the onset of acute liver disease. Coagulopathy (international normalized ratio [INR] 1.5 or higher) is invariably present. Subfulminant hepatic failure occurs when these findings appear between 8 weeks and 6 months after the onset of acute liver disease and carries an equally poor prognosis. Acute-on-chronic liver failure refers to acute deterioration in liver function in a person with preexisting chronic liver disease.
An estimated 1600 cases of acute liver failure occur each year in the United States. Acetaminophen toxicity is the most common cause, accounting for at least 45% of cases. Suicide attempts account for 44% of cases of acetaminophen-induced hepatic failure, and unintentional overdoses (“therapeutic misadventures”), which are often a result of a decrease in the threshold toxic dose because of chronic alcohol use or fasting and have been reported after weight loss surgery, account for at least 48%. Other causes include idiosyncratic drug reactions (the second most common cause, with antituberculosis drugs, antiepileptics, and antibiotics implicated most commonly), viral hepatitis, poisonous mushrooms (Amanita phalloides), shock, hyperthermia, Budd-Chiari syndrome, malignancy (most commonly lymphomas), Wilson disease, Reye syndrome, fatty liver of pregnancy and other disorders of fatty acid oxidation, autoimmune hepatitis, parvovirus B19 infection and, rarely, grand mal seizures. The risk of acute liver failure is increased in patients with diabetes mellitus, and outcome is worsened by obesity. Herbal and dietary supplements are thought to be contributory to acute liver failure in a substantial portion of cases, regardless of cause, and may be associated with lower rates of transplant-free survival. Acute-on-chronic liver failure is often precipitated by infection or an alcohol binge and alcoholic hepatitis.
Viral hepatitis now accounts for only 12% of all cases of acute liver failure. The decline of viral hepatitis as the principal cause of acute liver failure is due to universal vaccination of infants and children against hepatitis B and the availability of the hepatitis A vaccine. In endemic areas, hepatitis E is an important cause of acute liver failure. Hepatitis C is a rare cause of acute liver failure in the United States, but acute hepatitis A or B superimposed on chronic hepatitis C may cause fulminant hepatitis.
Gastrointestinal symptoms, systemic inflammatory response, renal dysfunction, and hemorrhagic phenomena are common. Adrenal insufficiency and subclinical myocardial injury manifesting as an elevated serum troponin I level often complicate acute liver failure. Jaundice may be absent or minimal early, but laboratory tests show severe hepatocellular damage. In acetaminophen toxicity, serum aminotransferase elevations are often towering (greater than 5000 units/L), and biomarkers of early detection are under study, including the detection of acetaminophen-protein adducts in serum. In acute liver failure due to microvesicular steatosis (eg, fatty liver of pregnancy), serum aminotransferase elevations may be modest (less than 300 units/L). Over 10% of patients have an elevated serum amylase level at least three times the upper limit of normal, often as a result of renal dysfunction. The blood ammonia level is typically elevated and correlates (along with the Model for End-Stage Liver Disease [MELD] score) with the development of encephalopathy and intracranial hypertension. Intracranial hypertension rarely develops when the blood ammonia level is less than 75 mcmol/L and is invariable when it is greater than 200 mcmol/L. The severity of extrahepatic organ dysfunction (as assessed by the Sequential Organ Failure Assessment [SOFA]) also correlates with the likelihood of intracranial hypertension. Acute kidney injury frequently complicates acute-on-chronic liver failure.
The treatment of acute liver failure is directed toward achieving metabolic and hemodynamic stability. Intravascular volume should be preserved, but large-volume infusions of hypotonic fluids should be avoided. Hypoglycemia should be prevented. Intermittent renal replacement therapy may be required. To preserve muscle mass and immune function, enteral administration of protein, 1–1.5 g/kg/day, is advised, with careful monitoring of the ammonia level. Cerebral edema and sepsis are the leading causes of death. Prophylactic antibiotic therapy decreases the risk of infection, observed in up to 90%, but has no effect on survival and is not routinely recommended. For suspected sepsis, broad coverage is indicated. Despite a high rate of adrenal insufficiency, corticosteroids are of uncertain value and may lower overall survival in patients with a high MELD score. Stress gastropathy prophylaxis with an H2-receptor blocker or proton pump inhibitor is recommended. Administration of acetylcysteine (140 mg/kg orally followed by 70 mg/kg orally every 4 hours for an additional 17 doses or 150 mg/kg in 5% dextrose intravenously over 15 minutes followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours) is indicated for acetaminophen toxicity up to 72 hours after ingestion. For massive acetaminophen overdoses, treatment with intravenous acetylcysteine may need to be extended in duration until the serum aminotransferase levels are declining and serum acetaminophen levels are undetectable. Treatment with acetylcysteine improves cerebral blood flow and oxygenation as well as transplant-free survival in patients with stage 1 or 2 encephalopathy due to fulminant hepatic failure of any cause. (Acetylcysteine treatment can prolong the prothrombin time, leading to the erroneous assumption that liver failure is worsening; it can also cause nausea, vomiting, and an anaphylactoid reaction [especially in persons with a history of asthma]. It may be detrimental in children with nonacetaminophen acute liver failure.) Penicillin G (300,000 to 1 million units/kg/day) or silibinin (silymarin or milk thistle), which is not licensed in the United States, is administered to patients with mushroom poisoning. Nucleoside analogs are recommended for patients with fulminant hepatitis B (see Chronic Viral Hepatitis), and intravenous acyclovir has shown benefit in those with herpes simplex virus hepatitis. Plasmapheresis combined with D-penicillamine has been used in fulminant Wilson disease. Subclinical seizure activity is common in patients with acute liver failure, but the value of prophylactic phenytoin is uncertain.
Early transfer to a liver transplantation center is essential. The head of the patient’s bed should be elevated to 30 degrees, and patients with stage 3 or 4 encephalopathy should be intubated. Extradural sensors may be placed to monitor intracranial pressure for impending cerebral edema with the goal of maintaining the intracranial pressure below 20 mm Hg and the cerebral perfusion pressure above 70 mm Hg. Recombinant activated factor VIIa may be administered to reduce the risk of bleeding associated with intracranial pressure monitoring. Lactulose is generally avoided. Mannitol, 0.5 g/kg, or 100–200 mL of a 20% solution by intravenous infusion over 10 minutes, may decrease cerebral edema but should be used with caution in patients with advanced chronic kidney disease. Intravenously administered hypertonic saline to induce hypernatremia (serum sodium concentration of 145–155 mEq/L [145–155 mmol/L]) also may reduce intracranial hypertension. Hypothermia to a temperature of 32–34°C may reduce intracranial pressure when other measures have failed and may improve survival long enough to permit liver transplantation, although a controlled trial showed no benefit and some authorities recommend a target core temperature of 35–36°C. The value of hyperventilation and intravenous prostaglandin E1 is uncertain. A short-acting barbiturate, propofol, or intravenous boluses of indomethacin, 25 mg, is considered for refractory intracranial hypertension. Nonbiologic liver support (eg, molecular adsorbent recirculating system [MARS], an albumin dialysis system), hepatic-assist devices using living hepatocytes, extracorporeal systems, hepatocyte transplantation, and liver xenografts have shown promise experimentally but have not been shown conclusively to reduce mortality in patients with acute liver failure. They may serve as a "bridge" to liver transplantation.
With earlier recognition of acute liver failure, the frequency of cerebral edema has declined, and overall survival has improved steadily since the 1970s and is now as high as 75%. The survival rate in fulminant hepatic failure with severe encephalopathy is as low as 20%, except for acetaminophen hepatotoxicity, in which the transplant-free survival is 65% and no more than 8% of patients undergo liver transplantation. For patients with fulminant hepatic failure of other causes, the outlook is poor in patients younger than 10 and older than 40 years of age and in those with an idiosyncratic drug reaction but appears to be improved when acetylcysteine is administered to patients with stage 1 or 2 encephalopathy. Spontaneous recovery is less likely for hepatitis B than for hepatitis A. Polymorphisms of the genes that encode keratins 8 and 18 appear to affect outcomes. Other adverse prognostic factors are a serum bilirubin level greater than 18 mg/dL (307.8 mcmol/L), INR higher than 6.5, onset of encephalopathy more than 7 days after the onset of jaundice, and a low factor V level (less than 20% of normal). For acetaminophen-induced fulminant hepatic failure, indicators of a poor outcome are acidosis (pH < 7.3), INR greater than 6.5, and azotemia (serum creatinine 3.4 mg/dL [283.22 mcmol/L] or higher), whereas a rising serum alpha-fetoprotein level predicts a favorable outcome. An elevated blood lactate level (greater than 3.5 mEq/L [3.5 mmol/L]), elevated blood ammonia level (greater than 211 mcg/dL [124 mcmol/L]), and possibly hyperphosphatemia (greater than 3.7 mg/dL [1.2 mmol/L]) also predict poor survival. One study has shown that patients with persistent elevation of the arterial ammonia level (211 mcg/dL [122 mcmol/L] or higher) for 3 days have greater rates of complications and mortality than those with decreasing ammonia levels. The development of thrombocytopenia in the first week is associated with the development of multiorgan system failure and a poor outcome. A number of prognostic indices have been proposed: the “BiLE” score, based on the serum bilirubin, serum lactate, and etiology; the Acute Liver Failure Early Dynamic (ALFED) model, based on the arterial ammonia level, serum bilirubin, INR, and hepatic encephalopathy; and the Acute Liver Failure Study Group (ALFSG) index, based on coma grade, INR, serum bilirubin and phosphorous levels, and serum levels of M30, a cleavage product of cytokeratin-18 caspase. The likelihood of transplant-free survival on admission has been reported to be predicted by a regression model that incorporates the grade of hepatic encephalopathy, etiology, vasopressor use, and log transformations of the serum bilirubin and INR. Emergency liver transplantation is considered for patients with stage 2 to stage 3 encephalopathy (see Cirrhosis) and is associated with a 70% survival rate at 5 years. For mushroom poisoning, liver transplantation should be considered when the interval between ingestion and the onset of diarrhea is less than 8 hours or the INR is 6.0 or higher, even in the absence of encephalopathy. Acute liver failure superimposed on chronic liver disease (acute-on-chronic liver failure) is often precipitated by a bacterial infection or active alcoholism and has a poor prognosis when associated with renal dysfunction.
All patients with acute liver failure should be hospitalized.
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et al; Acute Liver Failure Study Group. Thrombocytopenia is associated with multi-organ system failure in patients with acute liver failure. Clin Gastroenterol Hepatol. 2016 Apr;14(4):613–20.
et al. Risk factors and outcomes of acute kidney injury in patients with acute liver failure. Clin Gastroenterol Hepatol. 2015 Feb;13(2):352–9.
ESSENTIALS OF DIAGNOSIS
Defined by chronic infection (HBV, HCV, HDV) for longer than 3–6 months.
Diagnosis is usually made by antibody tests and viral nucleic acid in serum.
Chronic hepatitis is defined as chronic necroinflammation of the liver of more than 3–6 months’ duration, demonstrated by persistently elevated serum aminotransferase levels or characteristic histologic findings. In many cases, the diagnosis of chronic hepatitis may be made on initial presentation. The causes of chronic hepatitis include HBV, HCV, and HDV as well as autoimmune hepatitis; alcoholic and nonalcoholic steatohepatitis; certain medications, such as isoniazid and nitrofurantoin; Wilson disease; alpha-1-antiprotease deficiency; and, rarely, celiac disease. Mortality from chronic HBV and HCV infection has been rising in the United States, and HCV has surpassed HIV as a cause of death. Chronic hepatitis is categorized on the basis of etiology (eFigure 16–11, eFigure 16–12); the grade of portal, periportal, and lobular inflammation (minimal, mild, moderate, or severe); and the stage of fibrosis (none, mild, moderate, severe, cirrhosis). In the absence of advanced cirrhosis, patients are often asymptomatic or have mild nonspecific symptoms.
Mild chronic hepatitis (low power and high power).
Moderately severe chronic hepatitis (low power and high power).
1. Chronic Hepatitis B & Chronic Hepatitis D
Clinical Findings & Diagnosis
Chronic hepatitis B afflicts 248 million people worldwide (2 billion overall have been infected; endemic areas include Asia and sub-Saharan Africa) and up to 2.2 million (predominantly males) in the United States. It may be noted as a continuum of acute hepatitis B or diagnosed because of repeated detection of HBsAg in serum, often with elevated aminotransferase levels.
Four phases of HBV infection are recognized: immune tolerant phase, immune clearance phase, inactive HBsAg carrier state, and reactivated chronic hepatitis B phase. In the immune tolerant phase, HBeAg and HBV DNA are present in serum and are indicative of active viral replication, and serum aminotransferase levels are normal, with little necroinflammation in the liver. This phase is common in infants and young children whose immature immune system fails to mount an immune response to HBV. Persons in the immune tolerant phase and those who acquire HBV infection later in life may enter an immune clearance phase, in which aminotransferase levels are elevated and necroinflammation is present in the liver, with a risk of progression to cirrhosis (at a rate of 2–5.5% per year) and of hepatocellular carcinoma (at a rate of more than 2% per year in those with cirrhosis); low-level IgM anti-HBc is present in serum in about 70%.
Patients enter the inactive HBsAg carrier state when biochemical improvement follows immune clearance. This improvement coincides with disappearance of HBeAg and reduced HBV DNA levels (less than 105 copies/mL, or less than 20,000 international units/mL) in serum, appearance of anti-HBe, and integration of the HBV genome into the host genome in infected hepatocytes. Patients in this phase are at a low risk for cirrhosis (if it has not already developed) and hepatocellular carcinoma, and those with persistently normal serum aminotransferase levels infrequently have histologically significant liver disease, especially if the HBsAg level is low.
The reactivated chronic hepatitis B phase may result from infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core or core promoter region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV. So-called HBeAg-negative chronic hepatitis B accounts for less than 10% of cases of chronic hepatitis B in the United States, up to 50% in southeast Asia, and up to 90% in Mediterranean countries, reflecting in part differences in the frequencies of HBV genotypes. In reactivated chronic hepatitis B, there is a rise in serum HBV DNA levels and possible progression to cirrhosis (at a rate of 8–10% per year), particularly when additional mutations in the core gene of HBV are present. Risk factors for reactivation include male sex and HBV genotype C. In patients with either HBeAg-positive or HBeAg-negative chronic hepatitis B, the risk of cirrhosis and of hepatocellular carcinoma correlates with the serum HBV DNA level. Other risk factors include advanced age, male sex, alcohol use, cigarette smoking, HBV genotype C, and coinfection with HCV or HDV. HIV coinfection is also associated with an increased frequency of cirrhosis when the CD4 count is low.
Acute hepatitis D infection superimposed on chronic HBV infection may result in severe chronic hepatitis, which may progress rapidly to cirrhosis and may be fatal. Patients with long-standing chronic hepatitis D and B often have inactive cirrhosis and are at risk for decompensation and hepatocellular carcinoma. The diagnosis is confirmed by detection of anti-HDV or HDAg (or HDV RNA) in serum.
Patients with active viral replication (HBeAg and HBV DNA [105 copies/mL or more, or 20,000 international units/mL or more] in serum and elevated aminotransferase levels) may be treated with a nucleoside or nucleotide analog or with pegylated interferon. Nucleoside and nucleotide analogs are preferred because they are better tolerated and can be taken orally. For patients who are HBeAg-negative, the threshold for treatment is a serum HBV DNA level of 104 copies/mL or more, or 2000 international units/mL or more. If the threshold HBV DNA level for treatment is met but the serum ALT level is normal, treatment may still be considered in patients over age 35–40 if liver biopsy demonstrates a fibrosis stage of 2 of 4 (moderate) or higher. Therapy is aimed at reducing and maintaining the serum HBV DNA level to the lowest possible levels, thereby leading to normalization of the ALT level and histologic improvement. An additional goal in HBeAg-positive patients is seroconversion to anti-HBe, and some responders eventually clear HBsAg. Although nucleoside and nucleotide analogs generally have been discontinued 6–12 months after HBeAg-to-anti-HBe seroconversion, some patients (especially Asian patients) serorevert to HBeAg after discontinuation, have a rise in HBV DNA levels and recurrence of hepatitis activity, and require long-term therapy, which also is required when seroconversion does not occur. HBeAg-negative patients with chronic hepatitis B also generally require long-term therapy because relapse is frequent when therapy is stopped; a low serum HBsAg level identifies patients at low risk for relapse
The available nucleoside and nucleotide analogs—entecavir, tenofovir, lamivudine, adefovir, and telbivudine—differ in efficacy and rates of resistance; however, in HBeAg-positive patients, they all achieve an HBeAg-to-anti-HBe seroconversion rate of about 20% at 1 year, with higher rates after more prolonged therapy. The preferred first-line oral agents are entecavir and tenofovir. Entecavir is rarely associated with resistance unless a patient is already resistant to lamivudine. The daily dose is 0.5 mg orally for patients not resistant to lamivudine and 1 mg for patients who previously became resistant to lamivudine. Suppression of HBV DNA in serum occurs in nearly all treated patients, and histologic improvement is observed in 70% of patients. Entecavir has been reported to cause lactic acidosis when used in patients with decompensated cirrhosis. Tenofovir disoproxil fumarate, 300 mg orally daily, is equally effective and is used as a first-line agent or when resistance to a nucleoside analog has developed. Like entecavir, tenofovir has a low rate of resistance when used as initial therapy. Long-term use may lead to an elevated serum creatinine level and reduced serum phosphate level (Fanconi-like syndrome) that is reversible with discontinuation of the drug. Tenofovir alafenamide, 25 mg orally daily, is an alternative formulation of tenofovir that was approved by the FDA in 2016 and that may be associated with a lower rate of renal and bone toxicity than tenofovir disoproxil fumarate.
The first available nucleoside analog was lamivudine, 100 mg orally daily. By the end of 1 year of therapy with lamivudine, however, 15–30% of responders experience a relapse (and occasionally frank decompensation). as a result of a mutation in the polymerase gene (the YMDD motif) of HBV DNA that confers resistance to lamivudine. The rate of resistance reaches 70% by 5 years of therapy, and the drug is no longer considered first-line therapy in the United States but may be used in countries in which cost is a deciding factor. Adefovir dipivoxil has activity against wild-type and lamivudine-resistant HBV but is the least potent of the oral antiviral agents for HBV. The standard dose is 10 mg orally once a day for at least 1 year. As with lamivudine, only a small number of patients achieve sustained suppression of HBV replication with adefovir, and long-term suppressive therapy is often required. Resistance to adefovir occurs in up to 29% of patients treated for 5 years. Patients with underlying kidney dysfunction are at risk for nephrotoxicity from adefovir. Telbivudine, given in a daily dose of 600 mg orally, is more potent than either lamivudine or adefovir. Resistance to this drug may develop, however, particularly in patients who are resistant to lamivudine, and elevated creatine kinase levels are common in patients treated with telbivudine. Strategies using multiple drugs have generally not proved advantageous. Other antiviral agents are under study.
The development of resistance occasionally results in hepatic decompensation. Resistance is most likely to develop to lamivudine and may develop to adefovir and telbivudine, but these drugs are no longer used as first-line agents in the United States. Sequential addition of a second antiviral agent is usually effective after resistance to the first agent has developed. Combined use of peginterferon and a nucleoside or nucleotide analog has not been shown convincingly to have a substantial advantage over the use of either type of drug alone. Nucleoside and nucleotide analogs are well tolerated even in patients with decompensated cirrhosis (for whom the treatment threshold may be an HBV DNA level less than 104 copies/mL and therapy should be continued indefinitely) and may be effective in patients with rapidly progressive hepatitis B (“fibrosing cholestatic hepatitis”) following organ transplantation.
Nucleoside analogs are also recommended for inactive HBV carriers (and those positive only for anti-HBc) prior to the initiation of immunosuppressive therapy (including rituximab or anti-tumor necrosis factor antibody therapy) or cancer chemotherapy to prevent reactivation; entecavir has been shown to be more effective than lamivudine. In patients infected with both HBV and HIV, antiretroviral therapy, including two drugs active against both viruses (eg, tenofovir plus lamivudine or emtricitabine), has been recommended when treatment of HIV infection is indicated. Telbivudine and tenofovir are classified as pregnancy category B drugs, and lamivudine, a category C drug, has been shown to be safe in pregnant women with HIV infection. Antiviral therapy has been recommended, beginning in the third trimester, when the mother’s serum HBV DNA level is 200,000 international units/mL or higher to reduce levels at the time of delivery.
Peginterferon alfa-2a is still an alternative to the oral agents in selected cases. A dose of 180 mcg subcutaneously once weekly for 48 weeks leads to sustained normalization of aminotransferase levels, disappearance of HBeAg and HBV DNA from serum, appearance of anti-HBe, and improved survival in up to 40% of treated patients. A response is most likely in patients with a low baseline HBV DNA level and high aminotransferase levels and is more likely in those who are infected with HBV genotype A than with other genotypes (especially genotype D) and who have certain favorable polymorphisms of the IL28B gene. Moreover, many complete responders eventually clear HBsAg and develop anti-HBs in serum, and are thus cured. Relapses are uncommon in complete responders who seroconvert from HBeAg to anti-HBe. Peginterferon may be considered in order to avoid long-term therapy with an oral agent, as in young women who may want to become pregnant in the future. Patients with HBeAg-negative chronic hepatitis B have a response rate of 60% after 48 weeks of therapy with peginterferon, but the response may not be durable once peginterferon is stopped. A rapid decline in serum HBsAg titers predicts a sustained response and ultimate clearance of HBsAg. The response to peginterferon is poor in patients with HIV coinfection.
In chronic hepatitis D, peginterferon alfa-2b (1.5 mcg/kg/wk for 48 weeks) may lead to normalization of serum aminotransferase levels, histologic improvement, and elimination of HDV RNA from serum in 20–50% of patients, but relapse may occur and tolerance is poor. Nucleoside and nucleotide analogs are generally not effective in treating chronic hepatitis D; prenylation inhibitors and HBV-HDV−specific receptor blockers are under study
The course of chronic hepatitis B is variable. The sequelae of chronic hepatitis secondary to hepatitis B include cirrhosis, liver failure, and hepatocellular carcinoma. The 5-year mortality rate is 0–2% in those without cirrhosis, 14–20% in those with compensated cirrhosis, and 70–86% following decompensation. The risk of cirrhosis and hepatocellular carcinoma correlates with serum HBV DNA levels, and a focus of therapy is to suppress HBV DNA levels below 300 copies/mL (60 international units/mL). HBV genotype C is associated with a higher risk of cirrhosis and hepatocellular carcinoma than other genotypes. Antiviral treatment improves the prognosis in responders, prevents (or leads to regression of) cirrhosis, and decreases the frequency of liver-related complications (although the risk of hepatocellular carcinoma does not become as low as that in inactive HBV carriers and hepatocellular carcinoma may even occur after clearance of HBsAg). A risk score (PAGE-B) based on a patient’s age, sex, and platelet count has been reported to predict the 5-year risk of hepatocellular carcinoma in white patients taking entecavir or tenofovir.
