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CURRENT Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy, 3e
Chapter 38: Approach to the Patient with Jaundice & Abnormal Liver Tests
Norton J. Greenberger
ESSENTIALS OF DIAGNOSIS
ESSENTIALS OF DIAGNOSIS
Jaundice is most often caused by decompensation of preexisting chronic liver disease, alcoholic hepatitis, and gallstone disease.
Careful history, physical examination, and routine laboratory tests lead to accurate diagnosis in 85% of patients with jaundice.
Cirrhosis can be diagnosed on the basis of two physical findings (asterixis, ascites) and two laboratory findings (decreased serum albumin [<2.8
g/dL], prolonged prothrombin time [INR >1.6]).
Dilated intrahepatic bile ducts indicate obstruction from extrahepatic causes (stone, structure, tumor).
Absence of dilated ducts in jaundiced patients with serum bilirubin >10 mg/dL suggests intrahepatic cholestasis.
Sepsis, drugs, sickle cell disease, and chronic hepatitis are the most common causes of intrahepatic cholestasis.
GENERAL CONSIDERATIONS
Jaundice refers to the yellowish discoloration of tissue resulting from the deposition of bilirubin in tissues; this indicates that the serum bilirubin is
likely 3 mg/dL or higher. Jaundice most often is the result of acute or chronic liver disease, or biliary tract disease, and less commonly the result of
hemolytic disorders. The differential diagnosis of jaundice has changed significantly in the past decade due largely to a sharp decline in the incidence
of viral hepatitis types A and B as a result of immunization. The most common causes of jaundice in the adult population now are decompensation of
preexisting chronic liver disease, alcoholic hepatitis, sepsis and abnormal hemodynamic conditions, and gallstone disease.
PATHOGENESIS
Jaundice can occur as a result of acute or chronic parenchymal liver disease, extrahepatic biliary tract obstruction (due to stone, stricture, or tumor),
intrahepatic cholestasis (having several causes, as detailed in the following text), and hemolytic anemia. Serum bilirubin derives from the degradation
of senescent red cells in the reticuloendothelial system. Each day a normal individual destroys 50 mL of red blood cells, which gives rise to 7.5 g of
hemoglobin. Each gram of hemoglobin that is degraded results in production of 35 mg of bilirubin. Unconjugated bilirubin is liquid soluble, water
insoluble, and hence circulates bound to albumin. The hepatic processing of bilirubin involves uptake of unconjugated bilirubin, conjugation with
uridine diphosphate glucuronyl transferase, transfer to the bile canaliculus, and excretion into the intrahepatic biliary tree (Figure 38–1). Bilirubin is
excreted in the bile primarily as bilirubin diglucuronide (80%), bilirubin monoglucuronide (20%), and unconjugated bilirubin (<1%). Any disease
process that results in an increased load of unconjugated bilirubin presented to the liver, impaired conjugation, or impaired excretion of conjugated
bilirubin, either intrahepatic or extrahepatic, can lead to accumulation of bilirubin in the blood, resulting in jaundice.
Figure 38–1.
Anatomy of the intrahepatic biliary system. (Reproduced, with permission, from Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 10th ed.
London, UK: Blackwell Science, 1997.) (See also Table 37–4 for causes of intrahepatic cholestasis.)
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Figure 38–1.
Anatomy of the intrahepatic biliary system. (Reproduced, with permission, from Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 10th ed.
London, UK: Blackwell Science, 1997.) (See also Table 37–4 for causes of intrahepatic cholestasis.)
CLINICAL FINDINGS
A. Symptoms and Signs
On the basis of a detailed history and a carefully conducted physical examination, along with the routine liver tests summarized in the following text,
the examiner should be able to formulate a differential diagnosis and be correct in over 85% of the patients who present with jaundice and evidence of
liver disease. The importance of a careful history and physical examination along with critical evaluation of the standard liver tests cannot be
overemphasized.
Table 38–1 summarizes the specific information to be obtained from patients with jaundice or liver disease. The information is grouped into that
relating to viral hepatitis, medications, alcohol use, and miscellaneous relevant information.
Table 38–1.
Specific information to obtain from patients with jaundice or liver disease.
