26: Jaundice and Abnormal Liver Enzymes

The differential diagnosis of jaundice, or hyperbilirubinemia, is often organized pathophysiologically. It is helpful to review some basic physiology first.

1. Oxidation of the heme moiety of Hgb generates biliverdin, which is metabolized into unconjugated bilirubin, and then bound to albumin.

2. There are 3 steps in bilirubin metabolism in the liver:

   1. Uptake: The unconjugated bilirubin-albumin complex reaches the hepatocyte; bilirubin dissociates from albumin and then enters the hepatocyte.

   2. Conjugation: Unconjugated bilirubin and glucuronic acid combine to make conjugated bilirubin.

   3. Excretion: The hepatocyte excretes conjugated bilirubin into the bile.

      1. The rate-limiting step of bilirubin metabolism in the liver

      2. If excretion is impaired, conjugated bilirubin enters the hepatic sinusoids and then into the bloodstream.

3. Conjugated bilirubin in the bile is transported through the biliary ducts into the duodenum; it is not reabsorbed by the intestine.

   1. Can be excreted unchanged in the stool

   2. Can be converted to urobilinogen by colonic bacteria

      1. Urobilinogen can be reabsorbed, entering the portal circulation.

      2. Some is taken up by the liver and re-excreted into the bile.

      3. Some bypasses the liver and is excreted by the kidney, thus appearing in the urine in small amounts.

      4. Can be converted in the bowel to stercobilin rendering the stool brown.

4. Unconjugated bilirubin is not found in the urine because it is bound to albumin and cannot be filtered by the glomeruli.

5. Conjugated bilirubin is filtered and excreted in the urine when there is conjugated hyperbilirubinemia.

The first pivotal point in the differential diagnosis of hyperbilirubinemia is determining which kind of bilirubin is elevated.

Dark, tea-colored urine means the patient has conjugated hyperbilirubinemia.

Light stools, often described as “clay colored,” occur when extrahepatic obstruction prevents bilirubin from entering the intestine.

If the patient has unconjugated hyperbilirubinemia (> 50% of the bilirubin is unconjugated), use a pathophysiologic framework:

1. Increased bilirubin production

   1. Hemolysis

   2. Dyserythropoiesis

   3. Extravasation of blood into tissues

2. Impaired hepatic bilirubin uptake

   1. Heart failure

   2. Sepsis

   3. Drugs (rifampin, probenecid, chloramphenicol)

   4. Fasting

   5. Portosystemic shunts

3. Impaired bilirubin conjugation (decreased hepatic glucuronosyltransferase activity)

   1. Hereditary

      1. Gilbert syndrome

      2. Crigler-Najjar syndrome

   2. Acquired

      1. Neonates

      2. Hyperthyroidism

      3. Ethinyl estradiol

      4. Liver disease (causes mixed hyperbilirubinemia; usually predominantly conjugated)

      5. Sepsis

Most patients with unconjugated hyperbilirubinemia have hemolysis, Gilbert syndrome, heart failure, sepsis, or very advanced cirrhosis.

Although many sources organize the differential diagnosis for conjugated hyperbilirubinemia (when > 50% is conjugated) using a pathophysiologic framework, a more practical, clinical approach uses the results of other liver function tests:

1. Normal liver enzymes (ALT [SGPT], AST [SGOT])

   1. Sepsis or systemic infection

   2. Rotor syndrome

   3. Dubin-Johnson syndrome

2. Elevated liver enzymes

   1. Hepatocellular pattern: transaminases more elevated than alkaline phosphatase

      1. Marked transaminase elevations (> 1000 units/L)

         • (1) Acute viral hepatitis

         • (2) Ischemic hepatitis

         • (3) Medication- or toxin-induced hepatitis

         • (4) Autoimmune hepatitis

         • (5) Acute bile duct obstruction

         • (6) Acute Budd-Chiari syndrome

      2. Mild to moderate elevations (mild elevation: defined as < 5 times the upper limit of normal [approximately < 175–200 units/L])

         • (1) Alcoholic liver disease

         • (2) Medications/toxins

         • (3) Chronic hepatitis B or C

         • (4) Nonalcoholic fatty liver disease (NAFLD)

         • (5) Autoimmune hepatitis

         • (6) Hemochromatosis

         • (7) Wilson disease (in patients < 40 years old)

         • (8) Alpha-1-antitrypsin deficiency

   2. Cholestatic pattern: alkaline phosphatase more elevated than transaminases

      1. Extrahepatic cholestasis (bile duct obstruction)

         • (1) Common bile duct stone

         • (2) Benign stricture

         • (3) Benign polyp

         • (4) Malignancy (pancreatic cancer, cholangiocarcinoma, ampullary cancer)

         • (5) Periportal adenopathy

      2. Intrahepatic cholestasis (primarily due to impaired excretion)

         • (1) Hepatitis (viral, alcoholic)

         • (2) Intrahepatic cholestasis of pregnancy

         • (3) Cirrhosis

         • (4) Medications and toxins

         • (5) Sepsis

         • (6) Total parenteral nutrition

         • (7) Postoperative jaundice

         • (8) Infiltrative diseases (amyloidosis, lymphoma, sarcoidosis, tuberculosis)

         • (9) Primary sclerosing cholangitis

         • (10) Primary biliary cirrhosis

Regardless of how you organize this differential, the first step is to determine whether the hyperbilirubinemia is primarily unconjugated or conjugated. The differential of unconjugated hyperbilirubinemia is relatively limited. If the hyperbilirubinemia is conjugated, the second step is to determine whether there is extrahepatic obstruction or intrinsic liver dysfunction due to 1 of many possible etiologies. Although other liver function tests can serve as a guide, it is clear from the way the above differentials overlap that these tests are not very specific. Table 26-1 summarizes the commonly used liver tests. Figure 26-1 outlines the diagnostic approach to hyperbilirubinemia.

1. Jaundice

   1. Detectable on physical exam when total bilirubin is > 2.5–3.0 mg/dL.

      Scleral icterus is detectable before jaundice of the skin.

