ESSENTIALS OF DIAGNOSIS
Variable prodromal signs and symptoms.
Positive specific viral hepatitis tests.
Elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
Acute viral hepatitis is a worldwide problem, and in the United States alone there are probably between 200,000 and 700,000 cases per year according to the Centers for Disease Control and Prevention (CDC). Over 32% of cases are caused by hepatitis A virus (HAV), 43% by hepatitis B virus (HBV), 21% by hepatitis C virus (HCV), and the remainder are not identified. Although few deaths (~250) due to acute hepatitis are reported annually, considerable morbidity can result from chronic hepatitis caused by HBV and HCV infections, and mortality from complications can be pronounced for years to come.
Hepatitis A virus (HAV), first identified in 1973, is the prototype for the former diagnosis of infectious hepatitis. Over the past several decades, the incidence of HAV infection has varied considerably, and a high number of cases have gone unreported. HAV is a very small viral particle that is its own unique genus (hepatovirus).
Most individuals infected worldwide are children. In general, there are four patterns of HAV distribution (high, moderate, low, and very low), which roughly correspond to differing socioeconomic and hygienic conditions. Countries with poor sanitation have the highest rates of infection. Most children aged <9 years in these countries manifest evidence of HAV infection. Countries with moderate rates of infection have the highest incidence in later childhood; food- and waterborne outbreaks are more common. In countries with low endemicity, the peak age of infection is likely to be at early adulthood, and, in very low endemic countries, outbreaks are uncommon.
Hepatitis A is usually transmitted by ingestion of contaminated fecal material of an infected person by a susceptible individual. Contaminated food or water can be the source of infection, but occasionally infection can occur by contamination of different types of raw shellfish from areas contaminated by sewage. The virus can survive for 3–10 months in water. Other cases of infection by blood exposures have been reported but are less common. The incubation period for HAV averages 30 days, with a range of 15–50 days.
In countries of low endemicity, persons at greatest risk for infection include travelers to intermediate and high-HAV-endemic countries, men who have sex with men (MSMs), intravenous drug users, and persons with chronic liver disease, including those who have received transplants. In areas of high endemicity, all young children are at increased risk.
Currently in the United States, the CDC recommends that certain populations at increased risk be considered for preexposure vaccination; these include the groups listed earlier. In addition, the CDC now recommends universal immunization for all children aged >1 year. The immunization schedule consists of three doses for children and adolescents, and two for adults. In groups with the potential for high risk of exposure, including any adult aged >40 years, prevaccination testing for prior exposure may be cost-effective. The appropriate test is the total anti-HAV. Travelers aged <40 years who receive the vaccine may assume to be protected after receiving the first dose, although the second dose is desired for long-term protection. For certain travelers (older adults and those with underlying medical conditions), immunoglobulin (Ig) may be given in a different site for additional protection within 2 weeks of travel. A combination vaccine with HBV is available for persons aged >18 years who are immunocompetent and is used on the same three-dose schedule as HBV.
Immunoglobulin or hepatitis A vaccine (if previously unvaccinated) may also be used for postexposure prophylaxis in healthy patients between 12 months and 40 years of age, if given within 14 days, and would most often be used for household or intimate contacts of an infected person, in some institutional settings, or if a common source is identified. For persons with chronic illness, or those aged <12 months or >40 years, Ig is preferred.
The symptoms and signs of acute viral hepatitis are quite similar regardless of type and are difficult to distinguish on the basis of clinical findings. The prodrome for viral hepatitis is variable and may be manifested by anorexia, including changes in olfaction and taste, as well as nausea and vomiting, fatigue, malaise, myalgias, headache, photophobia, pharyngitis, cough, coryza, and fever. Dark urine and clay-colored stools may be noticed 1–5 days before jaundice.
Clinical jaundice varies considerably and may range from an anicteric state to rare hepatic coma. In acute HAV infection, jaundice is usually more pronounced in older age groups (ie, 70–80% in those aged 14 years) and rare in children aged <6 years (<10%). Weight loss may also be present, as well as an enlarged liver (70%) and splenomegaly (20%). Spider angiomata may be present without acute liver failure. Patients may also report a loss of desire for cigarette smoking or alcohol.