Clinical Findings & Diagnosis
Chronic hepatitis C develops in up to 85% of patients with acute hepatitis C. It is clinically indistinguishable from chronic hepatitis due to other causes and may be the most common. Worldwide, 170 million people are infected with HCV, with 1.8% of the US population infected. Peak prevalence in the United States (about 4%) is in persons born between 1945 and 1964. In approximately 40% of cases, serum aminotransferase levels are persistently normal. The diagnosis is confirmed by detection of anti-HCV by EIA. In rare cases of suspected chronic hepatitis C but a negative EIA, HCV RNA is detected by PCR testing. Progression to cirrhosis occurs in 20% of affected patients after 20 years, with an increased risk in men, those who drink more than 50 g of alcohol daily, and those who acquire HCV infection after age 40 years. The rate of fibrosis progression accelerates after age 50. African Americans have a higher rate of chronic hepatitis C but lower rates of fibrosis progression and response to therapy than whites. Immunosuppressed persons—including patients with hypogammaglobulinemia or HIV infection with a low CD4 count or those receiving immunosuppressants—appear to progress more rapidly to cirrhosis than immunocompetent persons with chronic hepatitis C. Tobacco and cannabis smoking and hepatic steatosis also appear to promote progression of fibrosis, but coffee consumption appears to slow progression. Persons with chronic hepatitis C and persistently normal serum aminotransferase levels usually have mild chronic hepatitis with slow or absent progression to cirrhosis; however, cirrhosis is present in 10% of these patients. Serum fibrosis testing (eg, FibroSure) or ultrasound elastography may be used to identify the absence of fibrosis or presence of cirrhosis.
The introduction of direct-acting and host-targeting antiviral agents has rapidly expanded the therapeutic armamentarium against HCV (Table 16–6). Standard therapy for HCV infection from the late 1990s to the early 2010s was a combination of peginterferon plus ribavirin, and ribavirin continues to be used in some all-oral regimens. Sustained virologic response rates (negative HCV RNA in serum at 24 weeks after completion of therapy) to peginterferon plus ribavirin were 45% in patients with HCV genotype 1 infection and 70–80% in those with genotype 2 or 3 infection. Response of genotype 1 infection to peginterferon plus ribavirin was associated most strongly with the CC genotype of the IFNL3 (IL28B) gene, with sustained response rates as high as 80%, compared to 40% for the CT genotype and 30% for the TT genotype.
Table 16–6.Direct-acting antiviral agents for HCV infection. |Favorite Table|Download (.pdf) Table 16–6. Direct-acting antiviral agents for HCV infection.
|Agent ||Genotype(s) ||Dose3 ||Comment |
|NS3/4A Protease Inhibitors |
|Boceprevir ||1 ||800 mg orally three times daily ||Used in combination with pegylated interferon and ribavirin; no longer marketed in United States |
|Telaprevir ||1 ||1125 mg orally twice daily ||Used in combination with pegylated interferon and ribavirin; no longer marketed in United States |
|Simeprevir ||1 and 4 ||150 mg orally once daily ||Used in combination with pegylated interferon and ribavirin or with sofosbuvir |
|Paritaprevir ||1 and 4 ||150 mg orally once daily ||Used in combination with ombitasvir and dasabuvir; ritonavir (100 mg) boosted;4 for genotype 1b with cirrhosis and genotype 1a, used with ribavirin. Used in combination with ombitasvir, ritonavir boosting, and ribavirin for genotype 45 |
|Asunaprevir1 ||1 and 4 ||200 mg orally twice daily ||Used in combination with daclatasvir or with daclatasvir and beclabuvir |
|Grazoprevir ||1, 4–6 ||100 mg orally once daily ||Used in combination with elbasvir6 |
|Glecaprevir1 ||1–6 ||200–300 mg orally once daily ||Used in combination with pibrentasvir with or without ribavirin |
|Voxilaprevir1 ||1–6 ||100 mg orally once daily ||Used in combination with sofosbuvir and velpatasvir |
|NS5A Inhibitors |
|Daclatasvir2 ||1–6 ||60 mg orally once daily ||Used in combination with sofosbuvir (genotypes 1–6, with or without ribavirin depending on presence of cirrhosis) or with pegylated interferon and ribavirin (genotype 4) or with asunaprevir (with or without beclabuvir; under study) |
|Ledipasvir ||1, 4-6 ||90 mg orally once daily ||Used in combination with sofosbuvir7 |
|Ombitasvir ||1 and 4 ||25 mg orally once daily ||Used in combination with paritaprevir (ritonavir boosted) with or without dasabuvir and with or without ribavirin as per paritaprevir above |
|Elbasvir ||1–6 ||50 mg orally once daily ||Used in combination with grazoprevir |
|Velpatasvir ||1–6 ||100 mg orally once daily ||Used in combination with sofosbuvir;8 may be used with sofosbuvir and voxilaprevir |
|Pibrentasvir1 ||1–6 ||120 mg orally once daily ||Used in combination with glecaprevir with or without ribavirin |
|NS5B Nucleos(t)ide Polymerase Inhibitor |
|Sofosbuvir ||1–6 ||400 mg orally once daily ||Used in combination with pegylated interferon and ribavirin (all genotypes) or with ribavirin alone (genotypes 2 and 3) or with simeprevir (genotypes 1 and 4) or with daclatasvir (all genotypes) or with ledipasvir (genotypes 1, 3, and 4) or with velpatasvir (all genotypes) or with velpatasvir and voxilaprevir (all genotypes) |
|NS5B Non-Nucleos(t)ide Polymerase Inhibitors |
|Dasabuvir ||1 and 4 ||250 mg orally twice daily ||Used in combination with paritaprevir (ritonavir boosted) and ombitasvir with or without ribavirin as per paritaprevir above |
|Beclabuvir1 ||1 ||75 mg orally twice daily ||Used in combination with daclatasvir and asunaprevir |
Higher rates of response were achieved in persons infected with HCV genotype 1 when a first-generation direct-acting antiviral agent—boceprevir or telaprevir (agents no longer available in the United States), nonstructural (NS) 3/4A serine protease inhibitors—was added to peginterferon plus ribavirin. Sustained response rates were as high as 75% for HCV genotype 1 with a standard three-drug regimen. With the addition of the protease inhibitor, the treatment duration for HCV genotype 1 infection could be shortened to 24 weeks, depending on the rapidity of clearance of HCV RNA from serum—so-called response-guided therapy.
Treatment with peginterferon-based therapy was associated with frequent, often distressing, side effects, and discontinuation rates were as high as 15–30%. Peginterferon alfa is contraindicated in pregnant or breastfeeding women and those with decompensated cirrhosis, profound cytopenias, severe psychiatric disorders, autoimmune diseases, or an inability to self-administer or comply with treatment. Men and women taking ribavirin must practice strict contraception until 6 months after the conclusion of therapy because of its teratogenic effects in animals. Ribavirin should be used with caution in persons over 65 years of age and in others in whom hemolysis could pose a risk of angina or stroke.
The definition of clearance of HCV RNA requires use of a sensitive real-time reverse transcriptase-PCR assay to monitor HCV RNA during treatment (the lower limit of quantification should be 25 international units/mL or less, and the limit of detection should be 10–15 international units/mL). After the introduction of all-oral regimens, the criterion for a sustained virologic response was shortened from 24 weeks to 12 weeks after the completion of treatment.
Several types of direct-acting antiviral agents have been developed. HCV protease inhibitors (“…previrs”) generally have high antiviral potency but differ with respect to the development of resistance (although resistance-associated variants of HCV tend not to persist after therapy is stopped). Some of the compounds show better response rates in HCV genotype 1b than in genotype 1a infection. The HCV protease inhibitors approved by the FDA in early 2017 are simeprevir, paritaprevir, and grazoprevir (Table 16–6). In HCV genotype 1 infection, simeprevir is less effective in patients with genotype 1a and a nonstructural protein Q80K mutation than in those without the mutation.
NS5A inhibitors (“…asvirs”) are characterized by high antiviral potency at picomolar doses. The cross-genotype efficacy of these agents varies. Ledipasvir was the first NS5A inhibitor approved by the FDA in 2014 (Table 16–6). Ledipasvir has potent activity against genotypes 1, 4, 5, and 6 HCV and has been formulated in combination with sofosbuvir. The combination is highly effective in both treatment-naive and treatment-experienced patients, even those with cirrhosis. The combination is given in a fixed dose of ledipasvir 90 mg and sofosbuvir 400 mg once daily for 12 weeks in HCV genotype 1–infected treatment-naive patients and treatment-experienced patients without cirrhosis and for 24 weeks in treatment-experienced patients with cirrhosis. In treatment-naive patients without cirrhosis, the duration of treatment can be shortened to 8 weeks if the baseline HCV RNA level is less than 6 million international units/mL. Sustained virologic response rates are well above 90%, including patients coinfected with HIV, and this regimen has emerged as a first-line therapy for HCV genotype 1. The combination of ledipasvir, sofosbuvir, and ribavirin achieves high rates of sustained virologic response in patients with HCV genotype 3 as well as in patients with HCV genotype 1 or 4 and advanced cirrhosis. Side effects are mild and include fatigue and headache. Concomitant use of a proton pump inhibitor, particularly twice-daily dosing in patients with cirrhosis, may reduce the effectiveness of the combination of ledipasvir and sofosbuvir. Re-treatment of occasional nonresponders or relapsers with resistance-associated substitutions (or variants) that persist for years with an alternative regimen that may include sofosbuvir is often effective. In 2016, the FDA approved another highly effective combination, the NS3/4A protease inhibitor grazoprevir 100 mg and the NS5A inhibitor elbasvir 50 mg daily for HCV genotypes 1 and 4; this combination is contraindicated in patients with advanced cirrhosis, and pretreatment testing for resistance-associated substitutions is recommended.
HCV polymerase inhibitors (“…buvirs”) are categorized as nucleoside or nucleotide analog and non-nucleoside polymerase inhibitors. Nucleoside analogs are active against all HCV genotypes and have a high barrier to resistance. Non-nucleoside polymerase inhibitors are the weakest class of compounds against HCV because of a low barrier to resistance. Most drugs in this class are more active against HCV genotype 1b than HCV genotype 1a. They have been developed to be used only in combination with the other direct-acting antiviral agents, mainly protease inhibitors and NS5A inhibitors. The first approved HCV NS5B nucleotide polymerase inhibitor was sofosbuvir in 2013.
Sofosbuvir was initially approved for use in combination with peginterferon and ribavirin in patients with HCV genotype 1 infection and with ribavirin alone in patients with HCV genotype 2 or 3 infection (see Table 16–6). Most patients with HCV genotypes 2 or 3 infection, including those with HIV coinfection, are cured with 12 or 24 weeks of therapy, respectively. HCV genotype 2 responds much better to interferon-free sofosbuvir-based therapy than HCV genotype 3, but the sustained virologic response is 20–30% lower in patients with cirrhosis, and the combination of sofosbuvir and ribavirin has been reported to cause lactic acidosis in some patients with advanced cirrhosis. Importantly, no sofosbuvir-resistant variants have been selected during therapy. The combination of sofosbuvir and simeprevir has been found to be effective in HCV genotype 1 infection and was approved by the FDA in 2014; the approval was extended to HCV genotypes 4, 5, and 6 in 2015.
The combination of paritaprevir (an NS3/4A protease inhibitor), boosted by ritonavir, plus ombitasvir (an NS5A inhibitor) and dasabuvir (an NS5B non-nucleoside polymerase inhibitor) is effective in HCV genotype-1 treatment-naive and prior nonresponders to interferon-based therapy, with or without cirrhosis, and was approved by the FDA in 2014. The same combination without dasabuvir was FDA approved in 2015 for HCV genotype 4 infection. Instances of hepatotoxicity have been reported with these regimens in patients with advanced cirrhosis. Daclatasvir in combination with sofosbuvir has proven effective in genotypes 1-, 2-, and 3-infected patients, including those coinfected with HIV, and was FDA approved in 2015 for HCV genotype 3 infection. The combination of velpatasvir, an NS5A inhibitor, and sofosbuvir is effective for all HCV genotypes (“pangenotypic”) and was approved in 2016. In patients with advanced cirrhosis, the addition of ribavirin to the regimen is recommended. The combination of daclatasvir and asunaprevir (not available in the United States) is highly effective in genotype 1b-, 4-, 5-, and 6-infected patients but less effective in genotype 1a-infected patients. The combination of daclatasvir, asunaprevir, and beclabuvir (a non-nucleoside NS5B inhibitor) is effective in genotype 1a- and 1b-infected patients but is not available in the United States. Other emerging drugs and regimens are shown in Table 16–6. As of early 2017, asunaprevir, beclabuvir, glecaprevir, pibrentasvir, and voxilaprevir were not available in the United States. When available, the combination of sofosbuvir, velpatasvir, and voxilaprevir is likely to be a “rescue” regimen for patients who have not responded to other regimens.
Despite the efficacy of the new regimens, their cost is high, and insurance coverage is often a barrier to their use. Additional factors to consider in the selection of a regimen are the presence of cirrhosis or kidney dysfunction, prior treatment, and potential drug interactions. Other agents that have been studied include NS3/4A protease inhibitors (eg, danoprevir, faldaprevir); polymerase inhibitors (eg, mericitabine); virus entry, assembly, and secretion inhibitors; microRNA-122 antisense oligonucleotides (eg, miravirsen); cyclophilin A inhibitors (eg, alisporivir); interferon lambda-3; and therapeutic vaccines. HCV genotype 1 is now easy to cure with oral direct-acting agents, with expected sustained virologic response rates well above 90%, and virtually all HCV genotype 2 infection is curable with all-oral regimens. HCV genotype 3 infection, particularly in association with cirrhosis, is the most challenging to treat. Nonetheless, interferon is rarely required, and the need for ribavirin is declining.
Antiviral therapy has been shown to be beneficial in the treatment of cryoglobulinemia associated with chronic hepatitis C; an acute flare of cryoglobulinemia may first require treatment with rituximab, cyclophosphamide plus methylprednisolone, or plasma exchange. As noted above, patients with HCV and HIV coinfection have been shown to respond well to treatment of HCV infection. Moreover, in persons coinfected with HCV and HIV, long-term liver disease–related mortality increases as HIV infection–related mortality is reduced by antiretroviral therapy. Occasional instances of reactivation of HBV infection, as well as herpesvirus, have occurred with direct-acting antiviral agents for HCV infection, and all candidates should be prescreened for HBV infection.
Chronic hepatitis C is an indolent, often subclinical disease that may lead to cirrhosis and hepatocellular carcinoma after decades. The overall mortality rate in patients with transfusion-associated hepatitis C may be no different from that of an age-matched control population. Nevertheless, mortality or transplantation rates clearly rise to 5% per year once cirrhosis develops, and mortality from cirrhosis and hepatocellular carcinoma due to hepatitis C is still rising. A risk score combining age, sex, platelet count, and AST-to-ALT ratio has been proposed. There is some evidence that HCV genotype 1b is associated with a higher risk of hepatocellular carcinoma than other genotypes. Antiviral therapy has a beneficial effect on mortality and quality of life, is cost-effective, appears to retard and even reverse fibrosis, and reduces (but does not eliminate) the risk of decompensated cirrhosis and hepatocellular carcinoma in responders with advanced fibrosis. Even patients who achieve a sustained virologic response remain at an increased risk for mortality compared with the general population. The risk of mortality from drug addiction is higher than that for liver disease in patients with chronic hepatitis C. HCV infection appears to be associated with increased cardiovascular mortality, especially in persons with diabetes mellitus and hypertension. Statin use has been reported to be associated with improved virologic response to antiviral therapy and decreased progression of liver fibrosis and frequency of hepatocellular carcinoma.
For liver biopsy.
For antiviral therapy.
et al. New therapeutic agents for chronic hepatitis B. Lancet Infect Dis. 2016 Feb;16(2):e10–21.
et al. Repeated measurements of hepatitis B surface antigen identify carriers of inactive HBV during long-term follow-up. Clin Gastroenterol Hepatol. 2016 Oct;14(10):1481–89.
et al. Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-analysis. Hepatology. 2016 Jan;63(1):319–33.
et al. Management of direct-acting antiviral agent failures. J Hepatol. 2015 Dec;63(6):1511–52.
et al. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: results from ERCHIVES. Hepatology. 2015 Aug;62(2):365–74.
et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015 Dec 31;373(27):2618–28.
et al. A clinician’s guide to drug-drug interactions with direct-acting antiviral agents for the treatment of hepatitis C viral infection. Hepatology. 2016 Feb;63(2):634–43.
European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2015. J Hepatol. 2015 Jul;63(1):199–236.
et al. Sofosbuvir with velpatasvir in treatment-naive noncirrhotic patients with genotype 1 to 6 hepatitis C virus infection: a randomized trial. Ann Intern Med. 2015 Dec;163(11):818–26.
et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015 Dec 1;373(27):2599–607.
et al. New perspectives for preventing hepatitis C virus liver graft infection. Lancet Infect Dis. 2016 Jun;16(6):735–45.
et al. Current concepts in diabetes mellitus and chronic liver disease: clinical outcomes, hepatitis C virus association, and therapy. Dig Dis Sci. 2016 Feb;61(2):371–80.
et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. Hepatology. 2016 Nov;64(5):1473–82.
et al. Emerging complexities with hepatitis C virus direct-acting antiviral regimens: less is still way more. Hepatology. 2016 Nov;64(5):1401–3.
et al. Association between serum level of hepatitis B surface antigen at end of entecavir therapy and risk of relapse in E antigen-negative patients. Clin Gastroenterol Hepatol. 2016 Oct;14(10):1490–8.
et al. Review article: long-term safety of nucleoside and nucleotide analogues in HBV-monoinfected patients. Aliment Pharmacol Ther. 2016 Jul;44(1):16–34.
et al. Efficacy and safety of ombitasvir, paritaprevir, and ritonavir in an open-label study of patients with genotype 1b chronic hepatitis C virus infection with and without cirrhosis. Gastroenterology. 2015 Oct;149(4):971–80.
et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: a randomized phase III study (ALLY-3+). Hepatology. 2016 May;63(5):1430–41.
et al. Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther. 2016 Jun;43(12):1253–61.
et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology. 2016 Jan;63(1):284–306.
et al. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther. 2016 Jun;43(12):1276–92.
et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016 Jun;16(6):685–97.
et al. Combination of tenofovir disoproxil fumarate and peginterferon α-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology. 2016 Jan;150(1):134–44.
et al; ION-4 Investigators. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015 Aug 20;373(8):705–13.
et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015 Apr;61(4):1127–35.
et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatology. 2016 May;63(5):1481–92.
et al. Hepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta-analysis. Ann Intern Med. 2016 Jan 5;164(1):30–40.
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et al. Reactivation of herpesvirus in patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2016 Nov;14(11):1662–6.
et al. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015 Jan;148(1):221–44.
et al. Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies. Gastroenterology. 2016 Jan;150(1):145–55.
et al. Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology. 2016 Jun;150(7):1590–8.
et al. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015 Jan;148(1):215–9.
et al. Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real-world cohort study. Hepatology. 2016 Dec;64(6):1893–9.
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et al. Lactic acidosis in patients with hepatitis C virus cirrhosis and combined ribavirin/sofosbuvir treatment. J Hepatol. 2016 Apr;64(4):790–9.
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ESSENTIALS OF DIAGNOSIS
Usually young to middle-aged women.
Chronic hepatitis with high serum globulins and characteristic liver histology.
Positive antinuclear antibody (ANA) and/or smooth muscle antibody in most common type.
Responds to corticosteroids.
Although autoimmune hepatitis is usually seen in young women, it can occur in either sex at any age. The incidence, which has been rising, and prevalence are estimated to be 8.5 and 107 per million population, respectively. Affected younger persons are often positive for HLA-B8 and HLA-DR3; older patients are often positive for HLA-DR4. The principal susceptibility allele among white Americans and northern Europeans is HLA DRB1*0301; HLA DRB1*0401 is a secondary but independent risk factor. Variants of the SH2B3 and CARD10 genes have also been identified.
The onset is usually insidious, but about 20% of cases present with acute (occasionally fulminant) hepatitis and some cases follow a viral illness (such as hepatitis A, Epstein-Barr infection, or measles) or exposure to a drug or toxin (such as nitrofurantoin, minocycline, or infliximab). Exacerbations may occur postpartum. Amenorrhea may be a presenting feature, and the frequency of depression appears to be increased. Thirty-four percent of patients, and particularly elderly patients, are asymptomatic. Typically, examination reveals a healthy-appearing young woman with multiple spider telangiectasias (see eFigure 16–3), cutaneous striae, acne, hirsutism, and hepatomegaly. Extrahepatic features include arthritis, Sjögren syndrome, thyroiditis, nephritis, ulcerative colitis, and Coombs-positive hemolytic anemia. Patients, especially elderly patients, with autoimmune hepatitis are at increased risk for cirrhosis, which, in turn, increases the risk of hepatocellular carcinoma (at a rate of about 1% per year).
Serum aminotransferase levels may be greater than 1000 units/L, and the total bilirubin is usually increased. Autoimmune hepatitis may be classified as type 1 or type 2, although the clinical features and response to treatment are similar between the two types. In type I (classic) autoimmune hepatitis, ANA or smooth muscle antibodies (either or both) are usually detected in serum. Serum gamma-globulin levels are typically elevated (up to 5–6 g/dL [0.05–0.06 g/L]); in such patients, the EIA for antibody to HCV may be falsely positive. Other antibodies, including atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and antibodies to histones, F-actin, and alpha-actinin may be found. Antibodies to soluble liver antigen (anti-SLA) characterize a variant of type I that is marked by severe disease, a high relapse rate after treatment, and absence of the usual antibodies (ANA and smooth muscle antibodies). Anti-SLA is directed against a transfer RNA complex responsible for incorporating selenocysteine into peptide chains—Sep (O-phosphoserine) tRNA: Sec (selenocysteine) tRNA synthase, or SEPSECS. Type II, seen more often in girls under age 14 in Europe, is characterized by circulating antibodies to liver-kidney microsome type 1 (anti-LKM1) —directed against cytochrome P450 2D6— without smooth muscle antibodies or ANA. In some cases, antibodies to liver cytosol type 1, directed against formiminotransferase cyclodeaminase, are detected. Type II autoimmune hepatitis can be seen in patients with autoimmune polyglandular syndrome type 1. Concurrent primary biliary cholangitis (PBC; formerly primary biliary cirrhosis) or primary sclerosing cholangitis (“overlap syndrome”) has been recognized in 7–13% and 6–11% of patients with autoimmune hepatitis, respectively. Liver biopsy is indicated to help establish the diagnosis (interface hepatitis (eFigure 16–13) is the hallmark), evaluate disease severity, and determine the need for treatment.
Autoimmune hepatitis: Typical histologic findings of autoimmune hepatitis are plasma cells (arrows) at the interface between the portal tract (top of figure) and lobule (bottom), with inflammatory cells spilling into the lobule, referred to as interface hepatitis. (Used, with permission, from James P. Grenert, MD.)
Simplified diagnostic criteria based on the detection of autoantibodies (1 point for a titer of > 1:40 or 2 points for a titer of > 1:80), elevated IgG levels (1 point for IgG level ≥ upper limit of normal or 2 points for level ≥ 1.1 times upper limit of normal), and characteristic histologic features (1 or 2 points depending on how typical the features are) and exclusion of viral hepatitis (2 points) can be useful for diagnosis; a score of 6 indicates probable and a score of 7 indicates definite autoimmune hepatitis with a high degree of specificity but moderate sensitivity. Diagnostic criteria for an overlap of autoimmune hepatitis and PBC (“Paris criteria”) have been proposed.