   2. For bilirubin > 3.0 mg/dL, sensitivity of physical exam is 78.4% and specificity is 68.8% (LR+ = 2.5, LR– = 0.31).

   3. For bilirubin > 15.0 mg/dL, sensitivity of physical exam is 96.4%.

2. Hepatomegaly

   1. On ultrasound, the upper limit of normal for the cephalocaudad dimension of the liver is 13 cm.

   2. While examiners are always correct when they report palpating the liver edge (LR+ = 233), a palpable liver edge is not a reliable sign of hepatomegaly (sensitivity, 39–71%; specificity, 56–85%; LR+, 1.9; LR–, 0.6) since the liver may be pushed caudally by enlarged lungs.

3. Splenomegaly

   1. Percussion methods have inadequate negative LRs (all around 0.45) and minimal positive LRs.

   2. Palpation of a spleen in a supine position is highly predictive of splenomegaly: LR+ = 8.5, LR– = 0.41.

4. Ascites

   1. The best 3 historical findings are

      1. Increased abdominal girth (LR+ = 4.1, LR− = 0.17)

      2. Recent weight gain (LR + = 3.2, LR– = 0.42)

      3. Ankle swelling (LR+ = 2.80, LR− = 0.10)

   2. The best physical exam findings are

      1. Fluid wave (LR+ = 5.3, LR− = 0.57)

      2. Shifting dullness (LR+ = 2.1, LR− = 0.4)

      3. Proper physical exam technique must be used to obtain these LRs.

   3. Ultrasound can detect minimal ascites, far less than could ever be detected on physical exam.

The pattern of the biochemical abnormalities is the next pivotal point to consider. The combination of a substantially elevated alkaline phosphatase and moderately elevated transaminases is consistent with a cholestatic pattern, due either to a disease causing intrahepatic cholestasis or to extrahepatic obstruction. Viral or alcoholic hepatitis, with or without cirrhosis, would be the most common diseases that cause both hepatocellular and cholestatic abnormalities; the AST being greater than the ALT is a pivotal finding that points toward alcoholic liver disease. The physical exam findings of hepatomegaly and splenomegaly both modestly increase the likelihood of chronic liver disease (LR+, 2.3 for hepatomegaly; 2.9 for splenomegaly). Extrahepatic obstruction must be considered also, since she could have an obstruction in addition to chronic liver disease. Cancer and stricture are more likely causes of painless jaundice than common bile duct stones. Pancreatic cancer is the most common malignancy that causes extrahepatic obstruction; cholangiocarcinoma and ampullary carcinoma are 2 other possibilities. Occasionally, obstruction is due to benign polyps in the biliary tree. Table 26-2 lists the differential diagnosis.

Leading Hypothesis: Alcoholic Liver Disease (ALD)

Textbook Presentation

Patients may be asymptomatic, have incidentally discovered hepatomegaly or transaminase elevation, have symptoms of acute alcoholic hepatitis, or have manifestations of cirrhosis. Some or all of these symptoms may develop in an individual patient during the course of the disease.

Disease Highlights

1. Alcohol ingestion is the most important risk factor for ALD.

   1. Beer and spirits are more associated with ALD than wine.

   2. Drinking outside of meal time and binge drinking increase the risk.

2. Other risk factors include female sex, African-American and Hispanic ethnicity, obesity, and genetic factors.

3. ALD is more frequent and worse in patients with other chronic liver diseases, especially hepatitis C.

4. There are 3 histologic stages: steatosis, alcoholic steatohepatitis, and chronic hepatitis with fibrosis or cirrhosis.

   1. Hepatic steatosis is generally asymptomatic.

      1. 70% of patients have hepatomegaly

      2. Occurs in up to 90% of patients who consistently consume > 6 drinks (60 g) per day

      3. Potentiates liver damage from other insults, such as viral hepatitis or acetaminophen toxicity, and promotes obesity-related liver disease.

      4. Usually completely reversible with abstinence from alcohol for 4–6 weeks

         • (1) Despite abstinence, cirrhosis will develop in 5–15% of patients with steatosis.

         • (2) Cirrhosis develops in 30% of those who continue to drink.

   2. Alcoholic steatohepatitis occurs in 15–30% of patients with ALD.

      1. Often presents acutely in the context of chronic liver disease

      2. Symptoms often include fever, hepatomegaly, ascites, encephalopathy, AST:ALT ratio > 1.5, and leukocytosis, all in the context of heavy alcohol use.

      3. Malnutrition is seen in 90% of patients.

      4. Concomitant cirrhosis is found in > 50% of patients with alcoholic hepatitis.

      5. 3-month mortality between 15% (mild alcoholic hepatitis) and 55% (severe alcoholic hepatitis)

      6. Several tools have been developed to risk stratify patients with alcoholic hepatitis.

         • (1) The Modified Discriminant Function (mDF) = 4.6 × (patient PT − control PT) + serum bilirubin level: patients with a score ≥ 32 have a poor prognosis

         • (2) The Mayo End-stage Liver Disease (MELD) score incorporates the total bilirubin, international normalized ratio (INR), and serum creatinine (http://www.mayoclinic.org/meld/mayomodel7.html).

           • (a) A MELD score > 11 is similar to an mDF ≥ 32 in predicting mortality.

           • (b) A MELD score > 20 1 week after admission had a sensitivity of 91% and specificity 85% for identifying patients who will die within 30 days.

         • (3) The Glasgow Alcoholic Hepatitis Score (GAHS) includes age, WBC count, BUN, PT/INR, and total bilirubin (http://www.mdcalc.com/glasgow-alcoholic-hepatitis-score/): a score ≥ 9 is associated with a poor prognosis and has an accuracy of 81% in predicting 28-day mortality

   3. Cirrhosis (also see Chapter 17, Edema)

      1. Increased risk in men who consume > 60–80 g/day and women who consume > 20 g/day of alcohol for ≥ 10 years

         • (1) Only 6–41% of such individuals develop cirrhosis

         • (2) Fibrosis develops in 40–60% of people who consume > 40–80 g/day for 25 years

      2. In patients without any other chronic liver disease, 21 drinks/week in men and 7–14/week in women probably will not lead to ALD.

      3. The prognosis of alcoholic cirrhosis varies, depending on whether the patient stops consuming alcohol.

         • (1) 5-year survival of 90% if patient becomes abstinent

         • (2) 5-year survival of 70% if patient continues to consume alcohol

         • (3) 5-year survival of 30–50% once complications of cirrhosis appear

Evidence-Based Diagnosis

1. ALD is diagnosed by documenting alcohol excess in the presence of liver disease.

2. Biomarkers such as GGT, AST, and ALT are not sensitive or specific enough to diagnose ALD; macrocytosis may be seen but is also insensitive

3. Alcoholic steatosis is diagnosed by seeing fatty infiltration on imaging in patients with excessive alcohol consumption.