Usually, the onset of symptoms coincides with the first evidence of abnormal laboratory values. Acute elevations of ALT and AST are seen, with levels as high as 4000 units or more in some patients. The ALT level is usually higher than the AST. When the bilirubin level is >2.5, jaundice may be obvious. Bilirubin levels may go from 5 to 20, usually with an equal elevation of conjugated and unconjugated forms. The prothrombin time is usually normal. If significantly elevated, it may signal a poor prognosis. The complete blood count may demonstrate a relative neutropenia, lymphopenia, or atypical lymphocytosis. Urobilinogen may be present in urine in the late preicteric stage.
Serum IgM antibody (anti-HAV) is present in the acute phase and usually disappears within 3 months, although occasionally it persists longer. IgG anti-HAV is used to detect previous exposure and persists for the lifetime of the patient. The more commonly available test for IgG anti-HAV is the total anti-HAV.
Treatment for the most part is symptomatic, with many clinicians prohibiting only alcohol during the acute illness phase. Most patients can be treated at home.
In the vast majority of patients with HAV, the disease resolves uneventfully within 3–6 months. Rarely, fulminant hepatitis may develop, with acute liver failure and high mortality rates. Rare cases of cholestatic hepatitis, with persistent bilirubin elevations, have also been reported. Some patients develop relapsing hepatitis, in which HAV is reactivated and shed in the stool. Affected patients demonstrate liver function test abnormalities, but virtually all recover completely. HAV does not progress to chronic hepatitis.
Hepatitis B virus (HBV) is a double-shelled DNA virus. The outer shell contains the hepatitis B surface (HBsAg). The inner core contains several other particles, including hepatitis core antigen (HBcAg) and HBeAg. These antigens and their subsequent antibodies are described in more detail later.
Worldwide, over 400 million people are infected with HBV, but the distribution is quite varied. More than 45% of the global population live in areas of high incidence (infections in >8% of population). There, the lifetime risk of infection is over 60%, and early childhood infections are very common. Intermediate-risk areas (infections in 2–7% of the population) represent 43% of the global population. The lifetime risk of infection in these areas is between 20% and 60%, and infections occur in various age groups. In low-risk areas (infections in <2%), which represent ~12% of the global population, the lifetime risk of infection is <20% and is usually limited to specific adult risk groups.
In the United States, HBV is normally a disease of young adults. The largest numbers of cases are reported in adults aged 20–39 years, but many cases in younger age groups may be asymptomatic and go unreported. Of the specific risk groups in the United States, over 50% in recent studies are those with sexual risk factors (more than one sex partner in the past 6 months, sexual relations with an infected person, or MSM transmission). Over 15% had a history of injection drug use, and 4% had other risk factors such as a household contact with HBV or a healthcare exposure. The mode of transmission can thus be sexual, parenteral, or perinatal, through contact of the infant’s mucous membranes with maternal infected blood at delivery.
Body fluids with the highest degree of concentration of HBV are blood, serum, and wound exudates. Moderate concentrations are found in semen, vaginal fluid, and saliva, and low or nondetectable amounts are found in urine, feces, sweat, tears, or breast milk. Saliva can be implicated in transmission through bites, but not by kissing.
The average incubation period for HBV is between 60 and 90 days, with a range of 45–180 days. Although the incidence of jaundice increases with age (<10% of children <5 years demonstrate icterus compared with 30–50% of those aged >35 years), the likelihood of chronic infection with HBV is greater when infection is contracted at a younger age. Between 30% and 90% of all children who contract HBV before the age of 5 years develop chronic disease, compared with 2–10% of those aged >35 years.
Current immunization recommendations in the United States call for routine immunization of all infants, children, adolescents, and adults in high-risk groups, including all diabetic patients aged 19–58 years, and all patients with chronic liver disease. Acknowledgment of a specific risk factor is not a requirement for immunizations. These recommendations include immunizing all children at birth, 1, and 6 months. Additionally, all high-risk groups should be screened, as well as all pregnant women. Prevaccination testing of patients in low-risk groups is probably not necessary, but in high-risk groups, this may be cost-effective. As illustrated in the first test scenario of Table 33-2, a negative HBsAg titer and a negative anti-HBs titer are evidence of susceptibility to HBV.