Prednisone with or without azathioprine improves symptoms; decreases the serum bilirubin, aminotransferase, and gamma-globulin levels; and reduces hepatic inflammation. Symptomatic patients with aminotransferase levels elevated 10-fold (or 5-fold if the serum globulins are elevated at least 2-fold) are optimal candidates for therapy, and asymptomatic patients with modest enzyme elevations may be considered for therapy depending on the clinical circumstances and histologic severity; however, asymptomatic patients usually remain asymptomatic, have either mild hepatitis or inactive cirrhosis on liver biopsy specimens, and have a good long-term prognosis without therapy.
Prednisone is given initially in a dose of 30 mg orally daily with azathioprine, 50 mg orally daily, which is generally well tolerated and permits the use of lower corticosteroid doses than a regimen beginning with prednisone 60 mg orally daily alone. Intravenous corticosteroids or prednisone, 60 mg orally daily, is recommended for patients with acute severe autoimmune hepatitis. Budesonide, 3 mg orally two or three daily, may be at least as effective as prednisone in noncirrhotic autoimmune hepatitis and associated with fewer side effects. Whether patients should undergo testing for the genotype or level of thiopurine methyltransferase prior to treatment with azathioprine to predict toxicity is debated. Blood counts are monitored weekly for the first 2 months of therapy and monthly thereafter because of the small risk of bone marrow suppression. The dose of prednisone is lowered from 30 mg/day after 1 week to 20 mg/day and again after 2 or 3 weeks to 15 mg/day. Treatment is response guided, and ultimately, a maintenance dose of 10 mg/day should be achieved. While symptomatic improvement is often prompt, biochemical improvement is more gradual, with normalization of serum aminotransferase levels after an average of 22 months. Histologic resolution of inflammation lags biochemical remission by 3–6 months, and repeat liver biopsy is recommended at least 3 months after the aminotransferase levels have normalized. Failure of aminotransferase levels to return to normal invariably predicts lack of histologic resolution.
The response rate to therapy with prednisone and azathioprine is 80%, with remission in 65% by 3 years. Older patients and those with HLA genotype DRB1*04 are more likely to respond than younger patients and those with HLA DRB1*03, hyperbilirubinemia, or a high MELD score (12 or higher, see Cirrhosis). Fibrosis may reverse with therapy and rarely progresses after apparent biochemical and histologic remission. Once complete remission is achieved, therapy may be withdrawn, but the subsequent relapse rate is 90% by 3 years. Relapses may again be treated in the same manner as the initial episode, with the same remission rate. After successful treatment of a relapse, the patient may continue taking azathioprine (up to 2 mg/kg) or the lowest dose of prednisone with or without azathioprine (50 mg/day) needed to maintain aminotransferase levels as close to normal as possible; another attempt at withdrawing therapy may be considered in patients remaining in remission long term (eg, 4 years or longer). During pregnancy, flares can be treated with prednisone, and maintenance azathioprine does not have to be discontinued.
Nonresponders to corticosteroids and azathioprine (failure of serum aminotransferase levels to decrease by 50% after 6 months) may be considered for a trial of cyclosporine, tacrolimus, sirolimus, everolimus, methotrexate, rituximab, or infliximab. Mycophenolate mofetil, 1 g twice daily, is an effective alternative to azathioprine in patients who cannot tolerate it but is less effective in nonresponders to azathioprine. Occasionally, 6-mercaptopurine may be tolerated in patients who do not tolerate azathioprine. Bone density should be monitored—particularly in patients receiving maintenance corticosteroid therapy—and measures undertaken to prevent or treat osteoporosis (see Chapter 26). Liver transplantation may be required for treatment failures and patients with a fulminant presentation, but the outcome may be worse than that for PBC because of an increased rate of infectious complications. As immunosuppression is reduced, the disease has been recognized to recur in up to 70% of transplanted livers at 5 years (and rarely to develop de novo); sirolimus can be effective in such cases. Overall long-term mortality of patients with autoimmune hepatitis appears to be twofold higher than that of the general population despite response to immunosuppressive therapy. Factors that predict the need for liver transplantation or that predict liver-related death include the following: (1) age 20 years or younger or older than 60 years at presentation, (2) low serum albumin level at diagnosis, (3) cirrhosis at diagnosis, (4) the presence of anti-SLA, and (5) incomplete normalization of the serum ALT level after 6 months of treatment.
INR greater than 1.6.
et al. Long-term prognostic significance of persisting histological activity despite biochemical remission in autoimmune hepatitis. Am J Gastroenterol. 2015 Jul;110(7):993–9.
European Association for the Study of the Liver. EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol. 2015 Oct;63(4):971–1004.
et al. Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis. J Hepatol. 2015 Mar;62(3):642–6.
et al. Efficacy of 6-mercaptopurine as second-line treatment for patients with autoimmune hepatitis and azathioprine intolerance. Clin Gastroenterol Hepatol. 2016 Mar;14(3):445–53.
et al. Prediction of short- and long-term outcome in patients with autoimmune hepatitis. Hepatology. 2015 Nov;62(5):1524–35.
et al. Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype. Aliment Pharmacol Ther. 2015 Jun;41(12):1281–7.
et al. A real-world study focused on the long-term efficacy of mycophenolate mofetil as first-line treatment of autoimmune hepatitis. Aliment Pharmacol Ther. 2016 May;43(10):1035–47.
ESSENTIALS OF DIAGNOSIS
Chronic alcohol intake usually exceeds 80 g/day in men and 30–40 g/day in women with alcoholic hepatitis or cirrhosis.
Fatty liver is often asymptomatic.
Fever, right upper quadrant pain, tender hepatomegaly, and jaundice characterize alcoholic hepatitis, but the patient may be asymptomatic.
AST is usually elevated but usually not above 300 units/L (6 mckat/L); AST is greater than ALT, usually by a factor of 2 or more.
Alcoholic hepatitis is often reversible but it is the most common precursor of cirrhosis in the United States.
Excessive alcohol intake can lead to fatty liver, hepatitis, and cirrhosis. Alcoholic hepatitis is characterized by acute or chronic inflammation and parenchymal necrosis of the liver induced by alcohol. Alcoholic hepatitis is often a reversible disease but the most common precursor of cirrhosis in the United States. It is associated with four to five times the number of hospitalizations and deaths as hepatitis C, which is the second most common cause of cirrhosis.
The frequency of alcoholic cirrhosis is estimated to be 10–15% among persons who consume over 50 g of alcohol (4 oz of 100-proof whiskey, 15 oz of wine, or four 12-oz cans of beer) daily for over 10 years (although the risk of cirrhosis may be lower for wine than for a comparable intake of beer or spirits). The risk of cirrhosis is lower (5%) in the absence of other cofactors such as chronic viral hepatitis and obesity. Genetic factors, including polymorphisms of the genes encoding palatin-like phospholipase domain-containing protein 3 (PNPLA3), tumor necrosis factor, cytochrome P450 2E1, glutathione S-transferase, and galectin-9 may also account for differences in susceptibility to and severity of liver disease. Women appear to be more susceptible than men, in part because of lower gastric mucosal alcohol dehydrogenase levels. Over 80% of patients with alcoholic hepatitis have been drinking 5 years or more before symptoms that can be attributed to liver disease develop; the longer the duration of drinking (10–15 or more years) and the larger the alcoholic consumption, the greater the probability of developing alcoholic hepatitis and cirrhosis. In individuals who drink alcohol excessively, the rate of ethanol metabolism can be sufficiently high to permit the consumption of large quantities without raising the blood alcohol level over 80 mg/dL.
Deficiencies in vitamins and calories probably contribute to the development of alcoholic hepatitis and its progression to cirrhosis. Many adverse effects of alcohol on the liver are thought to be mediated by tumor necrosis factor and by the oxidative metabolite acetaldehyde, which contributes to lipid peroxidation and induction of an immune response following covalent binding to proteins in the liver.
The clinical presentation of alcoholic liver disease can vary from asymptomatic hepatomegaly to a rapidly fatal acute illness or end-stage cirrhosis. A recent period of heavy drinking, complaints of anorexia and nausea, and the demonstration of hepatomegaly and jaundice (see eFigure 16–1) strongly suggest the diagnosis. Abdominal pain and tenderness, splenomegaly, ascites (see eFigure 16–6), fever, and encephalopathy may be present. Infection, including invasive aspergillosis, is common in patients with severe alcoholic hepatitis.
In patients with steatosis, mild liver enzyme elevations may be the only laboratory abnormality. Anemia (usually macrocytic) may be present. Leukocytosis with a shift to the left is common in patients with severe alcoholic hepatitis. Leukopenia is occasionally seen and resolves after cessation of drinking. About 10% of patients have thrombocytopenia related to a direct toxic effect of alcohol on megakaryocyte production or to hypersplenism.
AST is usually elevated but infrequently above 300 units/L (6 mckat/L). AST is greater than ALT, usually by a factor of 2 or more. Serum alkaline phosphatase is generally elevated, but seldom more than three times the normal value. Serum bilirubin is increased in 60–90% of patients with alcoholic hepatitis.
Serum bilirubin levels greater than 10 mg/dL (171 mcmol/L) and marked prolongation of the prothrombin time (6 seconds or more above control) indicate severe alcoholic hepatitis with a mortality rate as high as 50%. The serum albumin is depressed, and the gamma-globulin level is elevated in 50–75% of individuals, even in the absence of cirrhosis. Increased transferrin saturation, hepatic iron stores, and sideroblastic anemia are found in many alcoholic patients. Folic acid deficiency may coexist.
Imaging studies can detect moderate to severe hepatic steatosis reliably but not inflammation or fibrosis. Ultrasonography helps exclude biliary obstruction and identifies subclinical ascites. CT with intravenous contrast or MRI may be indicated in selected cases to evaluate patients for collateral vessels, space-occupying lesions of the liver, or concomitant disease of the pancreas.
Liver biopsy, if done, demonstrates macrovesicular fat and, in patients with alcoholic hepatitis, polymorphonuclear infiltration with hepatic necrosis, Mallory (or Mallory-Denk) bodies (alcoholic hyaline), and perivenular and perisinusoidal fibrosis (eFigure 16–14, eFigure 16–15). Micronodular cirrhosis may be present as well. The findings are identical to those of nonalcoholic steatohepatitis.
Alcoholic hepatitis. Liver biopsy specimen shows classic features of alcoholic hepatitis including pink Mallory hyaline within hepatocytes (black arrows), ballooning hepatocytes (circle), steatosis, and multiple neutrophils (green arrows). (Used, with permission, from James P. Grenert, MD.)
Alcoholic cirrhosis of the liver. A: Small regenerative nodules are separated by coarse bands of collagen in which are found blood vessels, bile ducts, and inflammatory cells. B: The regenerative nodule is composed of a disorganized mass of liver cells showing fatty change. There is no central hepatic vein in the nodule. (Reproduced, with permission, from Chandrasoma P, Taylor CR. Concise Pathology, 2nd ed. Originally published by Appleton & Lange. Copyright © 1995 by The McGraw-Hill Companies, Inc.)
Alcoholic hepatitis may be closely mimicked by cholecystitis and cholelithiasis and by drug toxicity. Other causes of hepatitis or chronic liver disease may be excluded by serologic or biochemical testing, imaging studies, or liver biopsy. A formula based on the AST/ALT ratio, body mass index, mean corpuscular volume, and sex has been reported to reliably distinguish alcoholic liver disease from nonalcoholic fatty liver disease (NAFLD).
Abstinence from alcohol is essential. Naltrexone, acamprosate, or baclofen may be considered in combination with counseling to reduce the likelihood of recidivism. Fatty liver is quickly reversible with abstinence. Every effort should be made to provide sufficient amounts of carbohydrates and calories in anorectic patients to reduce endogenous protein catabolism, promote gluconeogenesis, and prevent hypoglycemia. Nutritional support (35–40 [and no less than 21.5] kcal/kg with 1.2–1.5 g/kg as protein) improves liver disease, but not necessarily survival, in patients with malnutrition. Intensive enteral nutrition is difficult to implement, however. Use of liquid formulas rich in branched-chain amino acids does not improve survival beyond that achieved with less expensive caloric supplementation. The administration of micronutrients, particularly folic acid, thiamine, and zinc, is indicated, especially when deficiencies are noted; glucose administration increases the thiamine requirement and can precipitate Wernicke-Korsakoff syndrome if thiamine is not coadministered.
B. Pharmacologic Measures
Methylprednisolone, 32 mg/day orally, or the equivalent, for 1 month, may reduce short-term (but not 6-month) mortality in patients with alcoholic hepatitis and encephalopathy or a Maddrey discriminant function index (defined by the patient’s prothrombin time minus the control prothrombin time times 4.6 plus the total bilirubin in mg/dL) of 32 or more, or a MELD score of 18 or more (see Cirrhosis). Concomitant gastrointestinal bleeding or infection may not preclude treatment with corticosteroids if otherwise indicated. The combination of corticosteroids and N-acetylcysteine has been reported to improve 1-month but not 6-month survival and reduce the risk of hepatorenal syndrome and infections; the combination may be superior to corticosteroids alone, but more data are needed.
Pentoxifylline, 400 mg orally three times daily for 4 weeks, may reduce 1-month mortality rates in patients with severe alcoholic hepatitis, primarily by decreasing the risk of hepatorenal syndrome. It may be less effective in reducing short-term mortality than corticosteroids and is often used when corticosteroids are contraindicated. Whether the addition of pentoxifylline to prednisolone improves survival or reduces the frequency of hepatorenal syndrome compared with prednisolone alone is uncertain. Other experimental therapies include propylthiouracil, oxandrolone, S-adenosyl-l-methionine, infliximab, antioxidants, granulocyte colony-stimulating factor, anikinra, modulation of intestinal flora, and extracorporeal liver support. Colchicine does not reduce mortality in patients with alcoholic cirrhosis, and etanercept may increase mortality after 6 months.
The overall mortality rate is 34% (20% within 1 month) without corticosteroid therapy. Individuals in whom the prothrombin time prohibits liver biopsy have a 42% mortality rate at 1 year. Other unfavorable prognostic factors are older age, a serum bilirubin greater than 10 mg/dL (171 mcmol/L), hepatic encephalopathy, coagulopathy, azotemia, leukocytosis, sepsis and other infections, systematic inflammatory response syndrome, lack of response to corticosteroid therapy, and possibly a paucity of steatosis on a liver biopsy specimen and reversal of portal blood flow by Doppler ultrasonography. Concomitant gastrointestinal bleeding does not appear to worsen survival. Failure of the serum bilirubin level to decline after 7 days of treatment with corticosteroids predicts nonresponse and poor long-term survival, as does the Lille model (which includes age, serum creatinine, serum albumin, prothrombin time [or INR], serum bilirubin on admission, and serum bilirubin on day 7). The MELD score used for cirrhosis and the Glasgow alcoholic hepatitis score (based on age, white blood cell count, blood urea nitrogen, prothrombin time ratio, and bilirubin level) also correlate with mortality from alcoholic hepatitis and have higher specificities than the discriminant function and Lille score. A scoring system based on age, serum bilirubin, INR, and serum creatinine (ABIC) has been proposed, and at least one study has shown that the development of acute kidney injury is the most accurate predictor of 90-day mortality. The combination of the MELD score and Lille model has also been reported to be the best predictor of short-term mortality among the scoring systems. Histologic features associated with 90-day mortality include the degree of fibrosis and neutrophil infiltration, presence of metamitochondria, and bilirubinostasis.
Overall mortality from alcoholic liver disease has declined slightly in the United States since 1980. Nevertheless, the 3-year mortality rate of persons who recover from acute alcoholic hepatitis is 10 times greater than that of control individuals of comparable age; the 5-year mortality rate is as high as 85%. Histologically severe disease is associated with continued excessive mortality rates after 3 years, whereas the death rate is not increased after the same period in those whose liver biopsies show only mild alcoholic hepatitis. Complications of portal hypertension (ascites, variceal bleeding, hepatorenal syndrome), coagulopathy, and severe jaundice following recovery from acute alcoholic hepatitis also suggest a poor long-term prognosis. Alcoholic cirrhosis is a risk factor for hepatocellular carcinoma, and the risk is highest in carriers of the C282Y mutation for hemochromatosis or those with increased hepatic iron.
The most important prognostic consideration is continued excessive drinking. A 6-month period of abstinence is generally required before liver transplantation is considered, although this requirement has been questioned and early liver transplantation has been performed in selected patients with alcoholic hepatitis, with good outcomes. Optimal candidates have adequate social support, do not smoke, have no psychosis or personality disorder, are adherent to therapy, and have regular appointments with a psychiatrist or psychologist who specializes in addiction treatment. Patients with alcoholic liver disease are at higher risk for posttransplant malignancy than those with other types of liver disease because of alcohol and tobacco use.
Refer patients with alcoholic hepatitis who require liver biopsy for diagnosis.
et al. Treatment of alcohol use disorders in patients with alcoholic liver disease. J Hepatol. 2016 Sep;65(3):618–30.
et al. Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study. J Hepatol. 2015 May;62(5):1061–7.
SM (editor). Alcoholic liver disease. Clin Liver Dis. 2016;20(3):420–606. [Full issue]CrossRef
et al. Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia. Gastroenterology. 2016 Apr;150(4):785–90.
et al. Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis. Gastroenterology. 2015 Aug;149(2):398–406.e8.
et al. SIRS at admission is a predictor of AKI development and mortality in hospitalized patients with severe alcoholic hepatitis. Dig Dis Sci. 2016 Mar;61(3):920–9.
et al. Intensive enteral nutrition is ineffective for patients with severe alcoholic hepatitis treated with corticosteroids. Gastroenterology. 2016 Apr;150(4):903–10.
et al. Corticosteroids versus pentoxifylline for severe alcoholic hepatitis: a sequential analysis of randomized controlled trials. J Clin Gastroenterol. 2016 Nov/Dec;50(10):871–81.
et al. Variants in the LGALS9 gene are associated with development of liver disease in heavy consumers of alcohol. Clin Gastroenterol Hepatol. 2016 May;14(5):762–8.
et al. Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta-analysis. Gastroenterology. 2015 Oct;149(4):958–70.
et al; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619–28.
et al. Review article: Alcohol and gut microbiota—the possible role of gut microbiota modulation in the treatment of alcoholic liver disease. Aliment Pharmacol Ther. 2015 May;41(10):917–27.
DRUG- & TOXIN-INDUCED LIVER INJURY
ESSENTIALS OF DIAGNOSIS
Drug-induced liver injury can mimic viral hepatitis, biliary tract obstruction, or other types of liver disease.
Clinicians must inquire about the use of many widely used therapeutic agents, including over-the-counter “natural” and herbal products, in any patient with liver disease.
Many therapeutic agents may cause drug-induced liver injury, and up to 10% of patients with drug-induced liver injury die or undergo liver transplantation within 6 months of onset. The medications most commonly implicated are nonsteroidal anti-inflammatory drugs and antibiotics because of their widespread use. In any patient with liver disease, the clinician must inquire carefully about the use of potentially hepatotoxic drugs or exposure to hepatotoxins, including over-the-counter herbal and dietary supplements. In some cases, coadministration of a second agent may increase the toxicity of the first (eg, isoniazid and rifampin, acetaminophen and alcohol). A relationship between increased serum ALT levels in premarketing clinical trials and postmarketing reports of hepatotoxicity has been identified. Except for drugs used to treat tuberculosis and HIV infection and possibly azithromycin, the risk of hepatotoxicity is not increased in patients with preexisting cirrhosis, but hepatotoxicity may be more severe and the outcome worse when it does occur. Older persons may be at higher risk for hepatotoxicity from certain agents, such as amoxicillin-clavulanic acid, isoniazid, and nitrofurantoin, and more likely to have persistent and cholestatic, rather than hepatocellular, injury compared with younger persons. Drug toxicity may be categorized on the basis of pathogenesis or predominant histologic appearance. Drug-induced liver injury can mimic viral hepatitis, biliary tract obstruction, or other types of liver disease. The development of jaundice predicts a mortality rate of at least 10%. A useful resource is the website www.livertox.nih.gov/.
Categorization by Pathogenesis
Liver toxicity caused by this group of drugs is characterized by: (1) dose-related severity, (2) a latent period following exposure, and (3) susceptibility in all individuals. Examples include acetaminophen (toxicity is enhanced by fasting and chronic alcohol use because of depletion of glutathione and induction of cytochrome P450 2E1 and possibly reduced by statins, fibrates, and nonsteroidal anti-inflammatory drugs), alcohol, carbon tetrachloride, chloroform, heavy metals, mercaptopurine, niacin, plant alkaloids, phosphorus, pyrazinamide, tetracyclines, tipranavir, valproic acid, and vitamin A.
B. Idiosyncratic Reactions
Except for acetaminophen, most severe hepatotoxicity is idiosyncratic. Reactions of this type are (1) sporadic, (2) not related to dose above a general threshold of 100 mg/day, and (3) occasionally associated with features suggesting an allergic reaction, such as fever and eosinophilia (including drug rash with eosinophilia and systemic symptoms [DRESS] syndrome), which may be associated with a favorable outcome. In many instances, the drug is lipophilic, and toxicity results directly from a reactive metabolite that is produced only in certain individuals on a genetic basis. Drug-induced liver injury may be observed only during post-marketing surveillance and not during preclinical trials. Examples include abacavir, amiodarone, aspirin, carbamazepine, chloramphenicol, diclofenac, disulfiram, duloxetine, ezetimibe, flavocoxid (a “medical food”), fluoroquinolones (levofloxacin and moxifloxacin, in particular), flutamide, halothane, isoniazid, ketoconazole, lamotrigine, methyldopa, natalizumab, nevirapine, oxacillin, phenytoin, pyrazinamide, quinidine, rivaroxaban, streptomycin, thiazolidinediones, tolvaptan, and perhaps tacrine. Statins, like all cholesterol-lowering agents, may cause serum aminotransferase elevations but rarely cause true hepatitis, and even more rarely cause acute liver failure, and are no longer considered contraindicated in patients with liver disease. Most acute idiosyncratic drug-induced liver injury is reversible with discontinuation of the offending agent. Risk factors for chronicity (longer than 1 year) are older age, dyslipidemia, and severe acute injury.
Categorization by Histopathology
Drug-induced cholestasis results from inhibition or genetic deficiency of various hepatobiliary transporter systems. The following drugs cause cholestasis: anabolic steroids containing an alkyl or ethinyl group at carbon 17, azathioprine, cetirizine, cyclosporine, diclofenac, estrogens, febuxostat, indinavir (increased risk of indirect hyperbilirubinemia in patients with Gilbert syndrome), mercaptopurine, methyltestosterone, tamoxifen, temozolomide, and ticlopidine.
The following drugs cause inflammation of portal areas with bile duct injury (cholangitis), often with allergic features such as eosinophilia: amoxicillin-clavulanic acid (among the most common causes of drug-induced liver injury), azathioprine, azithromycin, captopril, celecoxib, cephalosporins, chlorothiazide, chlorpromazine, chlorpropamide, erythromycin, mercaptopurine, penicillamine, prochlorperazine, semisynthetic penicillins (eg, cloxacillin), and sulfadiazine. Ketamine abuse may cause secondary biliary cirrhosis. Cholestatic and mixed cholestatic-hepatocellular toxicity is more likely than pure hepatocellular toxicity to lead to chronic liver disease.