4. Alcoholic hepatitis is a clinical diagnosis.

   1. Criteria used in randomized trials of therapy include history of excessive alcohol consumption; serum bilirubin > 4.5 mg/dL; AST < 500 units/L; ALT < 300 units/L; exclusion of acute viral, autoimmune, obstructive, or malignant liver disease.

   2. Transaminases are elevated but generally < 6–7 times the upper limit of normal.

      1. AST:ALT ratio > 2 in 70–80% of patients, with ratios > 3 being more specific

      2. Another study showed mean ratio of 2.6 for patients with alcoholic liver disease, compared with mean of 0.9 for patients with nonalcoholic steatohepatitis; however, there was some overlap.

   3. GGTP (gamma-glutamyl transpeptidase) is often elevated, and the GGTP/alkaline phosphatase ratio is often > 2.5.

   4. Imaging (with ultrasound or CT) is most helpful for ruling out other diagnoses; can variably see fatty infiltration, hepatomegaly, ascites, or cirrhosis.

   5. Liver biopsy is the gold standard for diagnosis but is not always necessary.

5. Cirrhosis is diagnosed when portal hypertension is present or on biopsy (also see Chapter 17, Edema).

Treatment

1. Abstinence is the primary treatment for all forms of ALD.

2. Although the data are conflicting, current guidelines recommend that patients with severe alcoholic hepatitis, defined as an mDF score ≥ 32, should be treated with corticosteroids; pentoxifylline could be considered in patients intolerant of corticosteroids.

3. Patients with advanced disease or alcoholic hepatitis should be assessed for nutritional deficiencies and repleted as necessary.

Alternative Diagnosis: Pancreatic Cancer

Textbook Presentation

Patients with pancreatic cancer often have vague abdominal pain for weeks or months, followed by weight loss and perhaps the abrupt onset of painless jaundice.

Disease Highlights

1. > 90% of cases are ductal carcinomas; 70–80% are in the pancreatic head and 20–25% in the body or tail

2. Risk Factors

   1. Smoking (related to up to 20% of cases) and family history of pancreatic cancer (present in 7–10% of patients) are the most important risk factors.

   2. Other risk factors include the following:

      1. Family history of chronic pancreatitis, older age, male sex, African-American ethnic origin

      2. Diabetes, obesity

      3. Non-O blood group

      4. Occupational exposures (chlorinated hydrocarbon solvents and nickel)

      5. High fat diet; high meat/low vegetable diet

3. Clinical presentation (Table 26-3)

   1. Symptoms are insidious and often present for more than 2 months.

   2. Abdominal pain is a presenting complaint, occurring in up to 80% of patients.

      1. Often described as gnawing, visceral pain, sometimes radiating from the epigastrium to the sides or back.

      2. Sometimes improves with bending forward; worse at night or after eating.

      3. Back pain is prominent if splanchnic nerve or celiac plexus infiltration occurs.

   3. Weight loss is common.

   4. Jaundice

      1. In over 70% of patients with cancers in the head; more if mass is > 2 cm

      2. Can occur when the cancer is in the body but is then due to liver metastases

      3. Can be painless or associated with abdominal pain

   5. Less common presentations include acute pancreatitis, malabsorption, migratory thrombophlebitis, and GI bleeding.

Evidence-Based Diagnosis

1. The first imaging study in most patients presenting with jaundice is an ultrasound.

   1. The overall sensitivity for pancreatic cancer is 90%, with a lower sensitivity for tumors < 3 cm in size.

   2. The sensitivity may be less in obese patients or with less experienced sonographers.

2. If the ultrasound shows a pancreatic mass, the next test should be a triphasic pancreatic-protocol multidetector CT.

   1. Sensitivity = 86%; specificity = 90%

   2. Sensitivity lower for cancers < 2 cm (77%) compared with those > 2 cm (89%)

   3. Best test for determining potential resectability

3. If an initial ultrasound does not show a mass, pancreatic protocol CT, magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) should be done.

   1. MRCP is noninvasive and has sensitivity = 84%, specificity = 97% for detecting pancreatic cancer.

   2. EUS requires endoscopy but does not lead to as many complications as ERCP; sensitivity = 89–92%; specificity = 96%.

   3. ERCP is invasive and has a sensitivity of only 50–60% for detecting pancreatic cancer, with a specificity of 94%; complications include pancreatitis and hemorrhage.

4. CA 19–9

   1. For levels above 37–40 units/mL: sensitivity = 76–90%, specificity = 68–98%

   2. For levels above 100–120 units/mL, specificity = 87–100%

   3. For levels > 1000 units/mL, specificity = 94–100%

5. There is no universally accepted standard algorithm to diagnose pancreatic cancer; one approach is outlined in Figure 26-2.

Treatment

1. Complete resection is possible in ∼15% of patients; 5-year survival is still only 20–25%.

2. Palliative approach for patients with nonresectable cancer

   1. Biliary diversion, either percutaneous or surgical

   2. Radiation therapy for pain relief

   3. Gemcitabine for improved quality of life but not increased survival

   4. Median survival is 6 months.

With an LR– of 0.16, a normal CT scan does not always rule out pancreatic cancer. However, in this patient, given that her CT scan shows evidence of advanced liver disease (a more likely diagnosis for her), it is not necessary to do further imaging studies. The other active alternative, chronic hepatitis, is ruled out by her negative serologies. These test results, combined with her alcohol intake history, makes alcoholic liver disease the most likely diagnosis. At this point, some clinicians would proceed with treatment for alcoholic hepatitis, while others would confirm the diagnosis and, for prognostic purposes, establish the presence or absence of cirrhosis with a liver biopsy.

The differential diagnosis for fatigue, nausea, and vague abdominal pain is broad, but the pivotal findings of scleral icterus and tender hepatomegaly point toward a hepatic source.

Mr. R’s clinical picture is consistent with that of 90% of patients with viral hepatitis: a history of anorexia, malaise, and nausea, and a physical exam showing hepatomegaly, hepatic tenderness, or both. Hepatitis A is the most frequent cause of acute viral hepatitis; hepatitis C is the second most frequent but is usually asymptomatic acutely. Hepatitis B can also present acutely. By virtue of being common, alcoholic hepatitis is another active alternative diagnosis, and the presentation can mimic that of viral hepatitis. Biliary obstruction is always a consideration in patients with jaundice, but the prodrome and type of abdominal pain are not typical. Table 26-4 lists the differential diagnosis.