Table 33–2.Interpretation of the hepatitis B panel. ||Download (.pdf) Table 33–2.Interpretation of the hepatitis B panel.
|Tests ||Results ||Interpretation |
Immune because of natural
Immune because of hepatitis
|Acutely infected |
|Chronically infected |
|Four interpretations possiblea |
The vaccine contains components of HBsAg. Pretesting with anti-HB core antibody (anti-HBc) is probably the single best test, because it would identify those who are infected and those who have been exposed. Posttesting for vaccine is seldom recommended, except for individuals who may have difficulty mounting an immune response (eg, immunocompromised patients). In these patients, the HB surface antibody (anti-HBs) would be the appropriate test. Some authorities recommend revaccinating high-risk individuals if titer levels have fallen below 10 IU/L after 5–10 years, or if they have failed to mount an appropriate immune response with the standard dosing and schedule.
Children born to women of unknown hepatitis B status should receive a first dose of hepatitis B vaccine at birth and hepatitis B immune globulin (HBIG) within 7 days of birth if maternal blood is positive. Repeat testing of all infants born to HBV-infected mothers should be performed at 9–18 months with HBsAg and anti-HBs. Infants born to HBV-infected mothers should receive both the first dose of hepatitis B vaccine at birth as well as 0.5 mL of HBIG in separate sites within 12 hours after birth. Recommendations for postexposure prophylaxis of HBV can be reviewed in the current CDC recommendations.
Acute infection may range from an asymptomatic infection to cholestatic hepatitis to fulminant hepatic failure. HBsAg and other markers usually become positive about 6 weeks after infection and remain positive into the clinical signs of illness. Other biochemical abnormalities begin to show abnormalities in the prodromal phase and may persist several months, even with a resolving disease process. Anti-HB core IgM becomes positive early, with onset of symptoms, and both anti-HB core IGM and anti-HB core IgG may persist for many months or years. Anti-HBs is the last antibody to appear and may indicate resolving infection. The presence of HBeAg indicates active viral replication and increased infectivity (Figure 33-1). Liver function tests should be obtained early in the course of infection, and evidence of prolonged prothrombin time (>1.5 INR) should raise concern for hepatic failure. Patients who remain chronically infected may demonstrate HBsAg and HBeAg for at least 6 months, with a usual trend in liver function tests toward normal levels, although results may remain persistently elevated (Figure 33-2). Extrahepatic manifestations of HBV infection may occur and include serum sickness, polyarteritis nodosa, and membranoproliferative glomerulonephritis.
Acute hepatitis B virus infection with recovery.
Progression to chronic hepatitis B virus infection.
Complications of chronic infection may include progression to cirrhosis and hepatocellular carcinoma (HCC). Patients with active viral replication are at highest risk of chronic disease, with 15–20% developing progressive disease over a 5-year period. Continued positivity for HBeAg is associated with an increased risk of HCC. Most patients who are chronically infected remain HBsAg-positive for their lifetime. There is no general agreement concerning the appropriate screening for patients with chronic infection for HCC. Some experts would not screen carriers if all laboratory tests are normal but would screen with ultrasonography and α-fetoprotein for evidence of chronic active hepatitis every 2–3 years, and more frequently in patients with cirrhosis. It appears that the incidence of progression of disease is greater in countries with high endemicity, and clinicians in these countries screen as frequently as every 6 months.
Treatment for chronic disease depends on evidence of viral activity, HBeAg status, HIV and HCV comorbidity, histologic evidence of liver injury, and elevated liver function tests. Currently approved treatment modalities include interferon alfa, pegylated interferon, lamivudine, telbivudine, adefovir, tenofovir, and entecavir. Other new antiviral agents are currently being tested. Sensitive tests for determination of response to therapy, such as covalently closed circular DNA (cccDNA), may be more readily available in the future.