Viral hepatitis
Ask about:
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Chapter 38: Approach to the Patient with Jaundice &; Abnormal Liver Tests, Norton J. Greenberger
Blood transfusion (especially if before 1990) Page 2 / 12
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Intravenous drug use
Sexual practices:
• Analreceptive intercourse
liver disease. The importance of a careful history and physical examination along with critical evaluation of the standard liver tests cannot be
overemphasized. Access Provided by:
Table 38–1 summarizes the specific information to be obtained from patients with jaundice or liver disease. The information is grouped into that
relating to viral hepatitis, medications, alcohol use, and miscellaneous relevant information.
Table 38–1.
Specific information to obtain from patients with jaundice or liver disease.
Viral hepatitis
Ask about:
Blood transfusion (especially if before 1990)
Intravenous drug use
Sexual practices:
• Analreceptive intercourse
• Sex with a prostitute
• History of sexually transmitted disease
• Multiple sexual partners (>5/y)
• Intercourse with persons infected with hepatitis B or C
Contact with persons with jaundice
Changes in taste and smell
Needlestick exposure
Work in renal dialysis units
Work in trauma units, operating rooms, or other settings in which exposure to users of IV drugs may occur
Shared razors or toothbrushes
Body piercing (ears, nose)
Tattoos
Intranasal cocaine use
Special risk factors for hepatitis A:
No immunization (older adults)
• Travel to endemic areas
• Exposure in settings where clusters of hepatitis may occur (eg, institutions)
Medication use
Review:
All prescription medications
Ask specifically about:
All overthecounter drugs
Vitamins (especially vitamin A)
Any foods, herbal preparations, or home remedies purchased in a health food store
A l c o h o l u s e
Obtain detailed quantitative history of both recent and previous alcohol use from patient and family members
Ask whether patient has experienced withdrawal symptoms, or has been cited for drivingundertheinfluence
Miscellaneous information
Ask about:
Pruritus (suggests cholestasis either intrahepatic or extrahepatic)
Evaluation of jaundice (dark urine, light stools)
Recent changes in menstrual cycle (amenorrhea suggests chronic liver disease, often cirrhosis)
Review:
History of anemia, sickle cell disease, known hemoglobinopathy, artificial heart valves
Symptoms suggestive of biliary colic, chronic cholecystitis
Family history of liver disease, gallbladder disease
Adapted with permission from Schiff ER, Sorrell MF, Maddrey WC (eds). Schiff’s Diseases of the Liver. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
Table 38–2 summarizes characteristic findings on physical examination in patients with jaundice. Attention should be paid to the peripheral stigmata
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of liver disease, including spider angioma, which characteristically occurs above the clavicles in the distribution of the superior vena cava. More than 15
Chapter 38: Approach to the Patient with Jaundice &; Abnormal Liver Tests, Norton J. Greenberger Page 3 / 12
spider angiomata indicate the presence of significant liver disease and likely portal hypertension. The triad of gynecomastia, Dupuytren contracture,
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and parotid enlargement is a clear indication that alcohol is the most likely cause of the patient’s liver disease. Splenomegaly, ascites, and prominent
abdominal collateral veins indicate the presence of portal hypertension and in all likelihood the presence of esophageal or gastric varices, or both.
Symptoms suggestive of biliary colic, chronic cholecystitis
Family history of liver disease, gallbladder disease Access Provided by:
Adapted with permission from Schiff ER, Sorrell MF, Maddrey WC (eds). Schiff’s Diseases of the Liver. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
Table 38–2 summarizes characteristic findings on physical examination in patients with jaundice. Attention should be paid to the peripheral stigmata
of liver disease, including spider angioma, which characteristically occurs above the clavicles in the distribution of the superior vena cava. More than 15
spider angiomata indicate the presence of significant liver disease and likely portal hypertension. The triad of gynecomastia, Dupuytren contracture,
and parotid enlargement is a clear indication that alcohol is the most likely cause of the patient’s liver disease. Splenomegaly, ascites, and prominent
abdominal collateral veins indicate the presence of portal hypertension and in all likelihood the presence of esophageal or gastric varices, or both.