Acute viral hepatitis is unlikely in the absence of nausea, anorexia, malaise, hepatomegaly, or hepatic tenderness.

Pivotal points in Mr. R’s lab tests include the following: he has a conjugated hyperbilirubinemia with a hepatocellular pattern, marked elevation of the transaminases, and the ALT is greater than the AST. This pattern is consistent with viral hepatitis. Exploring his history, he does not have clear risk factors for hepatitis B or C, but does have potential exposure to contaminated food, suggesting possible hepatitis A.

Leading Hypothesis: Hepatitis A

Textbook Presentation

The classic presentation is the gradual onset of malaise, nausea, anorexia, and right upper quadrant pain, followed by jaundice.

Disease Highlights

1. Prevalence: Accounts for 20–40% of cases of viral hepatitis in the United States.

2. Clinical manifestations

   1. Symptoms develop in 70–80% of adults, compared with < 30% of children under the age of 6.

   2. Average incubation period is 25–30 days (range 15–49 days), followed by prodromal symptoms of fatigue, malaise, nausea, vomiting, anorexia, fever, and right upper pain; about 1 week later, jaundice appears.

   3. 70% of patients have jaundice, and 80% have hepatomegaly.

   4. Other physical findings include splenomegaly, cervical lymphadenopathy, rash, arthritis, and leukocytoclastic vasculitis.

   5. Uncommon extrahepatic manifestations include optic neuritis, transverse myelitis, thrombocytopenia, and aplastic anemia.

3. Transmission

   1. Fecal-oral transmission, either sporadically or in an epidemic form

      1. Contaminated water, shellfish, frozen strawberries, etc.

      2. Contamination from infected restaurant worker

      3. Exposure history not always clear

   2. No maternal-fetal transmission

4. Clinical course

   1. Generally self-limited, with rare cases of fulminant hepatic failure (0.015–0.5% of patients with hepatitis A)

      1. Fulminant course is more common in patients with underlying hepatitis C or other chronic liver diseases.

      2. 1.1% fatality rate in adults > age 40

   2. 85% of patients fully recover in 3 months, and nearly 100% by 6 months

   3. Transaminases normalize more rapidly than serum bilirubin.

5. Prevention

   1. Vaccination is available for preexposure prophylaxis.

      1. Immunity develops within 4 weeks in 90% of patients and within 26 weeks in 100% of patients.

      2. A second dose given 6–12 months later provides persistent immunity.

   2. Can use immune serum globulin with vaccination for postexposure prophylaxis.

      1. Immune globulin provides 3–5 months of protection against hepatitis A and can be used for preexposure prophylaxis in patients who need immediate coverage.

      2. Immune globulin is 69–89% effective in preventing symptomatic illness when used postexposure.

      3. A randomized trial comparing vaccination with immune globulin given within 14 days of exposure found that hepatitis A developed in 4.4% of vaccine recipients and 3.3% of immune globulin recipients (relative risk = 1.35 (95% confidence interval [CI], 0.70 to 2.67).

Evidence-Based Diagnosis

1. Liver function tests

   1. ALT and AST are generally over 1000 units/L, and may be as high as 10,000 units/L; ALT is generally > AST.

   2. Bilirubin is commonly > 10 mg/dL.

   3. Alkaline phosphatase is usually modestly elevated.

2. Antibody tests (Figure 26-3)

   1. Serum IgM anti-HAV detects acute illness, being positive even before the onset of symptoms and remaining positive for 4–6 months.

   2. LR+ = 99, LR− = 0.01

   3. Serum IgG anti-HAV appears in the convalescent phase of the disease and remains positive for decades.

Treatment

1. Supportive therapy: rest, oral hydration, and antiemetic medications as needed

2. Admit if INR is elevated or patient is unable to hydrate orally.

3. Liver transplant if fulminant hepatitis and liver failure occur

Considering the hepatocellular pattern of Mr. R’s liver test abnormalities, the acute onset of his symptoms, and his lack of signs of chronic liver disease, the pretest probability for some form of viral hepatitis is so high that it is not necessary to consider other diagnoses at this point. Although Mr. R’s history of food exposure suggests hepatitis A, it is generally necessary to test for all 3 of the primary hepatitis viruses since the exposure history for both hepatitis B and C is often unclear.

Alternative Diagnosis: Acute Hepatitis B

Textbook Presentation

The classic presentation is the gradual onset of malaise, nausea, anorexia, right upper quadrant pain, followed by jaundice. Hepatitis B is often subclinical.

Disease Highlights

1. Prevalence of hepatitis B virus (HBV) carriers

   1. About 5% worldwide, with substantial geographic variation

      1. 0.1–2% (low prevalence) in the United States, Canada, and Western Europe

      2. 2–8% (medium prevalence) in Mediterranean countries, Japan, central Asia, the Middle East, and Latin and South America

      3. 10–20% (high prevalence) in Southeast Asia, China, and sub-Saharan Africa

2. Clinical manifestations

   1. 70% of adult patients have subclinical infection or are anicteric; 30% of patients have icteric hepatitis

   2. Incubation period is 1–4 months.

   3. Symptoms are similar to those of hepatitis A, but serum sickness–like syndrome can be part of the prodrome (fever, urticarial rash, arthralgias).

   4. Fulminant hepatic failure occurs in 0.1–0.5% of patients, with a mortality rate of 70%.

3. Transmission

   1. In high prevalence areas, transmission is primarily perinatal, occurring in 90% of babies born to HBeAg-positive mothers and in 10–20% born to HBeAg-negative mothers.

   2. In medium prevalence areas, most infections occur from childhood exposure to contaminated household objects, via minor breaks in the skin or mucous membranes.

   3. In low prevalence areas, transmission is most often sexual, via percutaneous inoculation (eg, injection drug use, accidental needlestick, tattooing, body piercing, acupuncture), or from contaminated blood transfusion or medical equipment (such as dialysis equipment).