Hepatitis C virus (HCV) has become the most common bloodborne infection as well as the leading cause of chronic liver disease and subsequently, liver transplantation in the United States. Worldwide, more than 180 million people are infected, but the infection rates vary considerably. In the United States, it is estimated that approximately 4 million people may be infected with HCV; it is the main cause of death from liver disease. The responsible virus is an RNA virus of the Flaviviridae family. Six major genotypes, numbered 1 through 6, are known, with additional subtypes. There are varying distributions of these genotypes, and they may affect the progression of disease and the response to treatment regimens.
Hepatitis C is spread primarily through percutaneous exposure to blood. Since 1992, all donated blood has been screened for HCV. Injection drug use is responsible for >50% of new cases. Within 1–3 months after a first incident of needle sharing, 50–60% of intravenous drug users are infected. Other risk factors include use of intranasal cocaine, hemodialysis, tattooing (debatable), and vertical transmission, which is rare. Breastfeeding carries a low risk of transmission. Sexual transmission is uncertain but is probably 1–3% over the lifetime of a monogamous couple, one of whom is infected. Healthcare workers are at particular risk following a percutaneous exposure (1.8% average incidence).
One-time screening of all individuals born between 1945 and 1965 has been recommended by the CDC, along with screening of patients with known risk factors.
No immunizations are currently available for HCV infections. Prevention consists mainly of reduction of risk factors, including screening of blood and blood products, caution to prevent percutaneous injuries, and reduction in intravenous drug use.
The incubation period for HCV varies between 2 and 26 weeks, but most commonly is 6–7 weeks. Most patients with HCV are asymptomatic at the time of infection. However, >20% of all recognized cases of acute hepatitis in the United States are caused by HCV, and as many as 30% of adults who are infected may present with jaundice. Acute, fulminant hepatic failure is rare.
In contrast to HAV and HBV, most people infected with HCV (85%) develop a chronic infection. The incidence of significant liver disease is 20–30% for cirrhosis and 4% for liver failure; over 1–4% of patients with chronic infection develop HCC annually, or 11–19% over 4–11 years in one study. It appears that certain risk factors increase the likelihood of progression to serious disease. These include increased alcohol intake, age >40 years, HIV coinfection, and possibly male gender and other liver coinfections.
Extrahepatic manifestations of chronic infection are fairly common and are similar to those of HBV, including autoimmune conditions and renal conditions such as membranous glomerulonephritis.
Patients in a high-risk category for HCV should be tested with both an approved HCV antibody test such as the OraQuick HCV Rapid Antibody test or other approved tests and a confirmatory test by nucleic acid testing (NAT) to detect HCV RNA if positive. All patients with HCV infection should have quantitative NAT as well as HCV genotyping prior to therapy in order to predict a therapeutic response as well as duration of therapy. The appropriate role of liver biopsy in decisions concerning therapy is in a state of flux, particuarly regarding threatment for genotype 1 patients. Consultation with a liver specialist should be considered to ascertain the value of this additional information that a liver biopsy would provide.
Treatment for both acute and chronic HCV has undergone significant strides in more recent years. A recent study documents the conversion of a significant number of patients to negative serology when treated in the acute phase of infection. Chronic HCV genotype 1 is treated with either a combination of direct acting antibody drugs (DAA) such as simeprevir and sofosbuvir with or without an interferon regimen and/or ribavirin. Treatment recommendations are rapidly changing. The other genotypes are less sensitive to therapy with the protease inhibitors and are usually managed with only interferon and rivavirin. Other new treatments are currently under investigation.
It is important to immunize patients with chronic HCV infection for HAV, because the incidence of fulminant hepatitis A has been shown to be significantly increased in this population. Patients infected with HCV should also abstain from alcohol. It has also been recommended that HCV-infected individuals be vaccinated for HBV, owing to the poor prognosis of coinfected individuals. Chronic hepatitis C can also progress to cirrhosis and HCC, and appropriate screening measures as discussed under Hepatitis B apply to hepatitis C-infected patients as well.