B. Acute or Chronic Hepatitis
Medications that may result in acute or chronic hepatitis that is histologically and in some cases clinically similar to autoimmune hepatitis include minocycline and nitrofurantoin, most commonly, as well as aspirin, isoniazid (increased risk in HBV and HCV carriers), methyldopa, nonsteroidal anti-inflammatory drugs, propylthiouracil, terbinafine, tumor necrosis factor inhibitors, and varenicline. Histologic features that favor a drug cause include portal tract neutrophils and hepatocellular cholestasis. Hepatitis also can occur in patients taking cocaine, diclofenac, dimethyl fumarate, efavirenz, imatinib mesylate, ipilimumab, methylenedioxymethamphetamine (MDMA; Ecstasy), nafazodone (has a black box warning for a potential to cause liver failure), nevirapine (like other protease inhibitors, increased risk in HBV and HCV carriers), pioglitazone, ritonavir (greater rate than other protease inhibitors), rosiglitazone, saquinavir, sulfonamides, telithromycin, and zafirlukast, as well as a variety of alternative remedies (eg, chaparral, germander, green tea extracts, Herbalife products, Hydroxycut, jin bu huan, kava, saw palmetto, skullcap, possibly black cohosh, and other traditional Chinese herbal preparations), in addition to dietary supplements (eg, 1, 3-dimethylamylamine in OxyELITE Pro, a weight-loss supplement withdrawn from the US market). In patients with jaundice due to drug-induced hepatitis, the mortality rate without liver transplantation is at least 10%.
This type of liver injury may be produced by alcohol, amiodarone, corticosteroids, irinotecan, methotrexate, tamoxifen, vinyl chloride (in exposed workers), zalcitabine, and possibly oxaliplatin.
Often resulting from mitochondrial injury, this condition is associated with didanosine, stavudine, tetracyclines, valproic acid, and zidovudine.
Allopurinol, phenytoin, pyrazinamide, quinidine, and quinine can lead to granulomas.
3. Fibrosis and cirrhosis
Methotrexate and vitamin A are associated with fibrosis and cirrhosis.
4. Sinusoidal obstruction syndrome (veno-occlusive disease)
This disorder may result from treatment with antineoplastic agents (eg, pre–bone marrow transplant, oxaliplatin), and pyrrolizidine alkaloids (eg, Comfrey).
5. Peliosis hepatis (blood-filled cavities)
Peliosis hepatis may be caused by anabolic steroids and oral contraceptive steroids as well as azathioprine and mercaptopurine, which may also cause nodular regenerative hyperplasia.
Neoplasms may result from therapy with oral contraceptive steroids, including estrogens (hepatic adenoma but not focal nodular hyperplasia) and vinyl chloride (angiosarcoma).
Refer patients with drug- and toxin-induced hepatitis who require liver biopsy for diagnosis.
Patients with liver failure should be hospitalized.
et al. Identification and characterization of cefazolin-induced liver injury. Clin Gastroenterol Hepatol. 2015 Jul;13(7):1328–36.
et al. Categorization of drugs implicated in causing liver injury: critical assessment based on published case reports. Hepatology. 2016 Feb;63(2):590–603.
et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950–66.
et al. Drug-induced liver injury in patients with preexisting chronic liver disease in drug development: how to identify and manage? Gastroenterology. 2016 Dec;151(6):1046–51.
et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology. 2015 Jun;148(7):1340–52.
et al. A model to predict severity of drug-induced liver injury in humans. Hepatology. 2016 Sep;64(3):931–40.
et al. Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug- induced liver injury. Am J Gastroenterol. 2015 Oct;110(10):1450–9.
et al. Severe acute hepatocellular injury attributed to OxyELITE Pro: a case series. Dig Dis Sci. 2016 Sep;61(9):2741–8.
et al. Severe drug-induced liver injury related to therapy with dimethyl fumarate. Hepatology. 2016 Oct;64(4):1367–9.
et al. Risk of acute liver failure in patients with drug-induced liver injury: evaluation of Hy's law and a new prognostic model. Clin Gastroenterol Hepatol. 2015 Dec;13(13):2360–8.
et al. Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol. 2015 Feb;13(2):369–76.
et al. Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury. J Hepatol. 2016 Sep;65(3):532–42.
et al. Herbal products and the liver: a review of adverse effects and mechanisms. Gastroenterology. 2015 Mar;148(3):517–32.
et al. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2015 May;41(10):972–9.
NONALCOHOLIC FATTY LIVER DISEASE
Nonalcoholic fatty liver disease (NAFLD) is estimated to affect 20–45% of the US population and is increasing in prevalence. The principal causes of NAFLD are obesity (present in 40% or more of affected patients), diabetes mellitus (in 20% or more), and hypertriglyceridemia (in 20% or more) in association with insulin resistance as part of the metabolic syndrome. The risk of NAFLD in persons with metabolic syndrome is 4 to 11 times higher than that of persons without insulin resistance. Other causes of fatty liver include corticosteroids, amiodarone, diltiazem, tamoxifen, irinotecan, oxaliplatin, antiretroviral therapy, toxins (vinyl chloride, carbon tetrachloride, yellow phosphorus), endocrinopathies such as Cushing syndrome and hypopituitarism, polycystic ovary syndrome, hypothyroidism, hypobetalipoproteinemia and other metabolic disorders, obstructive sleep apnea (with chronic intermittent hypoxia), excessive dietary fructose consumption, starvation and refeeding syndrome, and total parenteral nutrition. Genetic factors, including polymorphisms of the gene that encodes apolipoprotein C3, are likely to play a role, and polymorphisms of the patatin-like phospholipase domain containing 3 (PNPLA3) gene modify the natural history of NAFLD and may account in part for an increased risk in Hispanics. A polymorphism of TM6SF2 is associated with advanced fibrosis and cirrhosis. The risk of NAFLD is increased in persons with psoriasis and appears to correlate with the activity of psoriasis. Soft drink consumption and cholecystectomy have been reported to be associated with NAFLD. Physical activity protects against the development of NAFLD.
In addition to macrovesicular steatosis, histologic features may include focal infiltration by polymorphonuclear neutrophils and Mallory hyalin, a picture indistinguishable from that of alcoholic hepatitis and referred to as nonalcoholic steatohepatitis (NASH), which affects 3–5% of the US population. In patients with NAFLD, older age, obesity, and diabetes mellitus are risk factors for advanced hepatic fibrosis and cirrhosis, whereas coffee consumption reduces the risk. Cirrhosis caused by NASH appears to be uncommon in African Americans. Persons with NAFLD are at increased risk for cardiovascular disease, chronic kidney disease, and colorectal cancer.
Microvesicular steatosis is seen with Reye syndrome, didanosine or stavudine toxicity, valproic acid toxicity, high-dose tetracycline, or acute fatty liver of pregnancy and may result in acute liver failure. Women in whom fatty liver of pregnancy develops often have a defect in fatty acid oxidation due to reduced long-chain 3-hydroxyacyl-CoA dehydrogenase activity.
Most patients with NAFLD are asymptomatic or have mild right upper quadrant discomfort. Hepatomegaly is present in up to 75% of patients, but stigmata of chronic liver disease are uncommon. Rare instances of subacute liver failure caused by previously unrecognized NASH have been described. Signs of portal hypertension generally signify advanced liver fibrosis or cirrhosis but occasionally occur in patients with mild and no fibrosis and severe steatosis.
Laboratory studies may show mildly elevated aminotransferase and alkaline phosphatase levels; however, laboratory values may be normal in up to 80% of persons with hepatic steatosis. In contrast to alcoholic liver disease, the ratio of ALT to AST is almost always greater than 1 in NAFLD, but it decreases to less than 1 as advanced fibrosis and cirrhosis develop. Antinuclear or smooth muscle antibodies and an elevated serum ferritin level may each be detected in one-fourth of patients with NASH. Elevated serum ferritin levels may signify so-called dysmetabolic iron overload syndrome and mildly increased body iron stores, which may play a causal role in insulin resistance and oxidative stress in hepatocytes and correlate with advanced fibrosis; the frequency of mutations in the HFE gene for hemochromatosis is not increased in patients with NAFLD. Iron deficiency is also common and associated with female sex, obesity, increased waist circumference, diabetes mellitus, and black or Native American race.
Macrovascular steatosis may be demonstrated on ultrasonography, CT, or MRI. However, imaging does not distinguish steatosis from steatohepatitis or detect fibrosis. Where available, magnetic resonance spectroscopy allows hepatic fat content to be quantitated; ultrasound elastography to assess liver stiffness can be used to estimate hepatic fibrosis.
Percutaneous liver biopsy is diagnostic and is the standard approach to assessing the degree of inflammation and fibrosis (eFigure 16–16). The risks of the procedure must be balanced against the impact of the added information on management decisions and assessment of prognosis. Liver biopsy is generally not recommended in asymptomatic persons with unsuspected hepatic steatosis detected on imaging but normal liver biochemistry test results. The histologic spectrum of NAFLD includes fatty liver, isolated portal fibrosis, steatohepatitis, and cirrhosis. A risk score for predicting advanced fibrosis, known as BARD, is based on body mass index more than 28, AST/ALT ratio 0.8 or more, and diabetes mellitus; it has a 96% negative predictive value (ie, a low score reliably excludes advanced fibrosis). Another risk score for advanced fibrosis, the NAFLD Fibrosis Score (http://nafldscore.com) based on age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio, has a positive predictive value of over 80% and identifies patients at increased risk for liver-related complications and death. A clinical scoring system to predict the likelihood of NASH in morbidly obese persons includes six predictive factors: hypertension, type 2 diabetes mellitus, sleep apnea, AST greater than 27 units/L (0.54 mckat/L), ALT greater than 27 units/L (0.54 mckat/L), and non-black race.
Nonalcoholic steatohepatitis (NASH). Liver biopsy histology demonstrates diffuse steatosis as well as ballooning degeneration of hepatocytes (circles). (Used, with permission, from James P. Grenert, MD.)
Treatment consists of lifestyle changes to remove or modify the offending factors. Weight loss, dietary fat restriction, and even moderate exercise (through reduction of abdominal obesity) often lead to improvement in liver biochemical tests and steatosis in obese patients with NAFLD. Loss of 3–5% of body weight appears necessary to improve steatosis, but loss of at least 10% may be needed to improve necroinflammation and fibrosis. Exercise may reduce liver fat with minimal or no weight loss and no reduction in ALT levels. Resistance training and aerobic exercise are equally effective in reducing hepatic fat content in patients with NAFLD and type 2 diabetes mellitus. Various drugs are under study. Vitamin E 800 international units/day (to reduce oxidative stress) appears to be of benefit in patients with NASH who do not have diabetes mellitus; there is concern that vitamin E may increase the risk of prostate cancer in men. Thiazolidinediones reverse insulin resistance and, in most relevant studies, have improved both serum aminotransferase levels and histologic features of steatohepatitis but lead to weight gain. Metformin, which reduces insulin resistance, improves abnormal liver chemistries but may not reliably improve liver histology. Pentoxifylline improves liver biochemical test levels but is associated with a high rate of side effects, particularly nausea. Ursodeoxycholic acid, 12–15 mg/kg/day, has not consistently resulted in biochemical and histologic improvement in patients with NASH but may be effective when given in combination with vitamin E. Hepatic steatosis due to total parenteral nutrition may be ameliorated—and perhaps prevented—with supplemental choline. Other approaches under study include obeticholic acid, a semisynthetic bile acid analog that has been approved for the treatment of primary biliary cholangitis as well as orlistat, an inhibitor of gastrointestinal lipases; recombinant human leptin; liraglutide, a glucagon-like protein-1-analog that promotes insulin secretion; L-carnitine, which regulates the turnover of fatty acids in phospholipid membranes; omega-3 fatty acids, which alter hepatic gene expression to favor fatty acid oxidation over lipogenesis; probucol, a lipid-lowering agent; elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta; losartan, an angiotensin antagonist; selective caspase inhibitors; and iron depletion therapy. Statins are not contraindicated in persons with NAFLD and may protect against histologic progression in some patients. Bariatric surgery may be considered in patients with a body mass index greater than 35 and leads to histologic regression of NASH in most patients. Liver transplantation is indicated in appropriate candidates with advanced cirrhosis caused by NASH, now the third most common (and most rapidly increasing) indication for liver transplantation in the United States. Liver transplantation for NASH with advanced cirrhosis may be associated with increased mortality from cardiovascular disease and sepsis compared with liver transplantation for other indications.
Fatty liver often has a benign course and is readily reversible with discontinuation of alcohol (or no more than one glass of wine per day, which may actually reduce the frequency of NASH in persons with NAFLD), or treatment of other underlying conditions; if untreated, fibrosis progresses at an average rate of 1 stage every 14 years, with a subset progressing more rapidly. In patients with NAFLD, the likelihood of NASH is increased by the following factors: obesity, older age, non–African American ethnicity, female sex, diabetes mellitus, hypertension, higher ALT or AST level, higher AST/ALT ratio, low platelet count, elevated fasting C-peptide level, and a high ultrasound steatosis score. NASH may be associated with hepatic fibrosis in 40% of cases with progression at a rate of 1 stage every 7 years; cirrhosis develops in 9–25%; and decompensated cirrhosis occurs in 30–50% of cirrhotic patients over 10 years. The course may be more aggressive in diabetic persons than in nondiabetic persons. Mortality is increased in patients with NAFLD, correlates with fibrosis stage, and is more likely to be the result of malignancy and cardiovascular disease than liver disease. Risk factors for mortality are older age, male sex, white race, smoking, higher body mass index, hypertension, diabetes mellitus, and cirrhosis. Steatosis is a cofactor for the progression of fibrosis in patients with other causes of chronic liver disease, such as hepatitis C. Hepatocellular carcinoma is a complication of cirrhosis caused by NASH, as it is for other causes of cirrhosis, and has been reported even in the absence of cirrhosis. NASH accounts for a substantial percentage of cases labeled as cryptogenic cirrhosis and can recur following liver transplantation. Central obesity is an independent risk factor for death from cirrhosis of any cause.
Refer patients with NAFLD who require liver biopsy for diagnosis.
et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015 Aug;149(2):389–97.
et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016 Feb 13;387(10019):679–90.
et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016 Sep 6;165(5):305–15.
et al. Statin use and non-alcoholic steatohepatitis in at-risk individuals. J Hepatol. 2015 Sep;63(3):705–12.
et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015 May;61(5):1547–54.
European Association for the Study of the Liver (EASL). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64(6):1388–402.
et al. Non-alcoholic fatty liver disease and cardiovascular risk: pathophysiological mechanisms and implications. J Hepatol. 2016 Aug;65(2):425–43.
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et al. Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2016 Dec;64(6):2234–43.
et al. Trends in the burden of nonalcoholic fatty liver disease in a United States cohort of veterans. Clin Gastroenterol Hepatol. 2016 Feb;14(2):301–8.
et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015 Aug;149(2):379–88.
et al. Perspectives on treatment for nonalcoholic steatohepatitis. Gastroenterology. 2016 Jun;150(8):1835–48.
et al. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice. Hepatology. 2016 Jun;63(6):2032–43.
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ESSENTIALS OF DIAGNOSIS
End result of injury that leads to both fibrosis and regenerative nodules.
May be reversible if cause is removed.
The clinical features result from hepatic cell dysfunction, portosystemic shunting, and portal hypertension.
Cirrhosis, the eighth leading cause of death in the United States with a prevalence rate of 0.27%, is the end result of hepatocellular injury that leads to both fibrosis and regenerative nodules throughout the liver. Hospitalization rates for cirrhosis and portal hypertension are rising in the United States. Causes include chronic viral hepatitis, alcohol, drug toxicity, autoimmune and metabolic liver diseases, and miscellaneous disorders. Celiac disease appears to be associated with an increased risk of cirrhosis. Many patients have more than one risk factor (eg, chronic hepatitis and alcohol use). Mexican Americans and African Americans have a higher frequency of cirrhosis than whites because of a higher rate of risk factors. In persons at increased risk for liver injury (eg, heavy alcohol use, obesity, iron overload), higher coffee and tea consumption reduces the risk of cirrhosis. The risk of hospitalization or death due to cirrhosis has been reported to correlate with protein and cholesterol consumption and with hyperuricemia and inversely with carbohydrate consumption.
The most common histologic classification divides cirrhosis into micronodular, macronodular, and mixed forms. These are descriptive terms rather than separate diseases, and each form may be seen in the same patient at different stages of the disease. In micronodular cirrhosis—typical of alcoholic liver disease (Laennec cirrhosis)—the regenerative nodules (eFigure 16–17) are no larger than the original lobules, ie, approximately 1 mm in diameter or less. Macronodular cirrhosis is characterized by larger nodules, which can measure several centimeters in diameter and may contain central veins (eFigure 16–18). This form corresponds more or less to postnecrotic (posthepatitic) cirrhosis but does not necessarily follow episodes of massive necrosis and stromal collapse. Clinically, cirrhosis is considered to progress through three stages that correlate with the thickness of fibrous septa: compensated, compensated with varices, and decompensated (ascites, variceal bleeding, encephalopathy, or jaundice).
Micronodular cirrhosis: Trichome stain of a liver biopsy specimen from a 33-year-old man with cirrhosis shows regenerative nodules (circle) surrounded by fibrosis (arrows) bridging from portal tracts to adjacent portal tracts and central veins. (Used, with permission, from James P. Grenert, MD.)
Cirrhosis: macronodular and postnecrotic (low power).
The clinical features of cirrhosis result from hepatocyte dysfunction, portosystemic shunting, and portal hypertension. Patients may have no symptoms for long periods. The onset of symptoms may be insidious or, less often, abrupt (eFigure 16–19). Fatigue, disturbed sleep, muscle cramps, and weight loss are common. In advanced cirrhosis, anorexia is usually present and may be extreme, with associated nausea and occasional vomiting, as well as reduced muscle strength and exercise capacity. Abdominal pain may be present and is related either to hepatic enlargement and stretching of Glisson capsule or to the presence of ascites (eFigure 16–20). Menstrual abnormalities (usually amenorrhea), erectile dysfunction, loss of libido, sterility, and gynecomastia may occur. Hematemesis is the presenting symptom in 15–25%. The risk of falls is increased in hospitalized patients with cirrhosis who are taking psychoactive medications.
Clinical effects of cirrhosis of the liver. (Reproduced, with permission, from Chandrasoma P, Taylor CE. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
Umbilical hernia from severe ascites in decompensated cirrhosis. In addition to marked abdominal distention and bulging flanks, umbilical hernias often develop as a consequence of increased intra-abdominal pressure in severe cases of cirrhotic ascites. (Used, with permission, from Neil Mehta, MD.)
Skin manifestations consist of spider telangiectasias (invariably on the upper half of the body) (eFigures 16–21 and 16–22) (see eFigure 16–3), palmar erythema (mottled redness of the thenar and hypothenar eminences) (eFigure 16–23) (see eFigure 16–4), and Dupuytren contractures. Evidence of vitamin deficiencies (glossitis and cheilosis) is common. Weight loss, wasting (due to sarcopenia), and the appearance of chronic illness are present. Jaundice—usually not an initial sign—is mild at first, increasing in severity during the later stages of the disease (see eFigure 16–1). In 70% of cases, the liver is enlarged, palpable, and firm if not hard and has a sharp or nodular edge; the left lobe may predominate. Splenomegaly is present in 35–50% of cases and is associated with an increased risk of complications of portal hypertension. The superficial veins of the abdomen (eFigure 16–24) and thorax are dilated, reflecting the intrahepatic obstruction to portal blood flow, as do rectal varices. The abdominal wall veins fill from below when compressed. Ascites, pleural effusions, peripheral edema, and ecchymoses are late findings. Encephalopathy, characterized by day-night reversal, asterixis, tremor, dysarthria, delirium, drowsiness and, ultimately coma also occurs late in the course except when precipitated by an acute hepatocellular insult or an episode of gastrointestinal bleeding or infection. Fever is present in up to 35% of patients and usually reflects associated alcoholic hepatitis, spontaneous bacterial peritonitis, or another intercurrent infection.
Spider telangiectasias of the thoracic wall in chronic liver disease. The small dilated blood vessels seen in patients with liver disease are called spider telangiectasias because they tend to radiate outward resembling a spider's web. (Used, with permission, from Neil Mehta, MD.)
Spider telangiectasias of the face in chronic liver disease. When these small dilated blood vessels near the skin surface appear on the face, they are usually around the nose (as seen here) or on the cheeks. (Used, with permission, from Neil Mehta, MD.)
Palmar erythema in chronic liver disease. Palmar erythema refers to reddening of the palms, specifically of the thenar and hypothenar eminences (arrows) and of the fingertips. This is a consequence of elevated circulating estrogen levels in chronic liver disease. (Used, with permission, from Neil Mehta, MD.)
Caput medusae in cirrhosis. A consequence of portal hypertension, distended and engorged superficial paraumbilical veins (arrows) that radiate from the umbilicus across the abdomen to join systemic veins, are referred to as a caput medusa (Latin for "head of Medusa"). (Used, with permission, from Neil Mehta, MD.)
Laboratory abnormalities are either absent or minimal in early or compensated cirrhosis. Anemia, a frequent finding, is often macrocytic; causes include suppression of erythropoiesis by alcohol as well as folate deficiency, hemolysis, hypersplenism, and occult or overt blood loss from the gastrointestinal tract. The white blood cell count may be low, reflecting hypersplenism, or high, suggesting infection. Thrombocytopenia, the most common cytopenia in cirrhotic patients, is secondary to alcoholic marrow suppression, sepsis, folate deficiency, or splenic sequestration. Prolongation of the prothrombin time may result from reduced levels of clotting factors (except factor VIII). However, bleeding risk correlates poorly with the prothrombin time because of concomitant abnormalities of fibrinolysis, and among hospitalized patients under age 45, cirrhosis is associated with an increased risk of venous thromboembolism.
Blood chemistries reflect hepatocellular injury and dysfunction, manifested by modest elevations of AST and alkaline phosphatase and progressive elevation of the bilirubin. Serum albumin decreases as the disease progresses; gamma-globulin levels are increased and may be as high as in autoimmune hepatitis. The risk of diabetes mellitus is increased in patients with cirrhosis, particularly when associated with HCV infection, alcoholism, hemochromatosis, or NAFLD. Vitamin D deficiency has been reported in as many as 91% of patients with cirrhosis. Patients with alcoholic cirrhosis may have elevated serum cardiac troponin I and B-type natriuretic peptide (BNP) levels. Blunted cardiac inotropic and chronotropic responses to exercise, stress, and drugs, as well as systolic and diastolic ventricular dysfunction in the absence of other known causes of cardiac disease (“cirrhotic cardiomyopathy”), and prolongation of the QT interval in the setting of a hyperkinetic circulation, are common in cirrhosis of all causes, but overt heart failure is rare in the absence of alcoholism. Relative adrenal insufficiency appears to be common in patients with advanced cirrhosis, even in the absence of sepsis, and may relate in part to reduced synthesis of cholesterol and increased levels of proinflammatory cytokines.
Ultrasonography is helpful for assessing liver size and detecting ascites or hepatic nodules, including small hepatocellular carcinomas (eFigures 16–25 and 16–26). Together with a Doppler study, it may establish patency of the splenic, portal, and hepatic veins (eFigure 16–27). Hepatic nodules are characterized further by contrast-enhanced CT (eFigure 16–28) or MRI. Nodules suspicious for malignancy may be biopsied under ultrasound or CT guidance.