4. Prevention of hepatitis B

   1. Vaccination for preexposure prophylaxis

   2. Vaccination and HB immune globulin within 12 hours for perinatal exposure and within 1 week for other postexposure prophylaxis (percutaneous, mucosal, or sexual)

   3. Vaccinated individuals will have positive hepatitis B surface antibody (HBsAb) tests.

Evidence-Based Diagnosis

1. Liver function tests: similar to hepatitis A

   1. Transaminases normalize in 1–4 months if acute infection resolves.

   2. Elevation of ALT for > 6 months indicates progression to chronic hepatitis (see below).

2. Acute infection is diagnosed by the presence of hepatitis B surface antigen (HBsAg) and IgM hepatitis B core antibody (IgM anti-HBc).

   1. HBsAg appears 1–6 weeks prior to symptoms or elevations of transaminases (Figure 26-4).

      1. Should be present in patients with acute symptoms

      2. Should clear in 4–6 months, although small amounts of viral DNA can be detected in serum and mononuclear cells for years after seroclearance

   2. IgM anti-HBc appears 1–2 weeks after HBsAg.

      1. The only marker of acute infection detectable during the “window period,” the several weeks to months between the disappearance of HBsAg and the appearance of HBsAb.

      2. Persists for up to 6 months after HBsAg is cleared

      3. LR+ = 27, LR− = 0.2

3. Previous infection is diagnosed by the presence of HBsAb and IgG anti-HBc.

   1. HBsAb appears weeks to months after disappearance of HBsAg

   2. HbsAb test characteristics: LR+ = 45, LR− = 0.1

Treatment

1. Supportive therapy: rest, oral hydration, and antiemetic medications as needed

2. Admit if INR is elevated or patient is unable to hydrate orally.

3. Antiviral therapy is used for chronic infection (see below) and antiviral therapy or liver transplant can be used for fulminant hepatitis.

Alternative Diagnosis: Chronic Hepatitis B

Textbook Presentation

Manifestations can range from asymptomatic, to isolated fatigue, to cirrhosis with portal hypertension. There is often no history of clinical acute hepatitis B.

Disease Highlights

1. Defined as presence of HBsAg for more than 6 months

2. Occurs when the hepatitis B specific CD4 and CD8 response is insufficient

3. Risk of progression from acute to chronic hepatitis B varies, depending on the host

   1. < 1% when the acute infection is acquired by an immunocompetent adult

   2. 90% when the infection is acquired perinatally

   3. 20% when the infection is acquired during childhood

4. 10–20% have extrahepatic findings (eg, polyarteritis nodosa, glomerular disease)

5. There are 4 phases of chronic HBV (Figure 26-5), categorized by the activity of the infection, as defined by levels of viral DNA, degree of transaminitis, and presence or absence of HBe antigen and antibody (HBe antigen is a secretory protein considered to be a marker of HBV replication and infectivity. The presence of HBeAg usually indicates high levels of viral DNA and rates of transmission.)

   1. The immune tolerant phase occurs when the infection is acquired perinatally.

   2. Infections acquired later in life begin in the immune active phase, characterized by intermittent flares in up to 25% of patients per year; 8–12% of patients per year seroconvert from HBeAg positive to HBeAg negative and become HBeAb positive.

   3. Most patients who seroconvert enter a lifelong inactive state; however, up to 20% revert to HBeAg positive or develop HBeAg negative chronic hepatitis.

6. Risk factors for progression from chronic hepatitis to cirrhosis include high viral DNA levels, longer duration of the immune active phase, male sex, increasing age, HBeAg positivity, genotype C, concurrent hepatitis C or HIV infection, severe inflammatory histology.

7. Hepatitis B cirrhosis leads to hepatic decompensation in 15–20% of patients over 5 years.

   1. 5-year survival rate is 80–85% in patients with compensated cirrhosis and 30–50% in those with decompensated cirrhosis.

   2. Each year, hepatocellular carcinoma develops in 3–6% of patients.

Evidence-Based Diagnosis

1. HBsAg is always positive.

2. See Figure 26-5 for patterns of HBeAg, HBV DNA, and ALT in different phases.

Treatment

1. The goals of treatment include suppression of viral DNA levels, HBeAg seroconversion, stopping or reducing hepatic inflammation and necrosis, and preventing progression to cirrhosis.

2. Current treatment options include interferon alfa, pegylated interferon-alfa-2a; nucleoside analogues such as lamivudine, and nucleotide analogues such as adefovir.

Alternative Diagnosis: Hepatitis C

Textbook Presentation

Most patients are asymptomatic, with jaundice developing in < 25%. When present, symptoms are similar to those of other viral hepatitis and last 2–12 weeks.

Disease Highlights

1. Accounts for about 15% of cases of acute hepatitis; the most common cause of chronic hepatitis in the United States

2. Prevalence and transmission rates

   1. Overall prevalence in the United States is 2%.

      1. 45% in US adults aged 20–59 with any history of injection drug use

      2. 8.9% in hemodialysis patients

      3. 4.3% in the general population born between 1945 and 1965

      4. 1–5% in needlestick exposures and monogamous partners of infected persons

      5. 10% in recipients of blood transfusions prior to 1992

   2. Transmission

      1. Since 1992, rarely acquired from blood transfusion in developed countries but contaminated blood still common in undeveloped countries

      2. Now, hepatitis C is primarily transmitted through injection drug use, with occasional cases due to ear or body piercing, sex with an injection drug user, or accidental needlesticks.

      3. Household contacts are rarely infected.

      4. Transmission between monogamous partners is < 1%/year; risk of sexual transmission is higher if index carrier also has HIV or there are multiple partners.

      5. Perinatal transmission occurs in 4–7% of cases; risk for transmission increases 4- to 5-fold if the mother has both hepatitis C and HIV.

      6. 15–30% of patients report no risk factors

3. Clinical course (Figure 26-6)

   1. Jaundice develops in only 10–20% of symptomatic patients.

   2. Fulminant hepatitis is rare.

   3. Extrahepatic manifestations are common, being found in about 75% of patients.

      1. Fatigue, arthralgias, paresthesias, myalgias, pruritus, and sicca syndrome are found in > 10% of patients.

      2. Vasculitis secondary to cryoglobulinemia is found in 1% of patients, although cryoglobulinemia is present in about 40%.

      3. Depression and anxiety are more common than in uninfected persons.

   4. 74–86% of patients have detectable HCV RNA at 6 months and therefore have chronic hepatitis C.