Hepatic encephalopathy is suggested by the presence of asterixis and behavioral alterations.
Table 38–2.
Characteristic physical findings in the patient with jaundice.
General inspection
Scleral icterus
Pallor
Wasting
Needle tracts
Evidence of skin excoriations
Ecchymosis or petechiae
Muscle tenderness and weakness
Lymphadenopathy
Evidence of pneumonia
Evidence of congestive heart failure
Peripheral stigmata of liver disease
Spider angiomata
Palmar erythema
Gynecomastia
Dupuytren contracture
Parotid enlargement
Testicular atrophy
Paucity of axillary and pubic hair
Eye signs mimicking hyperthyroidism
Abdominal examination
Hepatomegaly
Splenomegaly
Ascites
Prominent abdominal collateral veins
Bruits and rubs
Abdominal masses
Palpable gallbladder
Signs of decompensated hepatocellular disease
Jaundice
Ascites
Oliguric hepatic failure
Hepatic encephalopathy
• Fetor hepaticus
• Asterixis
• Behavioral alterations (confusion, disorientation, failure to complete simple mental tasks)
Adapted with permission from Schiff ER, Sorrell MF, Maddrey WC (eds). Schiff’s Diseases of the Liver. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
The following point bears special emphasis. A clinician can make a firm diagnosis of cirrhosis on the basis of two physical findings and two laboratory
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findings. These four features—the presence of asterixis and ascites, along with decreased serum albumin (<2.8 g/dL) and a prolonged prothrombin
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time—clearly indicate cirrhosis. This statement is based on an older Mayo Clinic study in which over 500 patients with chronic liver disease were
evaluated; the preceding compilation of clinical features was present in approximately 98% of patients with proven cirrhosis of the liver.
spider angiomata indicate the presence of significant liver disease and likely portal hypertension. The triad of gynecomastia, Dupuytren contracture,
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and parotid enlargement is a clear indication that alcohol is the most likely cause of the patient’s liver disease. Splenomegaly, ascites, and prominent
abdominal collateral veins indicate the presence of portal hypertension and in all likelihood the presence of esophageal or gastric varices, or both.
Hepatic encephalopathy is suggested by the presence of asterixis and behavioral alterations.
Table 38–2.
Characteristic physical findings in the patient with jaundice.
General inspection
Scleral icterus
Pallor
Wasting
Needle tracts
Evidence of skin excoriations
Ecchymosis or petechiae
Muscle tenderness and weakness
Lymphadenopathy
Evidence of pneumonia
Evidence of congestive heart failure
Peripheral stigmata of liver disease
Spider angiomata
Palmar erythema
Gynecomastia
Dupuytren contracture
Parotid enlargement
Testicular atrophy
Paucity of axillary and pubic hair
Eye signs mimicking hyperthyroidism
Abdominal examination
Hepatomegaly
Splenomegaly
Ascites
Prominent abdominal collateral veins
Bruits and rubs
Abdominal masses
Palpable gallbladder
Signs of decompensated hepatocellular disease
Jaundice
Ascites
Oliguric hepatic failure
Hepatic encephalopathy
• Fetor hepaticus
• Asterixis
• Behavioral alterations (confusion, disorientation, failure to complete simple mental tasks)
Adapted with permission from Schiff ER, Sorrell MF, Maddrey WC (eds). Schiff’s Diseases of the Liver. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
The following point bears special emphasis. A clinician can make a firm diagnosis of cirrhosis on the basis of two physical findings and two laboratory
findings. These four features—the presence of asterixis and ascites, along with decreased serum albumin (<2.8 g/dL) and a prolonged prothrombin
time—clearly indicate cirrhosis. This statement is based on an older Mayo Clinic study in which over 500 patients with chronic liver disease were
evaluated; the preceding compilation of clinical features was present in approximately 98% of patients with proven cirrhosis of the liver.
B. Laboratory Findings
Liver tests that are useful in the differential diagnosis of jaundice are summarized in Table 38–3. Four altered liver test findings point to a diagnosis of
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chronic liver disease (eg, cirrhosis): (1) decreased serum albumin, (2) elevated serum globulins, (3) prolonged prothrombin time, and (4) decreased
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cholesterol.