Other Types of Infectious Hepatitis
Over 97% of the viral hepatitis in the United States is either A, B, or C. Other types of viral hepatitis occur much less frequently, although worldwide, they may be more important.
Hepatitis D virus (HDV) can replicate only in the presence of HBV infection. HDV infection can occur either as a coinfection with HBV or as a superinfection in a chronically infected individual with HBV. Although coinfection can produce more severe acute disease, a superinfection poses the risk of more significant chronic disease, with 70–80% of patients developing cirrhosis. The mode of transfmission is most commonly percutaneous. The only tests commercially available in the United States are IgG–anti-HDV. Prevention of HDV depends on prevention HBV. There are no products currently available to prevent HDV infection in patients infected with HBV.
Hepatitis E virus (HEV) is the most common cause of enterically transmitted non-A, non-B hepatitis. Acute HEV infection is similar to other forms of viral hepatitis; no chronic form is known. Severity of illness increases with age, and for reasons that are unclear, case fatality rates are particularly high in pregnant women. Most cases of HEV reported in the United States have occurred in travelers returning from areas of high endemicity. In certain areas of the world (Mexico, North Africa, the Middle East, and Asia), epidemics of HEV may be common. Prevention includes avoidance of drinking water and other beverages of unknown purity, uncooked shellfish, and uncooked vegetables and fruits. No vaccines are currently available, although one recently developed has proven to be highly effective.
Acute Hepatitis: A Cost-Effective Approach
Because the vast majority of viral hepatitis cases are caused by HAV, HBV, or HCV, tests to determine the precise etiology are necessary for appropriate primary and secondary prevention for the patient, as well as potential for therapy. Figure 33-3 outlines one cost-effective approach. If these tests fail to indicate a diagnosis, the etiology may be due to less frequent causes of viral hepatitis such as Epstein-Barr virus, in which jaundice rarely accompanies infectious mononucleosis; cytomegalovirus or herpesvirus in immunocompromised patients; or other nonviral etiologies, such as alcoholic hepatitis, drug toxicity, Wilson disease, or an autoimmune hepatitis.
Cost-effective workup for acute viral hepatitis. (Reproduced, with permission, from Ahmed A, Keefe EB. Cost-effective evaluation of acute viral hepatitis. West J Med. 2000;172:29-32.)
E. Cost-effective evaluation of acute viral hepatitis. West J Med
et al.. NIH consensus development conference on management of hepatitis B. NIH Consens State Sci Statements
Centers for Disease Control and Prevention: Testing for HCV Infection: an update of guidance for clinicans and laboratorians. MMWR. 2013;62(18):362–365.
LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433–1444.
J. Hepatitis A. Am Fam Physician
. 2012; 86(11);1027–1034.
US Public Health Service. Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR
(CDC Morbidity & Mortality Weekly Report
Centers for Disease Control and Prevention, hepatitis information (references for immunization and testing, as well as patient information in several languages). http://www.cdc.gov/hepatitis/
Alcoholic liver disease includes several different disease entities, spanning a large clinical spectrum. These diseases range from the syndrome of acute fatty liver to severe liver damage as manifested by cirrhosis. Fatty liver is usually asymptomatic except for occasional hepatomegaly and is the histologic result of excessive use of alcohol over a several-day period. In perivenular fibrosis, fibrous tissue is deposited in the central areas of the liver, particularly the central veins; this indicates that the individual may then rapidly progress to more severe forms of liver disease. Patients can progress from this stage directly to cirrhosis. Alcoholic hepatitis is a condition in which necrosis of hepatic cells occurs as part of an inflammatory response, which includes polymorphonuclear cells, along with evidence of fibrosis. Cirrhosis may result from continued progression of disease from alcoholic hepatitis or may occur without evidence of prior alcoholic hepatitis. Cirrhosis is characterized by distortion of the liver structure, with bands of connective tissue forming between portal and central zones. Changes in hepatic blood circulation may also occur, resulting in portal hypertension. Additionally, evidence of abnormal fat metabolism, inflammation, and cholestasis may be seen. Progression to hepatocellular carcinoma (HCC) may also occur, although the exact risk of cirrhosis itself in the progression to HCC is not clear.