   5. Spontaneous clearance is more likely to occur in females, those infected with genotype 3, whites, and those with a low peak viral load.

4. Chronic hepatitis C

   1. Liver histology ranges from no fibrosis, to varying degrees of fibrosis, to cirrhosis; there are several scoring systems in use.

   2. There is no correlation between ALT levels and liver histology.

   3. Liver biopsy is indicated in many patients to guide treatment decisions (see Chapter 17, Edema for discussion of noninvasive methods to predict fibrosis and cirrhosis); the complication rate for liver biopsy is 1–5%.

   4. Cirrhosis develops in 5–25% of patients after 20 years of infection.

      1. Rates are low in community cohorts and cohorts of blood donors (4–7%).

      2. Rates are higher in other populations (24%).

      3. Liver histology is the best predictor of progression to cirrhosis.

      4. Other predictors of progression to cirrhosis include

         • (1) Age at infection (> 40 years of age → more progression)

         • (2) Longer duration of infection

         • (3) Consumption of alcohol > 50 g/d

         • (4) HIV or HBV coinfection

         • (5) Male sex

         • (6) Higher ALT

         • (7) Baseline fibrosis

         • (8) Possibly steatosis

      5. Hepatocellular carcinoma develops in 1–3% of cirrhotic patients per year.

5. Prevention

   1. No vaccine available

   2. No role for immunoglobulin

6. Screening guidelines

   1. Centers of Disease Control and Prevention and US Preventive Services Task Force recommend 1 time screening for all persons born between 1945 and 1965 as well as risk factor–based screening

   2. Risk–factor based screening includes

      1. History injection drug use

      2. Receipt of blood products prior to 1992

      3. Long-term hemodialysis

      4. Exposure to known HCV-positive blood (needlestick or mucosal exposure in health care workers)

      5. HIV infection

      6. Child of a HCV-positive woman

      7. History of multiple sex partners or sexually transmitted infections

Evidence-Based Diagnosis

1. Anti-HCV antibody tests (enzyme immunoassays)

   1. HCV antibodies generally detectable within 8–12 weeks of acquiring the infection.

   2. Sensitivity, 94–100%; specificity, 97–98%; LR+, 31–49; LR–, 0.01–0.06

   3. False-positive results do occur in low prevalence screening populations, with positive predictive values as low as 39%.

   4. False-negative results can occur in immunocompromised patients, such as organ transplant recipients, HIV-infected patients, hemodialysis patients, or those with hypogammaglobulinemia.

2. Quantitative HCV RNA tests (polymerase chain reaction and transcription-mediated amplification)

   1. Lower limit of detection using current methods is 10–50 international units/mL.

   2. Sensitivity, 96%; specificity, 99%; LR+, 96; LR–, 0.04

   3. Levels do not correlate with liver injury, duration of infection, or disease severity.

3. Genotype testing

   1. Used for prediction of response to treatment and choice of treatment duration

   2. Genotypes do not change, so this test needs to be done only once.

   3. In the United States, 71.5% of cases are from genotype 1, 13.5% from genotype 2, 5.5% from genotype 3, and 1.1% from genotype 4.

4. Choosing and interpreting hepatitis C tests

   1. American Association for the Study of Liver Disease Guidelines for testing:

      1. First, test for anti-HCV antibodies in patients in whom acute or chronic hepatitis C is suspected.

      2. Test for HCV RNA in patients with (1) a positive antibody test; (2) unexplained liver disease whose antibody test is negative and who are immunocompromised or in whom acute HCV infection is suspected.

   2. Table 26-5 summarizes the interpretation of hepatitis C tests.

Treatment

1. Goals of treatment: Prevention of cirrhosis and its complications, reduction of extrahepatic manifestations, and reduction of transmission

2. A sustained virologic response is defined as nondetectable HCV RNA 6 months after completion of therapy.

3. Current therapy includes pegylated interferon and ribavirin; the treatment approach is continuously evolving.

The best test of the liver’s synthetic function is the PT. It is important to check the INR in all patients with hepatitis to look for signs of liver failure.

Most patients with asymptomatic transaminase elevations have mild or moderate elevations; it is very unusual for patients with marked elevations to be asymptomatic. Therefore, the diagnostic thinking should focus on chronic diseases. The basic framework separates hepatic from nonhepatic causes.

1. Hepatic causes

   1. Marked elevations (> 1000 units/L)

      1. Acute viral hepatitis

      2. Ischemic hepatitis

      3. Medication- or toxin-induced hepatitis

      4. Autoimmune hepatitis

      5. Acute bile duct obstruction

      6. Acute Budd-Chiari syndrome

   2. Mild to moderate elevations

      1. ALD

      2. Medications/toxins

      3. Chronic hepatitis B or C

      4. NAFLD

      5. Autoimmune hepatitis

      6. Hemochromatosis

      7. Wilson disease (in patients < 40 years old)

      8. Alpha-1-antitrypsin deficiency

2. Nonhepatic causes

   1. Celiac disease

   2. Hyperthyroidism

   3. Inherited disorders of muscle metabolism or acquired muscle disease (AST elevation only)

   4. Strenuous exercise (AST elevation only)

In the absence of an obvious nonhepatic cause of liver enzyme elevations, the initial approach is to focus on the hepatic causes. The prevalence of the liver diseases in the differential diagnosis varies widely, depending on the population studied. For example, in a study of over 19,000 young, healthy military recruits, of whom 99 had enzyme elevations, only 11 were found to have any liver disease (4 had hepatitis B, 4 had hepatitis C, 2 had autoimmune hepatitis, 1 had cholelithiasis). A study of 100 blood donors with elevated enzymes found that 48% had alcoholic liver disease, 22% had NAFLD, and 17% had hepatitis C. In another study, patients with elevated enzymes in whom a diagnosis could not be made by history or blood tests underwent liver biopsy; NAFLD was found in over 50% of them.