Cirrhosis. Ultrasonogram shows increased echogenicity in the liver (L). Arrowhead shows ascitic fluid. (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)
Cirrhosis. A: Longitudinal ultrasonogram through the right upper abdomen in a patient with alcoholic liver disease. A markedly nodular liver (arrows) is seen in addition to a large amount of ascites (A). B: Transverse ultrasonogram from the same patient in which dilated tortuous vessels (arrows) adjacent to the spleen (S) are seen. These are typical for splenic varices in a patient with portal hypertension. (Courtesy of Peter W. Callen, MD.)
Portal hypertension. Color flow Doppler of the caput medusae (CM) (A) and recanalized ligamentum teres (LT) (B) shows the presence of blood flow. (Reprinted, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)
Cirrhosis. Contrast-enhanced CT demonstrates the classic features of cirrhosis–a nodular contour to the liver (yellow arrows) along with features of portal hypertension including ascites (red arrow), splenomegaly (black arrow), and distal esophageal varices (green arrow). (Used, with permission, from Nicholas Fidelman, MD.)
Liver biopsy may show inactive cirrhosis (fibrosis with regenerative nodules) with no specific features to suggest the underlying cause. Alternatively, there may be additional features of alcoholic liver disease, chronic hepatitis, NASH, or other specific causes of cirrhosis. Liver biopsy may be performed by laparoscopy or, in patients with coagulopathy and ascites, by a transjugular approach. Combinations of routine blood tests (eg, AST, platelet count), including the FibroSure test, serum markers of hepatic fibrosis (eg, hyaluronic acid, amino-terminal propeptide of type III collagen, tissue inhibitor of matrix metalloproteinase 1), and ultrasound or magnetic resonance elastography are potential alternatives to liver biopsy for the diagnosis or exclusion of cirrhosis. In persons with chronic hepatitis C, for example, a low FibroSure or elastography score reliably excludes advanced fibrosis, a high score reliably predicts advanced fibrosis, and intermediate scores are inconclusive.
Esophagogastroduodenoscopy confirms the presence of varices and detects specific causes of bleeding in the esophagus, stomach, and proximal duodenum. In selected cases, wedged hepatic vein pressure measurement may establish the presence and cause of portal hypertension.
The most common causes of cirrhosis are alcohol, chronic hepatitis C infection, NAFLD, and hepatitis B infection. The prevalence of NAFLD has been increasing steadily because of the rapidly increasing prevalence of obesity in the United States. Hemochromatosis is the most commonly identified genetic disorder that causes cirrhosis. Other diseases associated with cirrhosis include Wilson disease, alpha-1-antitrypsin (alpha-1-antiprotease) deficiency (eFigure 16–29), and celiac disease. PBC occurs more frequently in women than men. Secondary biliary cirrhosis may result from chronic biliary obstruction due to a stone, stricture, or neoplasm. Heart failure and constrictive pericarditis may lead to hepatic fibrosis (“cardiac cirrhosis”) complicated by ascites. Hereditary hemorrhagic telangiectasia can lead to portal hypertension because of portosystemic shunting and nodular transformation of the liver as well as high-output heart failure. Many cases of cirrhosis are “cryptogenic,” in which unrecognized NAFLD may play a role. Mutations in the gene encoding cytokeratin 8 have been associated with some cases of cryptogenic cirrhosis, and mutations that decrease the activity of telomerase and lead to shortening of telomeres accelerate progression of fibrosis in patients with chronic liver disease.
Upper gastrointestinal tract bleeding may occur from varices, portal hypertensive gastropathy (eFigure 16–30), or gastroduodenal ulcer (see Chapter 15). Varices may also result from portal vein thrombosis, which may complicate cirrhosis. Liver failure may be precipitated by alcoholism, surgery, and infection. Hepatic Kupffer cell (reticuloendothelial) dysfunction and decreased opsonic activity lead to an increased risk of systemic infection (which may be increased further by the use of proton pump inhibitors), and which increase mortality fourfold. These infections include nosocomial infections, which may be classified as spontaneous bloodstream infections, urinary tract infections, pulmonary infections, spontaneous bacterial peritonitis, Clostridium difficile infection, and intervention-related infections. These nosocomial infections are increasingly caused by multidrug-resistant bacteria. Osteoporosis occurs in 12–55% of patients with cirrhosis. The risk of hepatocellular carcinoma is increased greatly in persons with cirrhosis (see Chapter 39). Varices, ascites, and encephalopathy may arise when there is clinically significant portal hypertension (hepatic venous pressure gradient greater than 10 mm Hg).
Portal hypertensive gastropathy. Classic endoscopic "snake skin" appearance of portal hypertensive gastropathy, a common cause of chronic gastrointestinal bleeding in patients with cirrhosis. (Used, with permission, from Neil Mehta, MD.)
Most important is abstinence from alcohol. The diet should be palatable, with adequate calories (25–35 kcal/kg body weight per day in those with compensated cirrhosis and 35–45 kcal/kg/day in those with malnutrition) and protein (1–1.5 g/kg/day in those with compensated cirrhosis and 1.5 g/kg/day in those with malnutrition) and, if there is fluid retention, sodium restriction. In the presence of hepatic encephalopathy, protein intake should be reduced to no less than 60–80 g/day. Specialized supplements containing branched-chain amino acids to prevent or treat hepatic encephalopathy or delay progressive liver failure are generally unnecessary. Vitamin supplementation is desirable. Muscle cramps may be helped by L-carnitine, 300 mg orally four times a day. Patients with cirrhosis should receive the HAV, HBV, and pneumococcal vaccines and a yearly influenza vaccine. Liver transplantation in appropriate candidates is curative, and pharmacologic treatments to halt progression of or even reverse cirrhosis are being developed. Care coordination and palliative care, when appropriate, have been shown to improve outcomes and reduce readmission rates.
B. Treatment of Complications
Diagnostic paracentesis is indicated for patients who have new ascites or who have been hospitalized for a complication of cirrhosis; it reduces mortality, especially if performed within 12 hours of admission (eFigures 16–31 and 16–32). Serious complications of paracentesis, including bleeding, infection, or bowel perforation, occur in 1.6% of procedures and are associated with therapeutic (vs diagnostic) paracentesis and possibly with Child-Pugh class C, a platelet count less than 50,000/mcL (50 × 109/L), and alcoholic cirrhosis. In patients with coagulopathy, however, pre-paracentesis prophylactic transfusions do not appear to be necessary. In addition to a cell count and culture, the ascitic albumin level should be determined: a serum-ascites albumin gradient (serum albumin minus ascitic fluid albumin) greater than or equal to 1.1 suggests portal hypertension. An elevated ascitic adenosine deaminase level is suggestive of tuberculous peritonitis, but the sensitivity of the test is reduced in patients with portal hypertension. Occasionally, cirrhotic ascites is chylous (rich in triglycerides); other causes of chylous ascites are malignancy, tuberculosis, and recent abdominal surgery or trauma.
Position of patient for paracentesis. (Reproduced, with permission, from Chesnutt MS et al. Office & Bedside Procedures. Originally published by Appleton & Lange. Copyright © 1992 by The McGraw-Hill Companies, Inc.)
Aspiration of peritoneal fluid. (Reproduced, with permission, from Chesnutt MS et al. Office & Bedside Procedures. Originally published by Appleton & Lange. Copyright © 1992 by The McGraw-Hill Companies, Inc.)
Ascites in patients with cirrhosis results from portal hypertension (increased hydrostatic pressure); hypoalbuminemia (decreased oncotic pressure); peripheral vasodilation, perhaps mediated by endotoxin-induced release of nitric oxide from splanchnic and systemic vasculature, with resulting increases in renin and angiotensin levels and sodium retention by the kidneys; impaired hepatic inactivation of aldosterone; and increased aldosterone secretion secondary to increased renin production (eFigure 16–33). In individuals with ascites, the urinary sodium concentration is often less than 10 mEq/L (10 mmol/L). Free water excretion is also impaired in cirrhosis, and hyponatremia may develop.
Hypotheses put forward to explain the pathophysiology of ascites formation in patients with liver disease. Hypotheses involving actual or effective intravascular volume depletion in triggering ascites formation: (1) "underfilling" hypothesis; (2) "peripheral vasodilation" hypothesis. Hypotheses involving inappropriate increased renal sodium retention: (3) increased sympathetic tone; (4) increased endothelin-1 secretion; unknown hepatic product working directly (5) or indirectly via antagonism of atrial natriuretic peptide (6) or mechanisms (3) or (4) to trigger renal sodium retention. Regardless of the initiating mechanism, once ascites has formed, response to actual or effective intravascular volume depletion triggers (7) and (8). (Reproduced, with permission, from McPhee SJ et al [editors]. Pathophysiology of Disease: An Introduction to Clinical Medicine, 3rd ed. McGraw-Hill, 1999.)
In all patients with cirrhotic ascites, dietary sodium intake may initially be restricted to 2000 mg/day; the intake of sodium may be liberalized slightly after diuresis ensues. Nonsteroidal anti-inflammatory drugs are contraindicated, and angiotensin-converting enzyme inhibitors and angiotensin II antagonists should be avoided. In some patients, ascites diminishes promptly with bed rest and dietary sodium restriction alone. Fluid intake is often restricted (to 800–1000 mL/day) in patients with hyponatremia. Treatment of severe hyponatremia (serum sodium less than 125 mEq/L [125 mmol/L]) with vasopressin receptor antagonists (eg, intravenous conivaptan, 20 mg daily) can be considered but such treatment is expensive, causes thirst, and does not improve survival; oral tolvaptan is contraindicated in patients with liver disease because of potential hepatotoxicity.
Spironolactone, generally in combination with furosemide, should be used in patients who do not respond to salt restriction alone. An initial trial of furosemide 80 mg intravenously demonstrating a rise in urine sodium to 750 mmol in 8 hours may predict response to diuretic therapy. The dose of spironolactone is initially 100 mg orally daily and may be increased by 100 mg every 3–5 days (up to a maximal conventional daily dose of 400 mg/day, although higher doses have been used) until diuresis is achieved, typically preceded by a rise in the urinary sodium concentration. A “spot” urine sodium concentration that exceeds the potassium concentration correlates with a 24-hour sodium excretion greater than 78 mmol/day, which predicts diuresis in patients adherent to a salt-restricted diet. Monitoring for hyperkalemia is important. In patients who cannot tolerate spironolactone because of side effects, such as painful gynecomastia, amiloride (another potassium-sparing diuretic) may be used in a starting dose of 5–10 mg orally daily. Diuresis is augmented by the addition of a loop diuretic such as furosemide. This potent diuretic, however, will maintain its effect even with a falling glomerular filtration rate, with resulting prerenal azotemia. The dose of oral furosemide ranges from 40 mg/day to 160 mg/day, and blood pressure, urinary output, mental status, and serum electrolytes (especially potassium) should be monitored in patients taking the drug. The goal of weight loss in the ascitic patient without associated peripheral edema should be no more than 1–1.5 lb/day (0.5–0.7 kg/day).
b. Large-volume paracentesis
In patients with massive ascites and respiratory compromise, ascites refractory to diuretics (“diuretic resistant”), or intolerable diuretic side effects (“diuretic intractable”), large-volume paracentesis (more than 5 L) is effective. Intravenous albumin concomitantly at a dosage of 6–8 g/L of ascites fluid removed protects the intravascular volume and may prevent postparacentesis circulatory dysfunction, although the usefulness of this practice is debated and the use of albumin is expensive. Large-volume paracentesis can be repeated daily until ascites is largely resolved and may decrease the need for hospitalization. If possible, diuretics should be continued in the hope of preventing recurrent ascites.
c. Transjugular intrahepatic portosystemic shunt (tips)
TIPS is an effective treatment of variceal bleeding refractory to standard therapy (eg, endoscopic band ligation) and has shown benefit in the treatment of severe refractory ascites. The technique involves insertion of an expandable metal stent between a branch of the hepatic vein and the portal vein over a catheter inserted via the internal jugular vein. Increased renal sodium excretion and control of ascites refractory to diuretics can be achieved in about 75% of selected cases. The success rate is lower in patients with underlying chronic kidney disease. TIPS appears to be the treatment of choice for refractory hepatic hydrothorax (translocation of ascites across the diaphragm to the pleural space); video-assisted thoracoscopy with pleurodesis using talc may be effective when TIPS is contraindicated. Complications of TIPS include hepatic encephalopathy in 20–30% of cases, infection, shunt stenosis in up to 60% of cases, and shunt occlusion in up to 30% of cases when bare stents are used; polytetrafluoroethylene-covered stents are associated with long-term patency rates of 80–90%. Long-term patency often requires periodic shunt revisions. In most cases, patency can be maintained by balloon dilation, local thrombolysis, or placement of an additional stent. TIPS is particularly useful in patients who require short-term control of variceal bleeding or ascites until liver transplantation can be performed. In patients with refractory ascites, TIPS results in lower rates of ascites recurrence and hepatorenal syndrome but a higher rate of hepatic encephalopathy than occurs with repeated large-volume paracentesis; a benefit in survival has been demonstrated in one study and a meta-analysis. Chronic kidney disease, diastolic cardiac dysfunction, refractory encephalopathy, and hyperbilirubinemia (greater than 5 mg/dL [85.5 mcmol/L]) are associated with mortality after TIPS.
d. Peritoneovenous shunts
Peritoneovenous shunts are sometimes placed in patients with malignant ascites but are no longer used for refractory cirrhotic ascites because of a considerable complication rate: disseminated intravascular coagulation in 65% of patients (25% symptomatic; 5% severe), bacterial infections in 4–8%, heart failure in 2–4%, and variceal bleeding from sudden expansion of intravascular volume. TIPS is now preferred for refractory ascites.
2. Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis is heralded by abdominal pain, increasing ascites, fever, and progressive encephalopathy in a patient with cirrhotic ascites; symptoms are typically mild. (Analogously, spontaneous bacterial empyema may complicate hepatic hydrothorax and is managed similarly.) Risk factors in cirrhotic patients with ascites include gastroesophageal variceal bleeding and possibly use of a proton pump inhibitor. Paracentesis reveals an ascitic fluid with, most commonly, a total white cell count of up to 500 cells/mcL with a high polymorphonuclear (PMN) cell count (250/mcL or more) and a protein concentration of 1 g/dL (10 g/L) or less, corresponding to decreased ascitic opsonic activity. Rapid diagnosis of bacterial peritonitis can be made with a high degree of specificity with rapid reagent strips ("dipsticks") that detect leukocyte esterase in ascitic fluid, but the sensitivity is too low for routine use. Cultures of ascites give the highest yield—80–90% positive—using specialized culture bottles inoculated at the bedside. Common isolates are Escherichia coli and Streptococcus spp. Gram-positive cocci are the most common isolates in patients who have undergone an invasive procedure such as central venous line placement, and the frequency of enterococcal isolates is increasing. Anaerobes are uncommon. Pending culture results, if there are 250 or more PMNs/mcL or symptoms or signs of infection, intravenous antibiotic therapy should be initiated with cefotaxime, 2 g every 8–12 hours for at least 5 days. Alternative choices include ceftriaxone, amoxicillin-clavulanic acid, and levofloxacin (in patients not receiving fluoroquinolone prophylaxis). Oral ofloxacin, 400 mg twice daily for 7 days, or, in a patient not already taking a fluoroquinolone for prophylaxis against bacterial peritonitis, a 2-day course of intravenous ciprofloxacin, 200 mg twice daily, followed by oral ciprofloxacin, 500 mg twice daily for 5 days, may be effective alternative regimens in selected patients. A carbapenem has been recommended for patients with hospital-acquired spontaneous bacterial peritonitis, which is increasingly caused by multidrug-resistant organisms. Supplemental administration of intravenous albumin (which may have anti-inflammatory effects in addition to expanding plasma volume) prevents further renal impairment and reduces mortality, particularly in patients with a serum creatinine greater than 1 mg/dL (83.3 mcmol/L), blood urea nitrogen greater than 30 mg/dL (10.8 mmol/L), or total bilirubin greater than 4 mg/dL (68.4 mcmol/L). Response to therapy can be documented, if necessary, by a decrease in the PMN count of at least 50% on repeat paracentesis 48 hours after initiation of therapy. The overall mortality rate is high—up to 30% during hospitalization and up to 70% by 1 year. Mortality may be predicted by the 22/11 model: MELD score greater than 22 and peripheral white blood cell count higher than 11,000/mcL (11 ×109/L). Another model predictive of mortality includes the blood urea nitrogen, white blood cell count, Child-Pugh score, and mean arterial pressure. Patients with cirrhosis and septic shock have a high frequency of relative adrenal insufficiency, which if present requires administration of hydrocortisone.
In survivors of bacterial peritonitis, the risk of recurrent peritonitis may be decreased by long-term ciprofloxacin (eg, 500 mg orally once per day) or norfloxacin (400 mg orally daily; no longer available in the United States) or trimethoprim-sulfamethoxazole (eg, one double-strength tablet once per day). In cases of recurrent peritonitis, the causative organism is often resistant to fluoroquinolones and may become multidrug resistant in some cases. In high-risk cirrhotic patients without prior peritonitis (eg, those with an ascitic protein less than 1.5 g/dL and serum bilirubin greater than 3 mg/dL (51.3 mcmol/L), serum creatinine greater than 1.2 mg/dL (99.96 mcmol/L), blood urea nitrogen 25 mg/dL or more (9 mmol/L or more), or sodium 130 mEq/L or less [130 mmol/L or less]), the risk of peritonitis, hepatorenal syndrome, and mortality for at least 1 year may be reduced by prophylactic trimethoprim-sulfamethoxazole, one double-strength tablet once per day, ciprofloxacin, 500 mg once per day, or norfloxacin, 400 mg orally once a day (though not in the United States). In patients hospitalized for acute variceal bleeding, intravenous ceftriaxone (1 g per day), followed by oral trimethoprim-sulfamethoxazole (one double-strength tablet once per day) or ciprofloxacin (500 mg every 12 hours), for a total of 7 days, reduces the risk of bacterial peritonitis. Nonantibiotic prophylactic strategies, including probiotics, bile acids, and statins, are under study.
Hepatorenal syndrome occurs in up to 10% of patients with advanced cirrhosis and ascites. It is characterized by (1) azotemia (increase in serum creatinine level of greater than 0.3 mg/dL [26.5 mcmol/L]) within 48 hours or increase by 50% or more from baseline within the previous 7 days in the absence of current or recent nephrotoxic drug use, (2) macroscopic signs of structural kidney injury, (3) shock, and (4) failure of kidney function to improve following 2 days of diuretic withdrawal and volume expansion with albumin, 1 g/kg up to a maximum of 100 g/day. Oliguria, hyponatremia, and a low urinary sodium concentration are typical features. Hepatorenal syndrome is diagnosed only when other causes of acute kidney injury (including prerenal azotemia and acute tubular necrosis) have been excluded. Urinary neutrophil gelatinase-associated lipocalin levels (normal, 20 ng/mL) and other biomarkers may help distinguish hepatorenal syndrome (105 ng/mL) from chronic kidney disease (50 ng/mL) and other causes of acute kidney injury (325 ng/mL). Type I hepatorenal syndrome is typically associated with at least doubling of the serum creatinine to a level greater than 2.5 mg/dL (208.25 mcmol/L) or by halving of the creatinine clearance to less than 20 mL/min (0.34 mL/s/1.73 m2 BSA) in less than 2 weeks. Type II hepatorenal syndrome is more slowly progressive and chronic. The pathogenesis involves intense renal vasoconstriction, possibly because of impaired synthesis of renal vasodilators such as prostaglandin E2 and decreased total renal blood flow; histologically, the kidneys are normal. An acute decrease in cardiac output is often the precipitating event. In addition to discontinuation of diuretics, clinical improvement and an increase in short-term survival may follow intravenous infusion of albumin in combination with one of the following vasoconstrictor regimens for 7–14 days: oral midodrine plus octreotide, subcutaneously or intravenously; intravenous terlipressin (not yet available in the United States but the preferred agent where available); or intravenous norepinephrine. Oral midodrine, 7.5 mg three times daily, added to diuretics, increases the blood pressure and has also been reported to convert refractory ascites to diuretic-sensitive ascites. Prolongation of survival has been associated with use of MARS, a modified dialysis method that selectively removes albumin-bound substances. Improvement and sometimes normalization of kidney function may also follow placement of a TIPS; survival after 1 year is reported to be predicted by the combination of a serum bilirubin level less than 3 mg/dL (50 mcmol/L) and a platelet count greater than 75,000/mcL (75 ×109/L). Continuous venovenous hemofiltration and hemodialysis are of uncertain value in hepatorenal syndrome. Liver transplantation is the ultimate treatment of choice, but many patients die before a donor liver can be obtained. Mortality correlates with the MELD score and presence of a systemic inflammatory response. Type 1 hepatorenal syndrome is often irreversible in patients with a systemic infection. The 3-month probability of survival in cirrhotic patients with hepatorenal syndrome (15%) is lower than that for renal failure associated with infections (31%), hypovolemia (46%), and parenchymal kidney disease (73%).
4. Hepatic encephalopathy
Hepatic encephalopathy is a state of disordered central nervous system function resulting from failure of the liver to detoxify noxious agents of gut origin because of hepatocellular dysfunction and portosystemic shunting. A mutation in the promoter region of the kidney-type glutaminase gene has been reported to increase the risk of overt encephalopathy from about 19% to 40% in patients with cirrhosis. The clinical spectrum ranges from day-night reversal and mild intellectual impairment to coma. Patients with covert (formerly minimal) hepatic encephalopathy have no recognizable clinical symptoms but demonstrate mild cognitive, psychomotor, and attention deficits on standardized psychometric tests and an increased rate of traffic accidents. The stages of overt encephalopathy are (1) mild confusion, (2) drowsiness, (3) stupor, and (4) coma. A revised staging system known as SONIC (spectrum of neurocognitive impairment in cirrhosis) encompasses absent, covert, and stages 2 to 4 encephalopathy. Ammonia is the most readily identified and measurable toxin but is not solely responsible for the disturbed mental status. Central to the pathogenesis is low-grade cerebral edema and astrocyte swelling accompanied by reduced cerebral oxygen consumption and increased production of reactive oxygen and nitrogen oxide species that trigger RNA and protein modifications and neutrophil dysfunction and thereby affect brain function. Factors that contribute to cerebral edema are ammonia, hyponatremia, benzodiazepines, and cytokines. Bleeding into the intestinal tract may significantly increase the amount of protein in the bowel and precipitate encephalopathy. Other precipitants include constipation, alkalosis, and potassium deficiency induced by diuretics, opioids, hypnotics, and sedatives; medications containing ammonium or amino compounds; paracentesis with consequent hypovolemia; hepatic or systemic infection; and portosystemic shunts (including TIPS). The diagnosis is based primarily on detection of characteristic symptoms and signs, including asterixis. A smartphone app called EncephalApp using the “Stroop test” (asking the patient to name the color of a written word rather than the word itself, even when the word is the name of a different color) has proved useful for detecting covert hepatic encephalopathy. Psychometric testing and critical flicker frequency are used primarily as research tools. The role of neuroimaging studies (eg, cerebral PET, magnetic resonance spectroscopy) in the diagnosis of hepatic encephalopathy is evolving.
Protein is withheld during acute episodes if the patient cannot eat. When the patient resumes oral intake, protein intake should be 60–80 g/day as tolerated; vegetable protein is better tolerated than meat protein. Gastrointestinal bleeding should be controlled and blood purged from the gastrointestinal tract. This can be accomplished with 120 mL of magnesium citrate by mouth or nasogastric tube every 3–4 hours until the stool is free of gross blood or by administration of lactulose. The value of treating patients with covert hepatic encephalopathy is uncertain; probiotic agents may have some benefit.