It is known that women are more likely than men to develop alcoholic liver disease, although the reasons for this phenomenon are only now being clarified. There may be additional genetic factors, most notably in specific enzyme systems, such as the metabolism of tumor necrosis factor (TNF) and alcohol-metabolizing systems, which affect the development of disease. Concomitant disease, such as HCV infection, is also a risk factor. Other factors (eg, obesity) may also play a role in the progression of disease.
A history of drinking alcohol in excess of 80 g/day (six to eight drinks) is seen with the development of more advanced forms of the disease, although there is considerable individual variation. Numerous questionnaires have been designed for detection of excessive drinking, but the CAGE questionnaire (cut down, annoyed by criticism, guilty about drinking, eye-opener drinks) is probably the most useful.
Clinical findings may be limited at this stage to occasional hepatomegaly. Patients with alcoholic hepatitis may present with classic signs and symptoms of acute hepatitis, including weight loss, anorexia, fatigue, nausea, and vomiting. Hepatomegaly may be evident, as well as other signs of more advanced disease, such as cirrhosis, because the development of cirrhosis may occur concomitant with a new episode of alcoholic hepatitis. These signs include jaundice, splenomegaly, ascites, spider angiomas, and signs of other organ damage secondary to alcoholism (eg, dementia, cardiomyopathy, or peripheral neuropathy).
Various commercially available laboratory tests have been used to detect excessive alcohol intake in the early stages. The sensitivity and specificity of these tests vary. Liver function tests for elevations of AST, ALT, and GGT are frequently used. Elevation of mean corpuscular volume (MCV) has also been noted in patients with early-stage disease.
Transaminase levels are usually only mildly elevated in pure alcoholic hepatitis unless other disease processes, such as concomitant viral hepatitis, or acetaminophen ingestion are present; AST is usually elevated to ≤200 IU/L; and AST, to ≤500 IU/L. AST elevation is usually greater than that of ALT. Elevated prothrombin time and bilirubin levels have a significant negative prognostic indication. The presence of jaundice may have special significance in any actively drinking person and should be carefully evaluated. Several instruments have been used for evaluation of severity, but the most common is the Maddrey discriminant function (MDF):
A score > 32 is indicative of high risk of death.
Abstinence from alcohol is essential, and is probably the most important of all therapies. Recovery from the acute episode is associated with an 80% 7-year survival rate in patients who can abstain from alcohol versus 50% survival in those who continue drinking. The use of naltrexone or acamprosate in conjunction with counseling and support groups to prevent recidivism should be considered.
Initial treatment of the acutely ill patient centers on ensuring adequate volume replacement, with concern for the ability to handle normal saline. Diuretics should be avoided. Patients should be assessed for protein-calorie malnutrition and vitamin and mineral deficiencies. Adequate nutrition should be given to patients with severe disease, parenterally if necessary. There is no indication that avoidance of protein is helpful in patients with encephalopathy. Broad-spectrum antibiotics should be considered early in the treatment course. Many patients develop spontaneous peritonitis, pneumonia, or cellulitis, which should be treated aggressively. Corticosteroids have been suggested as beneficial, but considerable debate still ensues as to whether there is any benefit to survival, although current recommendations are that patients with severe disease (MDF ≥32) with or without encephalopathy and without contraindications for steroid use should be considered for a 4-week course of prednisone followed by a 2-week taper. Pentoxifylline, which modifies tumor necrosis factor alpha (TNFα), may also be considered, especially if steroids are contraindicated.
Liver transplantation may be an option. Alcoholic liver disease is currently the second most common reason for liver transplantation in the United States. To be considered for transplantation, patients should not have active alcoholic hepatitis, should have remained sober for more than 6 months, and should have had addictive treatment. The prognosis is excellent if relapse from drinking can be avoided. Relapse occurs in 15–30% of patients.