Pivotal points in Ms. H’s presentation include that the transaminase abnormalities are mild and probably chronic. The key findings in the history and physical exam are the patient’s diabetes and elevated body mass index (BMI). NAFLD is extremely common in obese, diabetic patients, so Ms. H is at high risk for this disease. She has no specific risk factors for viral hepatitis, but often the exposure history is unclear and these diagnoses cannot be ruled out without further testing. Her alcohol intake is minimal, but sometimes even small amounts of alcohol can cause liver enzyme elevations. Additionally, other drug and toxin exposure always should be considered. Even therapeutic doses of acetaminophen can cause transaminitis; in 1 study, 50% of patients taking 4 g of acetaminophen daily developed transaminases > 2 times the upper limit of normal. Mild transaminase elevations are seen in 0.5–3% of patients taking statins (it is not necessary to stop the statin in such cases, and the FDA no longer recommends routine testing after obtaining a baseline at the start of therapy). Finally, her family history of thyroid disease, presumably autoimmune, increases the likelihood of autoimmune hepatitis or hyperthyroidism. Hemochromatosis, a fairly common gene mutation, can present with liver enzyme abnormalities and diabetes mellitus. Table 26-6 lists the differential diagnosis.

Leading Hypothesis: NAFLD

Textbook Presentation

Patients are often asymptomatic but sometimes complain of vague right upper quadrant discomfort. It is common to identify patients by finding hepatomegaly on exam or asymptomatic transaminase elevations.

Disease Highlights

1. The definition of NAFLD is evidence of excessive fat in the liver, either by imaging or biopsy, in the absence of causes of secondary hepatic fat accumulation.

2. Secondary causes of excessive fat in the liver include significant alcohol use (> 14 drinks/week for women, > 21 for men), Wilson disease, jejunoileal bypass, prolonged total parenteral nutrition, protein-calorie malnutrition, and drugs (methotrexate, amiodarone, estrogens, corticosteroids, aspirin, cocaine, antiretroviral agents)

3. Patients with NAFLD have steatosis, either with or without inflammation.

   1. In simple steatosis (nonalcoholic fatty liver [NAFL]), there is no liver injury and the risk of progression to cirrhosis is minimal.

   2. Steatosis plus inflammation, with or without fibrosis, is called nonalcoholic steatohepatitis (NASH).

      1. Up to 21% of patients have regression of fibrosis.

      2. Up to 40% progress to more advanced fibrosis or cirrhosis

      3. The strongest predictor of progression is the degree of inflammation on the first biopsy.

   3. Liver failure develops over 7–10 years in 38–45% of patients with cirrhosis

   4. The risk of hepatocellular carcinoma in patients with NAFLD cirrhosis is less than that of patients with hepatitis C cirrhosis.

4. NAFLD can coexist with other chronic liver diseases.

5. Epidemiology

   1. Risk factors include the metabolic syndrome, obesity, type 2 diabetes mellitus, insulin resistance, hyperlipidemia, and family history of NAFLD.

   2. Prevalence varies based on population studied.

      1. Worldwide prevalence ranges from 6.3% to 33%; NASH prevalence 3–5%

      2. One US study found an overall NAFLD prevalence of 46% (58% in Hispanics, 44% in whites, 35% in African Americans); 30% had NASH

      3. 91% in obese patients (BMI > 35 kg/m²) undergoing bariatric surgery, with 37% having NASH

      4. Found in 69% of patients with type 2 diabetes mellitus, 50% of patients attending lipid clinics, 50% of morbidly obese patients

   3. Most common cause of abnormal liver test results in the United States.

Evidence-Based Diagnosis

1. Blood tests

   1. Transaminases elevation is usually < 400 units/L, with ALT > AST; in advanced fibrosis or cirrhosis, AST may be > ALT.

   2. Serum ferritin is elevated in 60% of patients but is rarely > 1000 mcg/L.

   3. Alkaline phosphatase is elevated in 30% of patients.

2. Imaging can detect steatosis when it replaces more than 30% of the liver volume; it cannot distinguish NAFL from NASH.

   1. Ultrasound: sensitivity, 60%; specificity, 93%; LR+, 8.6; LR–, 0.43

   2. CT scan: sensitivity, 82%; specificity, ∼95%; LR+, 16.4; LR–, 0.19

   3. MRI: sensitivity, ∼95%; specificity, ∼95%; LR+, 19; LR–, 0.05

3. Liver biopsy is the gold standard for diagnosis and staging.

   1. NASH is missed in 27% of single biopsies.

   2. Test characteristics of a single biopsy for the diagnosis of NASH: sensitivity, 73%; specificity, 92%; LR+, 8.6; LR–, 0.3

   3. Advanced fibrosis is less often missed: LR+, 7.7; LR–, 0.16

4. Liver biopsy should be considered when it is necessary to exclude other causes of chronic liver disease and in patients with a high risk of having NASH and advanced fibrosis.

   1. The NAFLD Fibrosis Score is used to identify high risk patients.

      1. Need to know age, BMI, diabetes status, ALT, AST, albumin, and platelet count

      2. On line calculator: http://nafldscore.com/

      3. A low score (< –1.455) reduces the likelihood of advanced fibrosis: sensitivity, 90%; specificity, 60%; LR+, 2.25; LR–, 0.16

      4. A high score (> 0.676) significantly increases the likelihood of advanced fibrosis: sensitivity, 67%; specificity, 97%; LR+, 22; LR–, 0.34

      5. 20–58% of patients studied were between the two cut offs and could not be classified.

   2. Patients with the metabolic syndrome are also considered high risk.

It is necessary to rule out other causes of liver disease listed in the above differential before diagnosing NAFLD.

Treatment

1. Weight loss can improve both steatosis and inflammation.

2. Exercise may improve steatosis independent of weight loss.

3. Diabetes and hyperlipidemia should be optimally treated.

4. Metformin has been studied and is not effective.

5. Vitamin E has been shown to improve histology in non-diabetic adults with biopsy proven NASH.

6. Pioglitazone is effective in reducing inflammation but not fibrosis; the long-term safety and efficacy are not established.

You should take a stepwise approach to evaluating asymptomatic liver enzyme abnormalities. As was done with Ms. H, the first step is to stop alcohol and, if possible, potentially hepatotoxic medications, and then remeasure the liver enzymes. Although aspects of the history can increase the likelihood of a specific diagnosis, the history is not sensitive or specific enough to make a diagnosis, and it is necessary to test somewhat broadly. If liver enzyme abnormalities persist after stopping alcohol and potentially hepatotoxic medications, the American Gastroenterological Association recommends beginning with a PT; serum albumin; CBC; hepatitis A, B, and C serologies; and iron studies (serum iron, total iron-binding capacity [TIBC], ferritin).