Lactulose, a nonabsorbable synthetic disaccharide syrup, is digested by bacteria in the colon to short-chain fatty acids, resulting in acidification of colon contents. This acidification favors the formation of ammonium ion in the NH4+ ↔ NH3 + H+ equation; NH4+ is not absorbable, whereas NH3 is absorbable and thought to be neurotoxic. Lactulose also leads to a change in bowel flora so that fewer ammonia-forming organisms are present. When given orally, the initial dose of lactulose for acute hepatic encephalopathy is 30 mL three or four times daily. The dose should then be titrated so that the patient produces 2–3 soft stools per day. When given rectally because the patient is unable to take medicines orally, the dose is 300 mL of lactulose in 700 mL of saline or sorbitol as a retention enema for 30–60 minutes; it may be repeated every 4–6 hours. Bowel cleansing with a polyethylene glycol colonoscopy preparation is also effective in patients with acute overt hepatic encephalopathy. Continued use of lactulose after an episode of acute encephalopathy reduces the frequency of recurrences. Lactilol is a less sweet disaccharide powder alternative available in some countries but not in the United States).
The ammonia-producing intestinal flora may also be controlled with an oral antibiotic. The nonabsorbable agent rifaximin, 550 mg orally twice daily, is preferred and has been shown as well to maintain remission of and reduce the risk of rehospitalization for hepatic encephalopathy over a 24-month period, with or without the concomitant use of lactulose. Metronidazole, 250 mg orally three times daily, has also shown benefit. In the past, neomycin sulfate, 0.5–1 g orally every 6 or 12 hours for 7 days, was used, but side effects (including diarrhea, malabsorption, superinfection, ototoxicity, and nephrotoxicity) were frequent, especially after prolonged use. Patients who do not respond to lactulose alone may improve with a course of an antibiotic added to treatment with lactulose.
Opioids and sedatives metabolized or excreted by the liver should be avoided. If agitation is marked, oxazepam, 10–30 mg, which is not metabolized by the liver, may be given cautiously by mouth or by nasogastric tube. Zinc deficiency should be corrected, if present, with oral zinc sulfate, 600 mg/day in divided doses. Sodium benzoate, 5 g orally twice daily, ornithine aspartate, 9 g orally three times daily, and L-acyl-carnitine (an essential factor in the mitochrondrial transport of long-chain fatty acids), 4 g orally daily, may lower blood ammonia levels, but there is less experience with these drugs than with lactulose. Flumazenil is effective in about 30% of patients with severe hepatic encephalopathy, but the drug is short-acting and intravenous administration is required. Use of special dietary supplements enriched with branched-chain amino acids is usually unnecessary except in occasional patients who are intolerant of standard protein supplements. Treatment with acarbose (an alpha-glucosidase inhibitor), ornithine phenylacetate, and glycerol phenylbutyrate is under study; other therapies being evaluated include prebiotic and probiotic agents to modulate gut flora, anti-inflammatory agents to reduce neuroinflammation, and extracorporeal albumin dialysis (MARS).
Hypoprothrombinemia caused by malnutrition and vitamin K deficiency may be treated with vitamin K (eg, phytonadione, 5 mg orally or intravenously daily); however, this treatment is ineffective when synthesis of coagulation factors is impaired because of hepatic disease. In such cases, correcting the prolonged prothrombin time requires large volumes of fresh frozen plasma (see Chapter 14). Because the effect is transient, plasma infusions are not indicated except for active bleeding or before an invasive procedure, and even then, their value has been questioned because of concomitant alterations in anti-hemostatic factors and because bleeding risk does not correlate with the INR. Recombinant activated factor VIIa may be an alternative but is expensive and poses a 1–2% risk of thrombotic complications. In fact, bleeding risk in critically ill patients with cirrhosis has been shown to correlate with bleeding on hospital admission, a platelet count less than 30,000/mcL (30 × 109/L), a fibrinogen level less than 60 mg/dL (1.764 mcmol/L), and an activated partial thromboplastin time greater than 100 seconds. Eltrombopag reduces the need for platelet transfusions in patients with cirrhosis and a platelet count less than 50,000/mcL (50 × 109/L) who undergo invasive procedures, but eltrombopag is associated with an increased risk of portal vein thrombosis and arterial thromboembolism.
6. Hemorrhage from esophageal varices
A: Esophageal varices: Upper endoscopy demonstrates four columns of esophageal varices. A consequence of portal hypertension, esophageal varices are one of the most common causes of life-threatening upper gastrointestinal bleeding. (Used, with permission, from Neil Mehta, MD.) B: Esophageal varices with "red wale" spots: Multiple "red wale" spots (arrows) seen on upper endoscopy usually signify recent esophageal variceal bleeding. (Used, with permission, from Neil Mehta, MD.) C: Band ligation of esophageal varices: Appearance after endoscopic banding (arrows) of two separate esophageal varices. (Used, with permission, from Neil Mehta, MD.)
7. Hepatopulmonary syndrome and portopulmonary hypertension
Shortness of breath in patients with cirrhosis may result from pulmonary restriction and atelectasis caused by massive ascites or hepatic hydrothorax. The hepatopulmonary syndrome—the triad of chronic liver disease, an increased alveolar-arterial gradient while the patient is breathing room air, and intrapulmonary vascular dilatations or arteriovenous communications that result in a right-to-left intrapulmonary shunt—occurs in 5–32% of patients with cirrhosis. The syndrome is presumed to result from enhanced pulmonary production of nitric oxide and polymorphisms in genes involved in the regulation of angiogenesis but does not correlate with the degrees of hepatic dysfunction and portal hypertension. A role for endothelial dysfunction is suggested by the finding of elevated levels of von Willebrand factor antigen in affected patients. Patients often have greater dyspnea (platypnea) and arterial deoxygenation (orthodeoxia) in the upright than in the recumbent position. The diagnosis should be suspected in a cirrhotic patient with a pulse oximetry level of 96% or less.
Contrast-enhanced echocardiography is a sensitive screening test for detecting pulmonary vascular dilatations, whereas macroaggregated albumin lung perfusion scanning is more specific and may be used to confirm the diagnosis. High-resolution CT may be useful for detecting dilated pulmonary vessels that may be amenable to embolization in patients with severe hypoxemia (PO2 less than 60 mm Hg [7.8 kPa]) who respond poorly to supplemental oxygen.
Medical therapy has been disappointing; experimentally, intravenous methylene blue, oral garlic powder, oral norfloxacin, and mycophenolate mofetil may improve oxygenation by inhibiting nitric oxide-induced vasodilatation and angiogenesis, and pentoxifylline may prevent hepatopulmonary syndrome by inhibiting production of tumor necrosis factor. Long-term oxygen therapy is recommended for severely hypoxemic patients. The syndrome may reverse with liver transplantation, although postoperative morbidity and mortality from severe hypoxemic respiratory failure are increased in patients with a preoperative arterial PO2 less than 44 mm Hg (5.9 kPa) or with substantial intrapulmonary shunting. TIPS may provide palliation in patients with hepatopulmonary syndrome awaiting transplantation.
Portopulmonary hypertension occurs in 0.7% of patients with cirrhosis and is thought to result from an excess of circulating vasoconstrictors, particularly endothelin-1. Female sex and autoimmune hepatitis have been reported to be risk factors, and large spontaneous portosystemic shunts are present in many affected patients and are associated with a lack of response to treatment. In cases confirmed by right-sided heart catheterization, treatment with the prostaglandin epoprostenol, the endothelin-receptor antagonists bosentan or ambrisentan, or the phosphodiesterase-5 inhibitors sildenafil or tadalafil may reduce pulmonary hypertension and thereby facilitate liver transplantation; beta-blockers worsen exercise capacity and are contraindicated, and calcium channel blockers should be used with caution because they may worsen portal hypertension. Liver transplantation is contraindicated in patients with moderate to severe pulmonary hypertension (mean pulmonary pressure greater than 35 mm Hg).
Liver transplantation is indicated in selected cases of irreversible, progressive chronic liver disease, acute liver failure, and certain metabolic diseases in which the metabolic defect is in the liver. Absolute contraindications include malignancy (except relatively small hepatocellular carcinomas in a cirrhotic liver—see Chapter 39), advanced cardiopulmonary disease (except hepatopulmonary syndrome), and sepsis. Relative contraindications include age over 70 years, morbid obesity, portal and mesenteric vein thrombosis, active alcohol or drug abuse, severe malnutrition, and lack of patient understanding. With the emergence of effective antiretroviral therapy for HIV disease, a major cause of mortality in these patients has shifted to liver disease caused by HCV and HBV infection; experience to date suggests that the outcome of liver transplantation is comparable to that for non–HIV-infected liver transplant recipients. Patients with alcoholism should be abstinent for 6 months. Liver transplantation should be considered in patients with worsening functional status, rising bilirubin, decreasing albumin, worsening coagulopathy, refractory ascites, recurrent variceal bleeding, or worsening encephalopathy; prioritization is based on the MELD score. Combined liver-kidney transplantation is indicated in patients with associated kidney failure presumed to be irreversible. The major impediment to more widespread use of liver transplantation is a shortage of donor organs. Adult living donor liver transplantation is an option for some patients, and extended-criteria donors are used. Five-year survival rates over 80% are now reported. Hepatocellular carcinoma, hepatitis B and C, and some cases of Budd-Chiari syndrome and autoimmune liver disease may recur in the transplanted liver. The incidence of recurrence of hepatitis B can be reduced by preoperative and postoperative treatment with a nucleoside or nucleotide analog and perioperative administration of HBIG, and hepatitis C can be treated with direct-acting antiviral agents. Immunosuppression is achieved with combinations of cyclosporine, tacrolimus, sirolimus, corticosteroids, azathioprine, and mycophenolate mofetil and may be complicated by infections, advanced chronic kidney disease, neurologic disorders, and drug toxicity, as well as graft rejection, vascular occlusion, or bile leaks. Patients taking these drugs are at risk for obesity, diabetes mellitus, and hyperlipidemia. A combination of prebiotics and probiotics before or on the day of transplantation reduces the rate of infection after surgery.
The risk of death from compensated cirrhosis is 4.7 times that of the risk in the general population, and the risk from decompensated cirrhosis is 9.7 times higher. Prognostic scoring systems for cirrhosis include the Child-Pugh score and MELD score (Table 16–7). The MELD score, which incorporates the serum bilirubin, creatinine, and sodium levels and the INR, is also a measure of mortality risk in patients with end-stage liver disease and is particularly useful for predicting short- and intermediate-term survival and complications of cirrhosis (eg, bacterial peritonitis) as well as determining allocation priorities for donor livers. Additional (MELD-exception) points are given for patients with conditions such as hepatopulmonary syndrome and hepatocellular carcinoma that may benefit from liver transplantation. The consistency of the MELD score among different hospitals may be improved when the INR is calibrated based on prothrombin time control samples that include patients with liver disease rather than those taking oral anticoagulants, but this approach is not readily available. A MELD score of 17 or more is required for liver transplant listing. In patients with a relatively low MELD score (less than 21) and a low priority for liver transplantation, an elevated hepatic venous pressure gradient, persistent ascites, hepatic encephalopathy, and a low health-related quality of life are additional independent predictors of mortality, and further modifications of the MELD score are under consideration. Only 50% of patients with severe hepatic dysfunction (serum albumin less than 3 g/dL [30 g/L]), bilirubin greater than 3 mg/dL [51.3 mcmol/L]), ascites, encephalopathy, cachexia, and upper gastrointestinal bleeding) survive 6 months without transplantation. The risk of death in this subgroup of patients with advanced cirrhosis is associated with muscle wasting, age 65 years or older, mean arterial pressure 82 mm Hg or less, renal failure, cognitive dysfunction, ventilatory insufficiency, prothrombin time 16 seconds or longer, delayed and suboptimal treatment of sepsis, and second infections. For cirrhotic patients admitted to an intensive care unit, the Royal Free Hospital score, consisting of the serum bilirubin, INR, serum lactate, alveolar-arterial oxygen gradient, and blood urea nitrogen, has been reported to predict mortality. Renal failure increases mortality up to sevenfold in patients with cirrhosis. Obesity and diabetes mellitus appear to be risk factors for clinical deterioration and cirrhosis-related mortality, as is continued alcohol use in patients with alcoholic cirrhosis. The use of beta-blockers for portal hypertension is beneficial early in the course but become ineffective and may be associated with reduced survival in patients with refractory ascites, spontaneous bacterial peritonitis, sepsis, or severe alcoholic hepatitis because of their negative effect on cardiac compensatory reserve. In general, beta-blockers should be discontinued when the systolic blood pressure is less than 90 mm Hg, the serum sodium level is less than 130 mEq/L, or acute kidney injury has developed, although results of some studies have challenged these guidelines. Patients with cirrhosis are at risk for the development of hepatocellular carcinoma, with rates of 3–5% per year for alcoholic and viral hepatitis-related cirrhosis. Liver transplantation has markedly improved the outlook for patients with cirrhosis who are candidates and are referred for evaluation early in the course. Patients with compensated cirrhosis are given additional priority for liver transplantation if they are found to have a lesion larger than 2 cm in diameter consistent with hepatocellular carcinoma. In-hospital mortality from cirrhosis declined from 9.1% in 2002 to 5.4% in 2010 and that from variceal bleeding in patients with cirrhosis declined from over 40% in 1980 to 15% in 2000. Patients hospitalized with cirrhosis and an infection are at high risk for subsequent infections, particularly if they are older, taking a proton pump inhibitor, or receiving antibiotic prophylaxis for spontaneous bacterial peritonitis. Medical treatments to reverse hepatic fibrosis are under investigation.
Table 16–7.Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems for staging cirrhosis. |Favorite Table|Download (.pdf) Table 16–7. Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems for staging cirrhosis.
|Child-Pugh Scoring System |
|Parameter ||Numerical Score |
|1 ||2 ||3 |
|Ascites ||None ||Slight ||Moderate to severe |
|Encephalopathy ||None ||Slight to moderate ||Moderate to severe |
|Bilirubin, mg/dL (mcmol/L) ||< 2.0 (34.2) ||2–3 (34.2–51.3) ||> 3.0 (51.3) |
|Albumin, g/dL (g/L) ||> 3.5 (35) ||2.8–3.5 (28–35) ||< 2.8 (28) |
|Prothrombin time (seconds increased) ||1–3 ||4–6 ||> 6.0 |
| ||Total Numerical Score and Corresponding Child-Pugh Class |
| ||Score ||Class |
| ||5–6 ||A |
| ||7–9 ||B |
| ||10–15 ||C |
|MELD Scoring System |
Original MELD = 11.2 loge (INR) + 3.78 loge (bilirubin [mg/dL]) + 9.57 loge (creatinine [mg/dL]) + 6.43. (Range 6–40); in 2016, the serum sodium was added as a component (referred to as the MELDNa score): MELDNa = MELD + (140 – Na) × (1 – 0.025 × MELD).
Stage 3–4 hepatic encephalopathy.
Worsening kidney function.
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et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology. 2015 Aug;62(2):567–74.
et al. Nonselective β-blockers and survival in patients with cirrhosis and ascites: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1096–104.
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et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology. 2016 Aug;64(2):556–68.
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PRIMARY BILIARY CHOLANGITIS
ESSENTIALS OF DIAGNOSIS
Occurs in middle-aged women.
Elevation of alkaline phosphatase, positive antimitochondrial antibodies, elevated IgM, increased cholesterol.
Characteristic liver biopsy.
In later stages, can present with fatigue, jaundice, features of cirrhosis, xanthelasma, xanthoma, steatorrhea.
Primary biliary cholangitis (formerly primary biliary cirrhosis, PBC) is a chronic disease of the liver characterized by autoimmune destruction of small intrahepatic bile ducts and cholestasis. The designation “primary biliary cholangitis” has replaced “primary biliary cirrhosis” because many patients do not have cirrhosis. The disease is insidious in onset, occurs usually in women aged 40–60 years, and is often detected by the chance finding of elevated alkaline phosphatase levels. Estimated incidence and prevalence rates in the United States are 4.5 and 65.4 per 100,000, respectively, in women, and 0.7 and 12.1 per 100,000, respectively, in men. These rates may be increasing. The frequency of the disease among first-degree relatives of affected persons is 1.3–6%, and the concordance rate in identical twins is high. PBC is associated with HLA DRB1*08 and DQB1 as well as the IL12A and IL12RB2 genes, which encode interleukin-12alpha and interleukin 12 receptor beta2, respectively, and IRF5-TNPO3, which encodes interferon regulatory factor 5-transportin 3. The disease may be associated with Sjögren syndrome, autoimmune thyroid disease, Raynaud syndrome, scleroderma, hypothyroidism, and celiac disease. Infection with Novosphingobium aromaticivorans or Chlamydophila pneumoniae may trigger or cause PBC. Other triggers, including viruses (such as human betaretrovirus), lactobacillus vaccination to prevent recurrent vaginitis, and xenobiotics, are also suspected. X-chromosome monosomy may be a predisposing factor. A history of urinary tract infections (caused by E coli or Lactobacillus delbrueckii) and smoking, and possibly use of hormone replacement therapy and hair dye, are risk factors, and clustering of cases in time and space argues for a causative role of environmental agents.
Many patients are asymptomatic for years. The onset of clinical illness is insidious and is heralded by fatigue (excessive daytime somnolence) and pruritus, which appears to correlate with elevated serum levels of the enzyme autotaxin and its product lysophosphatidic acid. With progression, physical examination reveals hepatosplenomegaly. Xanthomatous lesions may occur in the skin (eFigure 16–35) and tendons and around the eyelids. Jaundice, steatorrhea, and signs of portal hypertension are late findings, although occasional patients have esophageal varices despite an early histologic stage. Autonomic dysfunction, including orthostatic hypotension and associated fatigue and cognitive dysfunction, appear to be common. The risk of low bone density, osteoporosis, and fractures is increased in patients with PBC (who tend to be older women) possibly due in part to polymorphisms of the vitamin D receptor.
Tendinous xanthomas. (Reproduced, with permission, Sherlock S, Summerfield JA. Color Atlas of Liver Disease. Mosby, 1991.)
Blood counts are normal early in the disease. Liver biochemical tests reflect cholestasis with elevation of alkaline phosphatase, cholesterol (especially high-density lipoproteins), and, in later stages, bilirubin. Antimitochondrial antibodies (directed against the dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase or other 2-oxo-acid enzymes in mitochondria) are present in 95% of patients, and serum IgM levels are elevated. ANA directed against the nuclear pore complex (eg, against gp210 in the nuclear envelope) may be detected in specialized laboratories.
The diagnosis of PBC is based on the detection of cholestatic liver chemistries (often initially an isolated elevation of the alkaline phosphatase) and antimitochondrial antibodies in serum. Liver biopsy is not essential for diagnosis but permits histologic staging (eFigure 16–36): I, portal inflammation with granulomas; II, bile duct proliferation, periportal inflammation; III, interlobular fibrous septa; and IV, cirrhosis. Estimation of histologic stage by an “enhanced liver fibrosis (ELF) assay” that incorporates serum levels of hyaluronic acid, tissue inhibitor of metalloproteinase-1, and procollagen III aminopeptide has shown promise.
Primary biliary cholangitis. This autoimmune entity usually occurs in middle-aged women with serum antimitochrondial antibodies. On liver biopsy, the typical histologic appearance is one of destruction and discontinuity of the bile ductules and a dense lymphocytic infiltrate surrounding the biliary epithelium (black arrow). (Used, with permission, from James P. Grenert, MD.)
The disease must be differentiated from chronic biliary tract obstruction (stone or stricture), carcinoma of the bile ducts, primary sclerosing cholangitis, sarcoidosis, cholestatic drug toxicity (eg, chlorpromazine), and in some cases chronic hepatitis. Patients with a clinical and histologic picture of PBC but no antimitochondrial antibodies are said to have antimitochondrial antibody-negative PBC (previously termed “autoimmune cholangitis”), which has been associated with lower serum IgM levels and a greater frequency of smooth muscle antibodies and ANA. Many such patients are found to have antimitochondrial antibodies by immunoblot against recombinant proteins (rather than standard immunofluorescence). Some patients have overlapping features of PBC and autoimmune hepatitis.
Cholestyramine (4 g) in water or juice three times daily may be beneficial for pruritus; colestipol and colesevelam may be better tolerated but have not been shown to reduce pruritus. Rifampin, 150–300 mg orally twice daily, is inconsistently beneficial. Opioid antagonists (eg, naloxone, 0.2 mcg/kg/min by intravenous infusion, or naltrexone, starting at 12.5 mg/day by mouth) show promise in the treatment of pruritus but may cause opioid withdrawal symptoms. The 5-hydroxytryptamine (5-HT3) serotonin receptor antagonist ondansetron, 4 mg orally three times a day as needed, and the selective serotonin reuptake inhibitor sertraline, 75–100 mg/day orally, may also provide some benefit. For refractory pruritus, plasmapheresis or extracorporeal albumin dialysis may be needed. Modafinil, 100–200 mg/day orally, may improve daytime somnolence but is poorly tolerated. Deficiencies of vitamins A, D, and K may occur if steatorrhea is present and are aggravated when cholestyramine is administered. (See Chapter 26, Osteoporosis and Chapter 20, Sjögren syndrome.)
Because of its lack of toxicity, ursodeoxycholic acid (13–15 mg/kg/day in one or two doses) is the preferred medical treatment for PBC. It has been shown to slow the progression of disease (particularly in early-stage disease), stabilize histology, improve long-term survival, reduce the risk of developing esophageal varices, and delay (and possibly prevent) the need for liver transplantation. Complete normalization of liver biochemical tests occurs in 20% of treated patients within 2 years and 40% within 5 years, and survival is similar to that of healthy controls when the drug is given to patients with stage 1 or 2 PBC. Response rates have been reported to be lower in men than women (72% vs 80%) and higher in women diagnosed after age 70 than before age 30 (90% vs 50%). Ursodeoxycholic acid has also been reported to reduce the risk of recurrent colorectal adenomas in patients with PBC. Side effects include weight gain and rarely loose stools.
Obeticholic acid, a farsenoid-X receptor agonist, was approved by the FDA in 2016 for the treatment of PBC in patients with an incomplete response or intolerance to ursodeoxycholic acid. Obeticholic acid is begun in a dose of 5 mg orally daily and increased to 10 mg daily if necessary, based on the decline in serum alkaline phosphatase and bilirubin levels. The principal side effect is pruritus.
Colchicine (0.6 mg orally twice daily) and methotrexate (15 mg/wk orally) have had some reported benefit in improving symptoms and serum levels of alkaline phosphatase and bilirubin. Methotrexate may also improve liver histology in some patients, but overall response rates have been disappointing. Penicillamine, prednisone, and azathioprine have proved to be of no benefit. Budesonide may improve liver histology but worsens bone density. Mycophenolate mofetil, rituximab, and fenofibrate and other fibrates are under study. For patients with advanced disease, liver transplantation is the treatment of choice.