Other treatment methodologies in various stages of testing include other TNFα modifiers; antioxidant therapy with agents such as S-adenosyl-l-methionine (SAM-e), silymarin, or vitamin E; antifibrotics such as polyenylphosphatidylcholine (PPC); or other medications such as colchicine. Further studies are needed before these therapies can be recommended.
J. Advances in liver disease: alcoholic hepatitis, non-cirrhotic portal fibrosis, and complications of cirrhosis. Treatment of alcoholic hepatitis. J Gastroenterol Hepatol
. 2002; 17:448.
et al.. Alcoholic liver disease. Am J Gastroenterol
. 2010; 105:14–32.
FS. The management of cirrhotic ascites. Medscape Gen Med. 2002;4(4).
Nonalcoholic Fatty Liver Disease
A relatively new condition described around 1980, nonalcoholic fatty liver disease (NAFLD), encompasses a wide clinical spectrum of patients whose liver histology is similar to those of patients with alcohol-induced hepatitis, but without the requisite history. Women are affected more frequently than men. Many of these patients progress to cirrhosis. NAFLD is now the most common liver disease in the United States, occurring in ≤20% of the population in some studies. This condition is common in obese patients, as well as in patients with type 2 diabetes mellitus. It may be a part of the syndrome X, which includes obesity, diabetes mellitus, dyslipidemia, and hypertension. Clinical features include hepatomegaly (75%) and splenomegaly (25%), but no pathognomonic laboratory markers. Elevations of ALT and AST may be ≤5 times normal, with an AST:ALT ratio of <1. Evidence of steatosis can be seen on hepatic ultrasonography. Treatment includes weight reduction, treatment of diabetes, and treatment of lipid disorders. There is no current evidence of the efficacy of specific pharmacologic therapy.
Wilson disease, which is characterized by hepatolenticular degeneration, is caused by abnormal metabolism of copper. It is inherited in an autosomal-recessive pattern and has a prevalence in the general population of approximately 1 in 30,000. Although patients in asymptomatic stages may manifest only transaminasemia or Kayser-Fleischer rings (golden-greenish granular deposits in the limbus), hepatomegaly or splenomegaly may already be present. In most symptomatic patients (96%), the serum ceruloplasmin level is <20 mg/dL. In patients with more advanced disease, symptoms of acute hepatitis or cirrhosis may be present. Neurologic signs include dysarthria, tremors, abnormal movements, and psychological disturbances. HCC may occur in patients with advanced disease. Treatment includes penicillamine, trientine, or zinc salts.
An inborn error of iron metabolism leading to increased iron absorption from the diet, hemochromatosis is associated with diabetes, bronze skin pigmentation, hepatomegaly, loss of libido, and arthropathy. Patients may also show signs of cardiac or endocrine disorders. Symptoms usually first manifest between 40 and 60 years of age, and men are 10 times more likely than women to be affected. Hemochromatosis is the most common inherited liver disease in people of European descent. Physical signs include hepatomegaly (95% of symptomatic patients), which precedes abnormal liver function tests. Cardiac involvement includes congestive heart failure and arrhythmias. Many patients have cirrhosis by the time they are symptomatic (50–70%), 20% have fibrosis, and 10–20% have neither. HCC is common in patients with cirrhosis (30%) and is now the most common cause of death. Laboratory findings include elevated serum iron concentration, serum ferritin, and transferrin saturation. Therapy involves treatment of the complications of hemochromatosis, removal of excess iron by phlebotomy, and, in patients with cirrhosis, surveillance for HCC and treatment of hepatic and cardiac failure.
Autoimmune hepatitis is a hepatocellular inflammatory disease of unknown etiology. Diagnosis is based on histologic examination, hypergammaglobulinemia, and presence of serum autoantibodies. The condition may be difficult to discern from other causes of chronic liver disease, which need to be excluded before diagnosis. Immunoserologic tests that are essential for diagnosis are assays for antinuclear antibodies (ANAs), smooth-muscle antibodies (SMAs), antibodies to liver and kidney microsome type 1 (anti-LKM1), and anti-liver cytosol type 1 (anti-LCI), as well as perinuclear antineutrophil cytoplasmic antibodies (aANCAs). Treatment, when indicated, is usually immunosuppressive with either prednisone, azathioprine, or both.