Alternative Diagnosis: Hereditary Hemochromatosis

Textbook Presentation

Most patients are asymptomatic, but a few have extrahepatic manifestations of iron overload (see below). Some patients are identified by screening the family members of affected individuals.

Disease Highlights

1. An autosomal recessive disease causing deficiency of the iron regulatory hormone hepcidin, leading to increased intestinal iron absorption and accumulation in tissues

2. Iron deposition occurs throughout the reticuloendothelial system, leading to a broad range of potential manifestations.

   1. Liver manifestations range from hepatomegaly to fibrosis to cirrhosis; hepatocellular carcinoma risk is increased only in patients with cirrhosis.

   2. Any joint can be affected, but the second and third metacarpophalangeal joints are typical.

   3. Cardiac infiltration leads to cardiomyopathy.

   4. Other manifestations include secondary hypogonadism (pituitary infiltration), diabetes (pancreatic infiltration), and hypothyroidism (thyroid infiltration).

3. There are several possible gene mutations; the most common is the HFE C282Y mutation, thought to have initially occurred in a Viking or Celtic ancestor.

   1. In a meta-analysis of people of European ancestry with iron overload, 81% were homozygous for the HFE C282Y mutation.

   2. 5% were compound heterozygous for the C282Y/H63D mutation.

   3. In another study, nearly 100,000 primary care patients were screened for iron overload and HFE mutations; 299 homozygotes were found.

      1. The prevalence of homozygosity was 0.44% in whites, 0.11% in Native Americans, 0.027% in Hispanics, 0.014% in blacks, 0.012% in Pacific Islanders, and 0.000039% in Asians.

      2. The prevalence of heterozygosity for the mutation was 10% in whites, 5.7% in Native Americans, 2.9% in Hispanics, 2.3% in blacks, 2% in Pacific Islanders, and 0.12% in Asians.

4. The gene expression is quite variable, with the penetrance of iron overload in homozygotes (abnormal transferrin saturation or ferritin) ranging from 38% to 76%; clinical disease is found in only 2–38% of men and 1–10% of women.

5. 72% of patients with serum ferritin levels > 1000 mcg/L have cirrhosis, compared with 7.4% of those with ferritin levels < 1000 mcg/L.

6. Screening primary care populations for hemochromatosis is not recommended by the USPSTF or the American College of Physicians.

Evidence-Based Diagnosis

1. Liver biopsy with measurement of hepatic iron index is the gold standard.

2. Initial testing should be done with a transferrin saturation (serum iron/TIBC) and a serum ferritin (the test characteristics are for identifying homozygous patients).

   1. Transferrin saturation ≥ 50% in men

      1. Sensitivity, 82.4%; specificity, 92.5%

      2. LR+ = 10.9, LR− = 0.19

   2. Transferrin saturation ≥ 45% in women

      1. Sensitivity, 73.8%; specificity, 93.1%

      2. LR+ = 10.8, LR− = 0.28

   3. Ferritin ≥ 200 ng/mL in men

      1. Sensitivity, 78%; specificity, 76%

      2. LR+ = 3.25, LR− = 0.23

   4. Ferritin ≥ 200 ng/mL in women

      1. Sensitivity, 54%; specificity, 95%

      2. LR+ = 11, LR− = 0.48

3. Patients who have a transferrin saturation ≥ 45% and an elevated ferritin should undergo HFE gene testing, looking for the hereditary hemochromatosis mutations.

   All first-degree relatives of patients with hereditary hemochromatosis should undergo gene testing, regardless of the results of the iron studies.

   1. If C282Y/C282Y homozygous mutation is found

      1. If age is < 40 years, ferritin < 1000 ng/mL, and transaminases are normal, proceed to treatment.

      2. Otherwise, perform liver biopsy to determine severity.

   2. If other mutations or no mutations are found, look for other causes of iron overload or perform liver biopsy for diagnosis.

Treatment

Periodic phlebotomy to reduce the iron overload has been shown to reduce the risk of progression to cirrhosis.

Alternative Diagnosis: Autoimmune Hepatitis

Textbook Presentation

The clinical presentation is variable, ranging from asymptomatic transaminase elevation to nonspecific constitutional symptoms, to advanced liver disease.

Disease Highlights

1. A chronic inflammatory disease of the liver

2. Annual incidence of 1.4 cases/100,000; 3–4 times more common in women than in men

3. 72% of cases diagnosed after the age of 40 years

4. 36% of patients have cirrhosis at presentation; of those without cirrhosis at presentation, 12% will develop it over 10 years

   1. Risk factors for progression include time to normalization of ALT and number of relapses.

   2. Risk of developing hepatocellular carcinoma is 1–1.9%/year, occurring at a mean age of 60–63 years.

5. 50% 5-year mortality rate in untreated patients

6. Drug-induced autoimmune hepatitis, reported with minocycline, nitrofurantoin, atorvastatin, and infliximab, has a more benign course that idiopathic autoimmune hepatitis.

Evidence-Based Diagnosis

1. Autoantibodies

   1. Antinuclear antibodies (ANA): sensitivity, 32%; specificity, 76%; LR+, 1.3; LR–, 0.89

   2. Antismooth muscle antibody (SMA): sensitivity, 16%; specificity, 96%; LR+, 4; LR–, 0.87

   3. ANA and SMA: sensitivity, 43%; specificity, 99%; LR+, 43; LR–, 0.57

   4. Diagnostic criteria have been developed (Table 26-7).

      1. For a diagnosis of probable autoimmune hepatitis (6 points): sensitivity, 88%; specificity, 97%; LR+, 29; LR–, 0.12

      2. For a diagnosis of definite autoimmune hepatitis (≥ 7 points): sensitivity, 81%; specificity, 99%; LR+, 81; LR–, 0.19

Treatment

1. Treatment is indicated for all patients with evidence of active inflammation, either by transaminase elevation or histology.

2. Prednisone alone, or prednisone and azathioprine are used to induce remission; 90% of patients respond within 2 weeks.

3. Many patients require maintenance therapy, most commonly with azathioprine.

4. Other immunosuppressives are used in patients who do not respond to or cannot tolerate the first-line treatments.

5. Liver transplant is often successful in patients with cirrhosis and decompensated end-stage liver disease, although autoimmune hepatitis can recur in the transplanted liver.

Figure 26-7 outlines the diagnostic approach to a patient with an isolated elevation of the alkaline phosphatase.