Without liver transplantation, survival averages 7–10 years once symptoms develop but has improved for younger women since the introduction of ursodeoxycholic acid. Progression to liver failure and portal hypertension is associated with the presence of anti-gp210 and anticentromere antibodies, respectively, and may be accelerated by smoking. Patients with early-stage disease in whom the alkaline phosphatase and AST are less than 1.5 times normal and bilirubin is 1 mg/dL (17.1 mcmol/L) or less after 1 year of therapy with ursodeoxycholic acid (Paris II criteria) are at low long-term risk for cirrhosis and have a life expectancy similar to that of the healthy population. Pregnancy is well tolerated in younger patients. In advanced disease, an adverse prognosis is indicated by a high Mayo risk score that includes older age, high serum bilirubin, edema, low serum albumin, and prolonged prothrombin time as well as by variceal hemorrhage. Other prognostic models include the Globe index, which is based on age, serum bilirubin, serum albumin, serum alkaline phosphatase, and platelet count and, in treated patients, the UK-PBC score, which is based on the baseline serum albumin and platelet count and the serum bilirubin, aminotransferases, and alkaline phosphatase after 12 months of ursodeoxycholic acid. A prediction tool for varices has been proposed based on the serum albumin, serum alkaline phosphatase, platelet count, and splenomegaly. Fatigue is associated with an increased risk of cardiac mortality and may not be reversed by liver transplantation. Among asymptomatic patients, at least one-third will become symptomatic within 15 years. The risk of hepatocellular carcinoma appears to be increased in patients with PBC; risk factors include older age, male sex, prior blood transfusions, advanced histologic stage, signs of cirrhosis or portal hypertension, and a biochemical nonresponse to ursodeoxycholic acid. Liver transplantation for advanced PBC is associated with a 1-year survival rate of 85–90%. The disease recurs in the graft in 20% of patients by 3 years, but this does not seem to affect survival.
Stage 3–4 hepatic encephalopathy.
Worsening kidney function.
et al. Changing nomenclature for PBC: from 'cirrhosis' to 'cholangitis'. Hepatology. 2015 Nov;62(5):1620–2.
et al. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016 Mar;63(3):930–50.
et al. Primary biliary cirrhosis. Lancet. 2015 Oct 17;386(10003):1565–75.
et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther. 2016 Jan;43(2):283–93.
et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015 Apr;148(4):751–61.
C (editor). Advances in cholestatic liver diseases. Clin Liver Dis. 2016;20(1):1–203. [Full issue]
et al; POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016 Aug 18;375(7):631–43.
et al; Global PBC Study Group. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2016 Feb;65(2):321–9.
ESSENTIALS OF DIAGNOSIS
Usually suspected because of a family history or an elevated iron saturation or serum ferritin.
Most patients are asymptomatic; the disease is rarely recognized clinically before the fifth decade.
Hepatic abnormalities and cirrhosis, heart failure, hypogonadism, and arthritis.
HFE gene mutation (usually C282Y/C282Y) is found in most cases.
Hemochromatosis is an autosomal recessive disease caused in most cases by a mutation in the HFE gene on chromosome 6. The HFE protein is thought to play an important role in the process by which duodenal crypt cells sense body iron stores, and a mutation of the gene leads to increased iron absorption from the duodenum. A decrease in the synthesis or expression of hepcidin, the principal iron regulatory hormone, is thought to be a key pathogenic factor in all forms of hemochromatosis. About 85% of persons with well-established hemochromatosis are homozygous for the C282Y mutation (type 1a hemochromatosis). The frequency of the gene mutation averages 7% in Northern European and North American white populations, resulting in a 0.5% frequency of homozygotes (of whom 38–50% will develop biochemical evidence of iron overload but only 28% of men and 1% of women will develop clinical symptoms). Polymorphisms in modifier genes have been shown to lead to a high iron phenotype. The HFE gene mutation and hemochromatosis are uncommon in blacks and Asian American populations. A second genetic mutation (H63D) may contribute to the development of iron overload in a small percentage (1.5%) of persons who are compound heterozygotes for C282Y and H63D (type 1b); iron overload–related disease develops in few patients (particularly those who have a comorbidity such as diabetes mellitus and fatty liver). H63D homozygotes do not develop hemochromatosis but may be at increased risk for amyotrophic lateral sclerosis, and carriers may be at increased risk for non-cardia gastric cancer. A juvenile-onset variant that is characterized by severe iron overload, cardiac dysfunction, hypogonadotropic hypogonadism, and a high mortality rate is usually linked to a mutation of a gene on chromosome 1q designated HJV that produces a protein called hemojuvelin (type 2a) or, rarely, to a mutation in the HAMP gene on chromosome 19 that encodes hepcidin (type 2b). Rare instances of hemochromatosis result from mutations in the genes that encode transferrin receptor 2 (TFR2) (type 3) and ferroportin (SLC11A3) (type 4). Mutations in other genes associated with iron regulation have been identified in rare instances.
Hemochromatosis is characterized by increased accumulation of iron as hemosiderin in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys. Cirrhosis is more likely to develop in affected persons who drink alcohol excessively or have obesity-related hepatic steatosis than in those who do not. Eventually, hepatic and pancreatic insufficiency, heart failure, and hypogonadism may develop; overall mortality is increased slightly. Heterozygotes do not develop cirrhosis in the absence of associated disorders such as viral hepatitis or NAFLD.
The onset of clinical disease is usually after age 50 years—earlier in men than in women; however, because of widespread liver biochemical testing and iron screening, the diagnosis is usually made long before symptoms develop. Early symptoms are nonspecific (eg, fatigue, arthralgia). Later clinical manifestations include arthropathy (and ultimately the need for joint replacement surgery in some cases), hepatomegaly and evidence of hepatic dysfunction, skin pigmentation (combination of slate-gray due to iron and brown due to melanin, sometimes resulting in a bronze color), cardiac enlargement with or without heart failure or conduction defects, diabetes mellitus with its complications, and erectile dysfunction in men. Interestingly, population studies have shown an increased prevalence of liver disease but not of diabetes mellitus, arthritis, or heart disease in C282Y homozygotes. In patients in whom cirrhosis develops, bleeding from esophageal varices may occur, and there is a 15–20% frequency of hepatocellular carcinoma. Affected patients are at increased risk of infection with Vibrio vulnificus, Listeria monocytogenes, Yersinia enterocolitica, and other siderophilic organisms. The risk of porphyria cutanea tarda is increased in persons with the C282Y or H63D mutation, and C282Y homozygotes have twice the risk of colorectal and breast cancer than persons without the C282Y variant.
Laboratory findings include mildly abnormal liver tests (AST, alkaline phosphatase), an elevated plasma iron with greater than 45% transferrin saturation, and an elevated serum ferritin (although a normal iron saturation or a normal ferritin does not exclude the diagnosis). Affected men are more likely than affected women to have an elevated ferritin level. Testing for HFE mutations is indicated in any patient with evidence of iron overload. Interestingly, in persons with an elevated serum ferritin, the likelihood of detecting C282Y homozygosity decreases with increasing ALT and AST levels, which are likely to reflect hepatic inflammation and secondary iron overload.
MRI and CT may show changes consistent with iron overload of the liver, and MRI can quantitate hepatic iron stores and help assess the degree of hepatic fibrosis.
In patients who are homozygous for C282Y, liver biopsy is often indicated to determine whether cirrhosis is present. Biopsy can be deferred, however, in patients in whom the serum ferritin level is less than 1000 mcg/L, serum AST level is normal, and hepatomegaly is absent; the likelihood of cirrhosis is low in these persons. The combination of a serum ferritin level of 1000 mcg/L or more and a serum hyaluronic acid level of 46.5 mcg/L or more has been reported to identify all patients with cirrhosis, with a high specificity. Risk factors for advanced fibrosis include male sex, excess alcohol consumption, and diabetes mellitus. Liver biopsy is also indicated when iron overload is suspected even though the patient is neither homozygous for C282Y nor a C282Y/H63D compound heterozygote. In patients with hemochromatosis, the liver biopsy characteristically shows extensive iron deposition in hepatocytes and in bile ducts (eFigure 16–37), and the hepatic iron index—hepatic iron content per gram of liver converted to micromoles and divided by the patient’s age—is generally higher than 1.9. Only 5% of patients with hereditary hemochromatosis identified by screening in a primary care setting have cirrhosis.
Hemochromatosis. Gomori iron stain of a liver biopsy specimen shows a large amount of iron deposition, which appears blue, throughout the hepatic parenchyma, characteristic of hemochromatosis. (Used, with permission, from James P. Grenert, MD.)
Iron studies and HFE testing are recommended for all first-degree family members of a proband; children of an affected person (C282Y homozygote) need to be screened only if the patient’s spouse carries the C282Y or H63D mutation. General population screening for hemochromatosis is not recommended because the clinical penetrance of C282Y homozygosity and morbidity and mortality from hemochromatosis are low. Patients with otherwise unexplained chronic liver disease, chondrocalcinosis, erectile dysfunction, and type 1 diabetes mellitus (especially late-onset) should be screened for iron overload.
Affected patients are advised to avoid foods rich in iron (such as red meat), alcohol, vitamin C, raw shellfish, and supplemental iron. Weekly phlebotomies of 1 or 2 units (250–500 mL) of blood (each containing about 250 mg of iron) is indicated in all symptomatic patients, those with a serum ferritin level of at least 1000 mcg/L, and those with an increased fasting iron saturation and should be continued for up to 2–3 years to achieve depletion of iron stores. The hematocrit and serum iron values should be monitored. When iron store depletion is achieved (iron saturation less than 50% and serum ferritin level 50–100 mcg/L), phlebotomies (every 2–4 months) to maintain serum ferritin levels between 50 mcg/L and 100 mcg/L are continued, although compliance has been reported to decrease with time. Administration of a proton pump inhibitor, which reduces intestinal iron absorption, decreases the maintenance phlebotomy volume requirement. In C282Y homozygous women, a body mass index greater than 28 is associated with a lower phlebotomy requirement, possibly because hepcidin levels are increased by overweight. Complications of hemochromatosis—arthropathy, diabetes mellitus, heart disease, portal hypertension, and hypopituitarism—also require treatment.
The chelating agent deferoxamine is indicated for patients with hemochromatosis and anemia or in those with secondary iron overload due to thalassemia who cannot tolerate phlebotomies. The drug is administered intravenously or subcutaneously in a dose of 20–40 mg/kg/day infused over 24 hours and can mobilize 30 mg of iron per day; however, treatment is painful and time-consuming. Two oral chelators, deferasirox, 20 mg/kg once daily, and deferiprone, 25 mg/kg three times daily, have been approved for treatment of iron overload due to blood transfusions and may be appropriate in persons with hemochromatosis who cannot tolerate phlebotomy; however, these agents have a number of side effects and drug-drug interactions.
The course of hemochromatosis is favorably altered by phlebotomy therapy. Hepatic fibrosis may regress, and in precirrhotic patients, cirrhosis may be prevented. Cardiac conduction defects and insulin requirements improve with treatment. In patients with cirrhosis, varices may reverse, and the risk of variceal bleeding declines, although the risk of hepatocellular carcinoma persists. In those with an initial serum ferritin level greater than 1000 mcg/L (2247 pmol/L), the risk of death is fivefold greater than in those with a serum ferritin 1000 mcg/L (2247 pmol/L) or less. In treated patients, only those with a serum ferritin greater than 2000 mcg/L (4494 pmol/L) have increased mortality, mainly related to liver disease. In the past, liver transplantation for advanced cirrhosis associated with severe iron overload, including hemochromatosis, was reported to lead to survival rates that were lower than those for other types of liver disease because of cardiac complications and an increased risk of infections, but since 1997, posttransplant survival rates have been excellent. Following liver transplantation, serum iron studies and hepcidin levels are normal, and phlebotomy is not required.
et al. Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis. J Hepatol. 2015 Mar;62(3):682–9.
et al. Iron metabolism and related genetic diseases: a cleared land, keeping mysteries. J Hepatol. 2016 Feb;64(2):505–15.
et al. Proton pump inhibitors reduce the frequency of phlebotomy in patients with hereditary hemochromatosis. Clin Gastroenterol Hepatol. 2016 Jan;14(1):147–52.
ESSENTIALS OF DIAGNOSIS
Rare autosomal recessive disorder that usually occurs in persons under age 40.
Excessive deposition of copper in the liver and brain.
Serum ceruloplasmin, the plasma copper-carrying protein, is low.
Urinary excretion of copper and hepatic copper concentration are high.
Wilson disease (hepatolenticular degeneration) is a rare autosomal recessive disorder that usually occurs in persons under age 40. The worldwide prevalence is about 30 per million population. The condition is characterized by excessive deposition of copper in the liver and brain. The genetic defect, localized to chromosome 13, has been shown to affect a copper-transporting adenosine triphosphatase (ATP7B) in the liver and leads to copper accumulation in the liver and oxidative damage of hepatic mitochondria. Most patients are compound heterozygotes (ie, carry two different mutations). Over 500 mutations in the Wilson disease gene have been identified. The H1069Q mutation accounts for 37–63% of disease alleles in populations of Northern European descent. The major physiologic aberration in Wilson disease is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver, resulting in increased tissue deposition, especially in the liver, brain, cornea, and kidney.
Wilson disease tends to present as liver disease in adolescents and neuropsychiatric disease in young adults, but there is great variability, and onset of symptoms after age 40 is more common than previously thought. The diagnosis should always be considered in any child or young adult with hepatitis, splenomegaly with hypersplenism, Coombs-negative hemolytic anemia, portal hypertension, and neurologic or psychiatric abnormalities. Wilson disease should also be considered in persons under 40 years of age with chronic or fulminant hepatitis.
Hepatic involvement may range from elevated liver biochemical tests (although the alkaline phosphatase may be low) to cirrhosis and portal hypertension. In patients with acute liver failure (seen much more often in females than males), the diagnosis of Wilson disease is suggested by an alkaline phosphatase (in units/L)-to-total bilirubin (in mg/dL) ratio less than 4 and an AST-to-ALT ratio greater than 2.2. The neurologic manifestations of Wilson disease are related to basal ganglia dysfunction and include an akinetic-rigid syndrome similar to parkinsonism, pseudosclerosis with tremor, ataxia, and a dystonic syndrome. Dysarthria, dysphagia, incoordination, and spasticity are common. Migraines, insomnia, and seizures have been reported. Psychiatric features include behavioral and personality changes and emotional lability and may precede characteristic neurologic features. The risk of depression is increased. The pathognomonic sign of the condition is the brownish or gray-green Kayser-Fleischer ring (eFigure 16–38), which represents fine pigmented granular deposits in Descemet membrane in the cornea (Figure 16–4). The ring is usually most marked at the superior and inferior poles of the cornea. It is sometimes seen with the naked eye and is readily detected by slit-lamp examination. It may be absent in patients with hepatic manifestations only but is usually present in those with neuropsychiatric disease. Renal calculi, aminoaciduria, renal tubular acidosis, hypoparathyroidism, infertility, hemolytic anemia, and subcutaneous lipomas may occur.
Kayser-Fleischer ring. (Reproduced, with permission, from Yarze JC, Martin P, Munoz SJ, Friedman LS. Wilson's disease: Current status. Am J Med. 1992;92:643.)
Brownish Kayser-Fleischer ring at the rim of the cornea in a patient with Wilson disease. (From Marc Solioz, University of Berne; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)
The diagnosis can be challenging, even with the use of scoring systems (eg, the Leipzig criteria), and is generally based on demonstration of increased urinary copper excretion (greater than 40 mcg/24 h and usually greater than 100 mcg/24 h) or low serum ceruloplasmin levels (less than 14 mg/dL [140 mg/L]; less than 5 mg/dL [50 mg/L] is diagnostic), and elevated hepatic copper concentration (greater than 210–250 mcg/g of dry liver), as well as Kayser-Fleischer rings, neurologic symptoms, and Coombs-negative hemolytic anemia. However, increased urinary copper and a low serum ceruloplasmin level (by a standard immunologic assay) are neither completely sensitive nor specific for Wilson disease, although an enzymatic assay for ceruloplasmin appears to be more accurate. The ratio of exchangeable copper to total copper in serum has been reported to improve diagnostic accuracy. In equivocal cases (when the serum ceruloplasmin level is normal), the diagnosis may require demonstration of a rise in urinary copper after a penicillamine challenge, although the test has been validated only in children and is rarely used now. Liver biopsy may show acute or chronic hepatitis or cirrhosis. MRI of the brain may show evidence of increased basal ganglia, brainstem, and cerebellar copper even early in the course of the disease. If available, molecular analysis of ATP7B mutations can be diagnostic.
Early treatment to remove excess copper before it can produce hepatic or neurologic damage is essential. Early in treatment, restriction of dietary copper (shellfish, organ foods, nuts, mushrooms, and chocolate) may be of value. Oral penicillamine (0.75–2 g/day in divided doses taken 1 h before or 2 h after food) has been the drug of choice and enhances urinary excretion of chelated copper. Oral pyridoxine, 50 mg per week, is added because penicillamine is an antimetabolite of this vitamin. If penicillamine treatment cannot be tolerated because of gastrointestinal intolerance, hypersensitivity, autoimmune reactions, nephrotoxicity, or bone marrow toxicity, consider the use of trientine, 250–500 mg three times a day, a chelating agent as effective as penicillamine but with a lower rate of adverse effects. Trientine is increasingly used as a first-line agent despite its cost becoming exorbitant. Oral zinc acetate or zinc gluconate, 50 mg three times a day, interferes with intestinal absorption of copper, promotes fecal copper excretion, and has been used as first-line therapy in presymptomatic or pregnant patients and those with neurologic disease and as maintenance therapy after decoppering with a chelating agent, but adverse gastrointestinal effects often lead to discontinuation and its long-term efficacy and safety (including a risk of hepatotoxicity) have been questioned. Ammonium tetrathiomolybdate, which complexes copper in the intestinal tract, has shown promise as initial therapy for neurologic Wilson disease.
Treatment should continue indefinitely. The doses of penicillamine and trientine should be reduced during pregnancy. Supplemental vitamin E, an antioxidant, has been recommended but not rigorously studied. Once the serum nonceruloplasmin copper level is within the normal range (50–150 mcg/L), the dose of chelating agent can be reduced to the minimum necessary for maintaining that level. The prognosis is good in patients who are effectively treated before liver or brain damage has occurred, but long-term survival is reduced in patients with cirrhosis at diagnosis (84% after 20 years). Liver transplantation is indicated for fulminant hepatitis (often after plasma exchange or dialysis with MARS as a stabilizing measure), end-stage cirrhosis (with excellent outcomes), and, in selected cases, intractable neurologic disease, although survival is lower when liver transplantation is undertaken for neurologic disease than for liver disease. All first-degree relatives, especially siblings, require screening with serum ceruloplasmin, liver biochemical tests, and slit-lamp examination or, if the causative mutation is known, with mutation analysis.
All patients with Wilson disease should be referred for diagnosis and treatment.
Acute liver failure.
Stage 3–4 hepatic encephalopathy.
Worsening kidney function.
et al. Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis. Eur J Med Genet. 2016 Oct;59(10):532–9.
et al. Increased prevalence of subcutaneous lipomas in patients with Wilson disease. J Clin Gastroenterol. 2015 Aug;49(7):e61–3.
et al. Wilson disease: health-related quality of life and risk for depression. Clin Res Hepatol Gastroenterol. 2016 Jun;40(3):349–56.
ML. Long-term outcome for Wilson disease: 85% good. Clin Gastroenterol Hepatol. 2014 Apr;12(4):690–1.
et al. Prospective evaluation of the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample. Hepatology. 2015 Dec;62(6):1731–41.
HEPATIC VEIN OBSTRUCTION (Budd-Chiari Syndrome)
ESSENTIALS OF DIAGNOSIS
Right upper quadrant pain and tenderness.
Imaging studies show occlusion/absence of flow in the hepatic vein(s) or inferior vena cava.
Clinical picture is similar in sinusoidal obstruction syndrome but major hepatic veins are patent.
Factors that predispose patients to hepatic vein obstruction, or Budd-Chiari syndrome, including hereditary and acquired hypercoagulable states, can be identified in 75% of affected patients; multiple disorders are found in up to 45%. Up to 50% of cases are associated with polycythemia vera or other myeloproliferative neoplasms (which has a risk of Budd-Chiari syndrome of 1%). These cases are often associated with a specific mutation (V617F) in the gene that codes for JAK2 tyrosine kinase and may otherwise be subclinical. In some cases, somatic mutations in the gene coding for calreticulin have been found. Other predispositions to thrombosis (eg, activated protein C resistance [factor V Leiden mutation] [25% of cases], protein C or S or antithrombin deficiency, hyperprothrombinemia [factor II G20210A mutation] [rarely], the methylenetetrahydrofolate reductase TT677 mutation, antiphospholipid antibodies) may be identified in other cases. Hepatic vein obstruction may be associated with caval webs, right-sided heart failure or constrictive pericarditis, neoplasms that cause hepatic vein occlusion, paroxysmal nocturnal hemoglobinuria, Behçet syndrome, blunt abdominal trauma, use of oral contraceptives, and pregnancy. Some cytotoxic agents and pyrrolizidine alkaloids (Comfrey or “bush teas”) may cause sinusoidal obstruction syndrome (previously known as veno-occlusive disease because the terminal venules are often occluded), which mimics Budd-Chiari syndrome clinically. Sinusoidal obstruction syndrome is common in patients who have undergone hematopoietic stem cell transplantation, particularly those with pretransplant serum aminotransferase elevations or fever during cytoreductive therapy with cyclophosphamide, azathioprine, carmustine, busulfan, or etoposide or those receiving high-dose cytoreductive therapy or high-dose total body irradiation. In India, China, and South Africa, Budd-Chiari syndrome is associated with a poor standard of living and often the result of occlusion of the hepatic portion of the inferior vena cava, presumably due to prior thrombosis. The clinical presentation is mild but the course is frequently complicated by hepatocellular carcinoma.
The presentation is most commonly subacute but may be fulminant, acute, or chronic. Clinical manifestations generally include tender, painful hepatic enlargement, jaundice, splenomegaly, and ascites. With chronic disease, bleeding varices and hepatic encephalopathy may be evident; hepatopulmonary syndrome may occur.
Hepatic imaging studies may show a prominent caudate lobe, since its venous drainage may be occluded. The screening test of choice is contrast-enhanced, color, or pulsed-Doppler ultrasonography, which has a sensitivity of 85% for detecting evidence of hepatic venous or inferior vena caval thrombosis. MRI with spin-echo and gradient-echo sequences and intravenous gadolinium injection allows visualization of the obstructed veins and collateral vessels. Direct venography can delineate caval webs and occluded hepatic veins (“spider-web” pattern) most precisely.
Percutaneous or transjugular liver biopsy in Budd-Chiari syndrome may be considered when the results of noninvasive imaging are inconclusive and frequently shows characteristic centrilobular congestion (eFigure 16–39) and fibrosis and often multiple large regenerative nodules. Liver biopsy is often contraindicated in sinusoidal obstruction syndrome because of thrombocytopenia, and the diagnosis is based on clinical findings.
Liver biopsy—centrilobular congestion (nutmeg liver).