Drug-Induced Liver Disease
More than 600 drugs or other medicinals have been implicated in liver disease. Worldwide, drug-induced liver disease represents approximately 3% of all adverse drug reactions; in the United States, more than 20% of cases of jaundice in the elderly are caused by drugs. Acetaminophen and other drugs account for 25–40% of fulminant hepatic failure. Diagnosis is based on the discovery of abnormalities in hepatic enzymes or the development of a hepatitis like syndrome or jaundice. Most cases occur within 1 week to 3 months of exposure, and symptoms rapidly subside after cessation of the drug, returning to normal within 4 weeks of acute hepatocellular injury. Hepatic damage may manifest as acute hepatocellular injury (isoniazid, acetaminophen), cholestatic injury (contraceptive steroids, chlorpromazine), granulomatous hepatitis (allopurinol, phenylbutazone), chronic hepatitis (methotrexate), vascular injury (herbal tea preparations with toxic plant alkaloids), or neoplastic lesions (oral contraceptive steroids).
Statins, on the other hand, are widely used and can commonly cause mild liver enzyme elevations, but mild elevations of ALT or AST (<3 times the upper limit of normal) do not appear to contribute to liver toxicity.
Primary Biliary Cirrhosis
This autoimmune disease of uncertain etiology is manifested by inflammation and destruction of interlobular and septal bile ducts, which can cause chronic cholestasis and biliary cirrhosis. It is predominantly a disease of middle-aged women (female-to-male ratio of 9:1) and is particularly prevalent in northern Europe. The condition may be diagnosed on routine testing or be suspected in women with symptoms of fatigue or pruritus, or in susceptible individuals with elevated serum alkaline phosphatase, cholesterol, and IgM levels. Antimitochondrial antibodies are frequently found. Ursodeoxycholic acid is the only therapy currently available, although some patients may benefit from liver transplantation.
Hepatocellular carcinoma is the most common malignant tumor of the liver; it is the fifth most common cancer in men and the eighth most common in women. Incidence increases with age, but the mean age in ethnic Chinese and African populations is lower. Signs of worsening cirrhosis may alert the clinician to consider HCC, but, in many cases, the onset is subtle. There are no specific hepatic function tests to detect HCC, but elevated serum tumor markers, most notably α-fetoprotein, are useful. Ultrasonography can detect the majority of HCC but may not distinguish it from other solid lesions. CT and MRI are also helpful in making the diagnosis. Risk factors for HCC include HBV, HCV, all etiologic forms of cirrhosis, ingestion of foods with aflatoxin B1, and smoking. In these patients, ultrasonography and α-fetoprotein measurements every 4–6 months are recommended. In moderate-risk patients (ie, with later-onset HBV), measurement of α-fetoprotein every 6 months and annual ultrasound study are suggested.
Benign tumors include hepatocellular adenomas, which have become more common with the use of oral contraceptive steroids, and cavernous hemangiomas, which may occur with pregnancy or oral contraceptive steroid use and are the most common benign tumor of the liver.
Liver abscesses can be the result of infections of the biliary tract or can have an extrahepatic source such as diverticulitis or inflammatory bowel disease. In ~40% of cases, no source of infection is found. The most common organisms are Escherichia coli, Klebsiella, Proteus, Pseudomonas, and Streptococcus species. Amebic liver abscesses are the most common extraintestinal manifestation of amebiasis, which occurs in >10% of the world’s population and is most prevalent in the United States in young Hispanic adults. Amebic abscesses may have an acute presentation, with symptoms present for several weeks; few patients report typical intestinal symptoms such as diarrhea. Ultrasonography or CT scans with serologic tests such as enzyme-linked immunosorbent assay (ELISA) or indirect fluorescent antibody tests help confirm the diagnosis.
et al.. How should we manage patients with non-alcoholic fatty liver disease in 2007? J Gastroenterol Hepatol
et al.. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51(6):2103–2213.
E. Statins and elevated liver tests: what’s the fuss? J Fam Practice