Ascites should be treated with salt and fluid restriction and diuretics. Treatable causes of Budd-Chiari syndrome should be sought. Prompt recognition and treatment of an underlying hematologic disorder may avoid the need for surgery; however, the optimal anticoagulation regimen is uncertain, and anticoagulation is associated with a high risk of bleeding, particularly in patients with portal hypertension and those undergoing invasive procedures. Low-molecular-weight heparins are preferred over unfractionated heparin because of a high rate of heparin-induced thrombocytopenia with the latter. Infusion of a thrombolytic agent into recently occluded veins has been attempted with success. Defibrotide, an adenosine receptor agonist that increases endogenous tissue plasminogen activator levels, has been approved by the FDA for the prevention and treatment of sinusoidal obstruction syndrome. The drug is given as an intravenous infusion every 6 hours for a minimum of 21 days. Serious adverse effects include hypotension and hemorrhage, and the drug is expensive. TIPS placement may be attempted in patients with Budd-Chiari syndrome and persistent hepatic congestion or failed thrombolytic therapy and possibly in those with sinusoidal obstruction syndrome. Late TIPS dysfunction is less frequent with the use of polytetrafluoroethylene-covered stents than uncovered stents. TIPS is now preferred over surgical decompression (side-to-side portacaval, mesocaval, or mesoatrial shunt), which, in contrast to TIPS, has generally not been proven to improve long-term survival. Older age, a higher serum bilirubin level, and a greater INR predict a poor outcome with TIPS. Balloon angioplasty, in some cases with placement of an intravascular metallic stent, is preferred in patients with an inferior vena caval web and is being performed increasingly in patients with a short segment of thrombosis in the hepatic vein. Liver transplantation can be considered in patients with acute liver failure, cirrhosis with hepatocellular dysfunction, and failure of a portosystemic shunt, and outcomes have improved with the advent of patient selection based on the MELD score. Patients with Budd-Chiari syndrome often require lifelong anticoagulation and treatment of the underlying myeloproliferative disease; antiplatelet therapy with aspirin and hydroxyurea has been suggested as an alternative to warfarin in patients with a myeloproliferative disorder. For all patients with Budd-Chiari syndrome, a poor outcome has been reported to correlate with Child-Pugh class C and a lack of response to interventional therapy of any kind.
The overall 5-year survival rate is 50–90% with treatment (but less than 10% without intervention). Adverse prognostic factors in patients with Budd-Chiari syndrome are older age, high Child-Pugh score, ascites, encephalopathy, elevated total bilirubin, prolonged prothrombin time, elevated serum creatinine, concomitant portal vein thrombosis, and histologic features of acute liver disease superimposed on chronic liver injury; 3-month mortality may be predicted by the Rotterdam score, which is based on encephalopathy, ascites, prothrombin time, and bilirubin. A serum ALT level at least fivefold above the upper limit of normal on presentation indicates hepatic ischemia and also predicts a poor outcome, particularly when the ALT level decreases slowly. The risk of hepatocellular carcinoma is increased; risk factors include cirrhosis, combined hepatic vein and inferior vena cava obstruction, and a long-segment interior vena cava block.
All patients with hepatic vein obstruction should be hospitalized.
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European Association for the Study of the Liver. EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol. 2016 Jan;64(1):179–202.
et al. Good clinical outcomes in Budd-Chiari syndrome with hepatic vein occlusion. Dig Dis Sci. 2016 Oct;61(10):3054–60.
et al. Incidence and risk factors of hepatocellular carcinoma in patients with hepatic venous outflow tract obstruction. Aliment Pharmacol Ther. 2015 May;41(10):961–71.
et al. Hepatic venous outflow tract obstruction: treatment outcomes and development of a new prognostic score. Aliment Pharmacol Ther. 2016 Jun;43(11):1154–67.
THE LIVER IN HEART FAILURE
Ischemic hepatitis, also called ischemic hepatopathy, hypoxic hepatitis, shock liver, or acute cardiogenic liver injury may affect 2.5 of every 100 patients admitted to an intensive care unit and results from an acute fall in cardiac output due to acute myocardial infarction, arrhythmia, or septic or hemorrhagic shock, usually in a patient with passive congestion of the liver. Clinical hypotension may be absent (or unwitnessed). In some cases, the precipitating event is arterial hypoxemia due to respiratory failure, sleep apnea, severe anemia, heat stroke, carbon monoxide poisoning, cocaine use, or bacterial endocarditis. More than one precipitant is common. Statin therapy prior to admission may protect against ischemic hepatitis. The hallmark is a rapid and striking elevation of serum aminotransferase levels (often greater than 5000 units/L); an early rapid rise in the serum lactate dehydrogenase (LD) level (with an ALT-to-LD ratio less than 1.5) is also typical. Elevations of serum alkaline phosphatase and bilirubin are usually mild, but jaundice is associated with worse outcomes. The prothrombin time may be prolonged, and encephalopathy or hepatopulmonary syndrome may develop. The mortality rate due to the underlying disease is high (particularly in patients receiving vasopressor therapy or with septic shock, acute kidney disease, or coagulopathy), but in patients who recover, the aminotransferase levels return to normal quickly, usually within 1 week—in contrast to viral hepatitis.
In patients with passive congestion of the liver (“nutmeg liver”) due to right-sided heart failure, the serum bilirubin level may be elevated, occasionally as high as 40 mg/dL (684 mcmol/L), due in part to hypoxia of perivenular hepatocytes, and the level is a predictor of mortality and morbidity. Serum alkaline phosphatase levels are normal or slightly elevated, and aminotransferase levels are only mildly elevated in the absence of superimposed ischemia. Hepatojugular reflux is present, and with tricuspid regurgitation the liver may be pulsatile. Ascites may be out of proportion to peripheral edema, with a high serum ascites-albumin gradient (greater than or equal to 1.1) and a protein content of more than 2.5 g/dL (25 g/L). A markedly elevated serum N-terminal-proBNP or BNP (greater than 364 pg/mL [364 ng/L]) level has been reported to distinguish ascites due to heart failure from ascites due to cirrhosis in the absence of renal insufficiency. In severe cases, signs of encephalopathy may develop.
et al. Serum B-type natriuretic peptide in the initial workup of patients with new onset ascites: a diagnostic accuracy study. Hepatology. 2014 Mar;59(3):1043–51.
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et al. The incidence and outcomes of ischemic hepatitis: a systematic review with meta-analysis. Am J Med. 2015 Dec;128(12):1314–21.
NONCIRRHOTIC PORTAL HYPERTENSION
Causes of noncirrhotic portal hypertension include extrahepatic portal vein obstruction (portal vein thrombosis often with cavernous transformation [portal cavernoma]), splenic vein obstruction (presenting as gastric varices without esophageal varices), schistosomiasis, nodular regenerative hyperplasia, and arterial-portal vein fistula. Idiopathic noncirrhotic portal hypertension is common in India and has been attributed to chronic infections, exposure to medications or toxins, prothrombotic disorders, immunologic disorders, and genetic disorders that result in obliterative vascular lesions in the liver. It is rare in Western countries, where increased mortality is attributable to associated disorders and older age. Portal vein thrombosis may occur in 10–25% of patients with cirrhosis, is associated with the severity of the liver disease, and may be associated with hepatocellular carcinoma but not with increased mortality. Other risk factors are oral contraceptive use, pregnancy, chronic inflammatory diseases (including pancreatitis), injury to the portal venous system (including surgery), other malignancies, and treatment of thrombocytopenia with eltrombopag. Portal vein thrombosis may be classified as type 1, involving the main portal vein; type 2, involving one (2a) or both (2b) branches of the portal vein; or type 3, involving the trunk and branches of the portal vein. Additional descriptors are occlusive or nonocculsive, recent or chronic, the extent (eg, into the mesenteric vein), and the nature of any underlying liver disease. Splenic vein thrombosis may complicate pancreatitis or pancreatic cancer. Pylephlebitis (septic thrombophlebitis of the portal vein) may complicate intra-abdominal inflammatory disorders such as appendicitis or diverticulitis, particularly when anaerobic organisms (especially Bacteroides species) are involved. Nodular regenerative hyperplasia results from altered hepatic perfusion and can be associated with collagen vascular diseases; myeloproliferative disorders; and drugs, including azathioprine, 5-fluorouracil, and oxaliplatin. In patients infected with HIV, long-term use of didanosine and use of a combination of didanosine and stavudine have been reported to account for some cases of noncirrhotic portal hypertension often due to nodular regenerative hyperplasia, and genetic factors may play a role. The term “obliterative portal venopathy” is used to describe primary occlusion of intrahepatic portal veins in the absence of cirrhosis, inflammation, or hepatic neoplasia.
Acute portal vein thrombosis usually causes abdominal pain. Aside from splenomegaly, the physical findings are not remarkable, although hepatic decompensation can follow severe gastrointestinal bleeding or a concurrent hepatic disorder, and intestinal infarction may occur when portal vein thrombosis is associated with mesenteric venous thrombosis. Ascites may occur in 25% of persons with noncirrhotic portal hypertension. Covert hepatic encephalopathy is reported to be common in patients with noncirrhotic portal vein thrombosis.
Liver biochemical test levels are usually normal, but there may be findings of hypersplenism. An underlying hypercoagulable state is found in many patients with portal vein thrombosis; this includes myeloproliferative neoplasms (often associated with a specific mutation [V617F] in the gene coding for JAK2 tyrosine kinase, which is found in 24% of cases of portal vein thrombosis, or occasionally with a mutation in the gene coding for calreticulin), mutation G20210A of prothrombin, factor V Leiden mutation, protein C and S deficiency, antiphospholipid syndrome, mutation TT677 of methylenetetrahydrofolate reductase, elevated factor VIII levels, hyperhomocysteinemia, and a mutation in the gene that codes for thrombin-activatable fibrinolysis inhibitor. It is possible, however, that in many cases evidence of hypercoagulability is a secondary phenomenon due to portosystemic shunting and reduced hepatic blood flow.
Color Doppler ultrasonography and contrast-enhanced CT are usually the initial diagnostic tests for portal vein thrombosis. Magnetic resonance angiography (MRA) of the portal system is generally confirmatory. EUS may be helpful in some cases. In patients with jaundice, magnetic resonance cholangiography may demonstrate compression of the bile duct by a large portal cavernoma (portal biliopathy), a finding that may be more common in patients with an underlying hypercoagulable state than in those without one. In patients with pylephlebitis, CT may demonstrate an intra-abdominal source of infection, thrombosis or gas in the portal venous system, and a hepatic abscess.
Endoscopy shows esophageal or gastric varices. Needle biopsy of the liver may be indicated to diagnose schistosomiasis, nodular regenerative hyperplasia, and noncirrhotic portal fibrosis and may demonstrate sinusoidal dilatation.
If splenic vein thrombosis is the cause of variceal bleeding, splenectomy is curative. For other causes of noncirrhotic portal hypertension, band ligation (or, less commonly, sclerotherapy) followed by beta-blockers to reduce portal pressure is initiated for variceal bleeding, and portosystemic shunting (including TIPS) is reserved for failures of endoscopic therapy; rarely progressive liver dysfunction requires liver transplantation. Anticoagulation particularly with low-molecular-weight heparin or thrombolytic therapy may be indicated for isolated acute portal vein thrombosis (and leads to at least partial recanalization in up to 75% of cases) and possibly for acute splenic vein thrombosis; an oral anticoagulant is continued long-term if a hypercoagulable disorder is identified or if an acute portal vein thrombosis extends into the mesenteric veins. The use of enoxaparin to prevent portal vein thrombosis and hepatic decompensation in patients with cirrhosis has shown promise.
All patients with noncirrhotic portal hypertension should be referred.
et al. Pylephlebitis: through these portals pass bad bugs. Dig Dis Sci. 2016 Oct;61(10):2807–11.
et al. Portal vein thrombosis is not associated with increased mortality among patients with cirrhosis. Clin Gastroenterol Hepatol. 2015 Mar;13(3):585–93.
et al. Role of the transjugular intrahepatic portosystemic shunt in the management of severe complications of portal hypertension in idiopathic noncirrhotic portal hypertension. Hepatology. 2016 Jul;64(1):224–31.
et al. Review article: portal vein obstruction—epidemiology, pathogenesis, natural history, prognosis and treatment. Aliment Pharmacol Ther. 2015 Feb;41(3):276–92.
et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology. 2015 Feb;61(2):660–7.
et al. Toward a comprehensive new classification of portal vein thrombosis in patients with cirrhosis. Gastroenterology. 2016 Oct;151(4):574–7.
ESSENTIALS OF DIAGNOSIS
Fever, right upper quadrant pain, jaundice.
Often in setting of biliary disease, but up to 40% are “cryptogenic” in origin.
Detected by imaging studies.
The incidence of liver abscess is 3.6 per 100,000 population in the United States and has increased since the 1990s. The liver can be invaded by bacteria via (1) the bile duct (acute “suppurative” [formerly ascending] cholangitis); (2) the portal vein (pylephlebitis); (3) the hepatic artery, secondary to bacteremia; (4) direct extension from an infectious process; and (5) traumatic implantation of bacteria through the abdominal wall. Risk factors for liver abscess include older age and male sex. Predisposing conditions and factors include presence of malignancy, diabetes mellitus, inflammatory bowel disease, and cirrhosis; necessity for liver transplantation; and use of proton pump inhibitors. Pyogenic liver abscess has been observed to be associated with a subsequent increased risk of gastrointestinal malignancy.
Acute cholangitis resulting from biliary obstruction due to a stone, stricture, or neoplasm is the most common identifiable cause of hepatic abscess in the United States. In 10% of cases, liver abscess is secondary to appendicitis or diverticulitis. At least 40% of abscesses have no demonstrable cause and are classified as cryptogenic; a dental source is identified in some cases. The most frequently encountered organisms are E coli, Klebsiella pneumoniae, Proteus vulgaris, Enterobacter aerogenes, and multiple microaerophilic and anaerobic species (eg, Streptococcus anginosus [also known as S milleri]). Liver abscess caused by virulent strains of K pneumoniae may be associated with thrombophlebitis of the portal or hepatic veins and hematogenously spread septic ocular or central nervous system complications. Staphylococcus aureus is usually the causative organism in patients with chronic granulomatous disease. Uncommon causative organisms include Salmonella, Haemophilus, Yersinia, and Listeria. Hepatic candidiasis, tuberculosis, and actinomycosis are seen in immunocompromised patients and those with hematologic malignancies. Rarely, hepatocellular carcinoma can present as a pyogenic abscess because of tumor necrosis, biliary obstruction, and superimposed bacterial infection (see Chapter 39). The possibility of an amebic liver abscess must always be considered (see Chapter 35).
The presentation is often insidious. Fever is almost always present and may antedate other symptoms or signs. Pain may be a prominent complaint and is localized to the right upper quadrant or epigastric area. Jaundice, tenderness in the right upper abdomen, and either steady or spiking fever are the chief physical findings. The risk of acute kidney injury is increased.
Laboratory examination reveals leukocytosis with a shift to the left. Liver biochemical tests are nonspecifically abnormal. Blood cultures are positive in 50–100% of cases.
Chest radiographs usually reveal elevation of the diaphragm if the abscess is in the right lobe of the liver. Ultrasonography, CT, or MRI may reveal the presence of intrahepatic lesions (eFigures 16–40 and 16–41). On MRI, characteristic findings include high signal intensity on T2-weighted images and rim enhancement. The characteristic CT appearance of hepatic candidiasis, usually seen in the setting of systemic candidiasis, is that of multiple “bull’s-eyes,” but imaging studies may be negative in neutropenic patients.
Liver abscess. CT shows the abscess as a low-density mass (A). S, spleen; L, liver. (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)
Multiple hepatic and splenic pyogenic abscesses. The liver contains multiple lucent fluid collections with irregular margins and abnormal septations. These collections were the result of a staphylococcal infection and represent pyogenic abscesses. The spleen also contains abscesses.
Treatment should consist of antimicrobial agents (generally a third-generation cephalosporin such as cefoperazone 1–2 g intravenously every 12 hours and metronidazole 500 mg intravenously every 6 hours) that are effective against coliform organisms and anaerobes. Antibiotics are administered for 2–3 weeks, and sometimes up to 6 weeks. If the abscess is at least 5 cm in diameter or the response to antibiotic therapy is not rapid, intermittent needle aspiration, percutaneous or endoscopic ultrasound-guided catheter drainage or stent placement or, if necessary, surgical (eg, laparoscopic) drainage should be done. Other suggested indications for abscess drainage are patient age of at least 55 years, symptom duration of at least 7 days, and involvement of two lobes of the liver. The underlying source (eg, biliary disease, dental infection) should be identified and treated. The mortality rate is still substantial (at least 5% in most studies) and is highest in patients with underlying biliary malignancy or severe multiorgan dysfunction. Other risk factors for mortality include older age, cirrhosis, chronic kidney disease, and other cancers. Hepatic candidiasis often responds to intravenous amphotericin B (total dose of 2–9 g). Fungal abscesses are associated with mortality rates of up to 50% and are treated with intravenous amphotericin B and drainage.
Nearly all patients with pyogenic hepatic abscess should be hospitalized.
et al. Pyogenic liver abscess is associated with increased risk of acute kidney injury: a nationwide population-based cohort study. Medicine (Baltimore). 2016 Jan;95(3):e2489.
et al. EUS-guided drainage of hepatic abscess and infected biloma using short and long metal stents (with videos). Gastrointest Endosc. 2015 Jun;81(6):1463–9.
et al. Proton pump inhibitor use significantly increases the risk of cryptogenic liver abscess: a population-based study. Aliment Pharmacol Ther. 2015 Jun;41(11):1175–81.
Benign neoplasms of the liver must be distinguished from hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastases (see Chapter 39). The most common benign neoplasm of the liver is the cavernous hemangioma, often an incidental finding on ultrasonography or CT (eFigure 16–42). This lesion may enlarge in women who take hormonal therapy and must be differentiated from other space-occupying intrahepatic lesions, usually by contrast-enhanced MRI, CT, or ultrasonography (eFigure 16–43). Rarely, fine-needle biopsy is necessary to differentiate these lesions and does not appear to carry an increased risk of bleeding. Surgical resection of cavernous hemangiomas is infrequently necessary but may be required for abdominal pain or rapid enlargement, to exclude malignancy, or to treat Kasabach-Merritt syndrome (consumptive coagulopathy complicating a hemangioma).
Hemangioma. Postcontrast CT scans demonstrate (A) early peripheral enhancement (arrow) and (B) delayed central filling (arrowhead). L, liver; S, spleen. (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)
Hemangioma of the liver. Early post-contrast (M-7a) and late post-contrast (M-7b). Hemangiomas are the most common primary tumors of the liver, demonstrate progressive, centripetal contrast enhancement (arrows), and are uncommonly found in patients with cirrhosis. They are predominantly found in women and usually benign. (Used, with permission, from Nicholas Fidelman, MD).
In addition to rare instances of sinusoidal dilatation and peliosis hepatis, two distinct benign lesions with characteristic clinical, radiologic, and histopathologic features have been described in women taking oral contraceptives—focal nodular hyperplasia and hepatocellular adenoma. Focal nodular hyperplasia occurs at all ages and in both sexes and is probably not caused by the oral contraceptives. It is often asymptomatic and appears as a hypervascular mass, often with a central hypodense “stellate” scar on contrast-enhanced ultrasonography, CT, or MRI (eFigure 16–44). Microscopically, focal nodular hyperplasia consists of hyperplastic units of hepatocytes that stain positively for glutamine synthetase with a central stellate scar containing proliferating bile ducts (eFigure 16–45). It is not a true neoplasm but a proliferation of hepatocytes in response to altered blood flow. Focal nodular hyperplasia is associated with an elevated angiopoietin 1/angiopoietin 2 mRNA ratio that is thought to promote angiogenesis and may also occur in patients with cirrhosis, with exposure to certain drugs such as azathioprine, and in antiphospholipid syndrome. The prevalence of hepatic hemangiomas is increased in patients with focal nodular hyperplasia.
Focal nodular hyperplasia on MRI (post-contrast). A post-contrast MRI image shows a bright, well-circumscribed hyperenhancing lesion in the right lobe of the liver that has a "central stellate scar" (arrow) without findings of cirrhosis. These characteristics are typical of focal nodular hyperplasia. (Used, with permission, from Nicholas Fidelman, MD.)
Focal nodular hyperplasia.
Hepatocellular adenoma occurs most commonly in women in the third and fourth decades of life and is usually caused by oral contraceptives; acute abdominal pain may occur if the tumor undergoes necrosis or hemorrhage. The tumor may be associated with mutations in (1) the gene coding for hepatocyte nuclear factor 1 alpha (HNF1alpha) in 30–40% of cases (characterized by steatosis and a low risk of malignant transformation, although in men concomitant metabolic syndrome appears to increase the risk of malignant transformation); (2) the gene coding for beta-catenin (characterized by a high rate of malignant transformation) in 10–20% of cases; or (3) neither gene with the designation of inflammatory adenoma (previously termed “telangiectatic focal nodular hyperplasia”), which is associated with a high body mass index and serum biomarkers of inflammation (such as C-reactive protein) in 40–55% of cases. Unclassified adenomas account for 5–10% of tumors. Rare instances of multiple hepatocellular adenomas in association with maturity-onset diabetes of the young occur in families with a germline mutation in HNF1alpha. Hepatocellular adenomas (inflammatory or unclassified adenomas) also occur in patients with glycogen storage disease and familial adenomatous polyposis. The tumor is hypovascular. Grossly, the cut surface appears structureless. As seen microscopically, the hepatocellular adenoma consists of sheets of hepatocytes without portal tracts or central veins (eFigure 16–46).
Cystic neoplasms of the liver, such as cystadenoma and cystadenocarcinoma, must be distinguished from simple and echinococcal cysts, von Meyenburg complexes (hamartomas), and polycystic liver disease.
The only physical finding in focal nodular hyperplasia or hepatocellular adenoma is a palpable abdominal mass in a minority of cases. Liver function is usually normal. Contrast-enhanced ultrasonography, arterial phase helical CT, and especially multiphase dynamic MRI with contrast can distinguish an adenoma from focal nodular hyperplasia in 80–90% of cases and may suggest a specific subtype of adenoma (eg, homogeneous fat pattern in HNF1alpha-mutated adenomas and marked and persistent arterial enhancement in inflammatory adenomas).
While oral contraceptives should not necessarily be discontinued in women who have focal nodular hyperplasia, affected women who continue taking oral contraceptives should undergo annual ultrasonography for 2–3 years to ensure that the lesion is not enlarging. The prognosis is excellent. Hepatocellular adenoma may undergo bleeding, necrosis, and rupture, often after hormone therapy, in the third trimester of pregnancy, or in men in whom the rate of malignant transformation is high. Resection is advised in all affected men and in women in whom the tumor causes symptoms or is 5 cm or greater in diameter, even in the absence of symptoms. If an adenoma is less than 5 cm in size, resection is also recommended if a beta-catenin gene mutation is present in a biopsy sample. In selected cases, laparoscopic resection or percutaneous radiofrequency ablation may be feasible. Rarely, liver transplantation is required. Regression of benign hepatic tumors may follow cessation of oral contraceptives. Transarterial embolization is the initial treatment for adenomas complicated by hemorrhage.
et al. Management of hepatocellular adenoma: recent advances. Clin Gastroenterol Hepatol. 2015 Jul;13(7):1221–30.
et al. Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set. JAMA Surg. 2015 Apr;150(4):337–42.
European Association for the Study of the Liver (EASL). EASL clinical practice guidelines on the management of benign liver tumours. J Hepatol. 2016 Aug;65(2):386–98.
et al. Evidence of good prognosis of hepatocellular adenoma in post-menopausal women. J Hepatol. 2016 Dec;65(6):1163–70.
et al. Benign solid tumors of the liver: management in the modern era. J Gastrointest Surg. 2015 Jun;19(6):1157–68.
et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014 Sep;109(9):1328–47.