Table 38–3.
findings. These four features—the presence of asterixis and ascites, along with decreased serum albumin (<2.8 g/dL) and a prolonged prothrombin
time—clearly indicate cirrhosis. This statement is based on an older Mayo Clinic study in which over 500 patients with chronic liver disease were
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evaluated; the preceding compilation of clinical features was present in approximately 98% of patients with proven cirrhosis of the liver.
B. Laboratory Findings
Liver tests that are useful in the differential diagnosis of jaundice are summarized in Table 38–3. Four altered liver test findings point to a diagnosis of
chronic liver disease (eg, cirrhosis): (1) decreased serum albumin, (2) elevated serum globulins, (3) prolonged prothrombin time, and (4) decreased
cholesterol.
Table 38–3.
Differential test results in patients with acute, chronic, and obstructive hepatobiliary disease.
Acute Liver Chronic Liver
Obstructive Liver Disease
Disease Disease
Cholesterol NL NL↓ NL
Hepatitis serologies (A, B, C), EBV, May be helpful — —
CMV
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBD, common bile duct; CMV, cytomegalovirus; EBV, EpsteinBarr virus; NL, normal limits; PT,
prothrombin time; PTT, partial thromboplastin time; ↓ decreased; ↑ increased.
aSpecial circumstances may apply.
The serum bilirubin level exceeds 20 mg/dL rarely in patients with acute viral hepatitis, infrequently in patients with cirrhosis, and rarely in those with
obstructive jaundice due to a common duct stone or pancreatic cancer. The highest serum bilirubin levels are seen in cirrhosis with accompanying
oliguric hepatic failure (ie, hepatorenal syndrome). The explanation for this is that if extrahepatic obstruction is present, the serum bilirubin level will
rise to about 15 mg/dL but the compensatory mechanism is the kidney and the excess bilirubin will be excreted, resulting in bilirubinuria. In oliguric
hepatic failure this compensatory mechanism is lost, which explains why the highest serum bilirubin levels are seen in advanced cirrhotic liver disease
with hepatorenal syndrome.
Serum aminotransferases are characteristically increased to values above 400 IU/L in acute viral hepatitis and are usually less than 400 IU/L in cirrhosis
and less than 400 IU/L in over 90% of patients with obstructive jaundice. Of note, in patients with choledocholithiasis with or without cholangitis,
serum aminotransferases may be in the hepatitis range (ie, 800–1000 IU/L); however, within 2–3 days elevated values will fall abruptly.
Serum alkaline phosphatase is disproportionately elevated in obstructive jaundice, with values four to tenfold or greater than normal, whereas these
values usually are normal or minimally elevated in acute viral hepatitis or cirrhosis. Serum albumin and globulin levels are very helpful in that both are
usually normal in acute viral hepatitis and usually normal with obstructive jaundice of brief duration. The serum albumin level is frequently decreased
in cirrhosis whereas globulins are increased, and the finding of hypergammaglobulinemia and hypoalbuminemia in someone with liver disease almost
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always means that the patient has chronic liver disease.
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The prothrombin time and partial thromboplastin time are usually both normal in acute viral hepatitis. However, in a patient with acute viral hepatitis,
a prolonged prothrombin time and an international normalized ratio (INR) greater than 1.8 may be the harbinger of submassive necrosis of the liver
serum aminotransferases may be in the hepatitis range (ie, 800–1000 IU/L); however, within 2–3 days elevated values will fall abruptly. Access Provided by:
Serum alkaline phosphatase is disproportionately elevated in obstructive jaundice, with values four to tenfold or greater than normal, whereas these
values usually are normal or minimally elevated in acute viral hepatitis or cirrhosis. Serum albumin and globulin levels are very helpful in that both are
usually normal in acute viral hepatitis and usually normal with obstructive jaundice of brief duration. The serum albumin level is frequently decreased
in cirrhosis whereas globulins are increased, and the finding of hypergammaglobulinemia and hypoalbuminemia in someone with liver disease almost
always means that the patient has chronic liver disease.
The prothrombin time and partial thromboplastin time are usually both normal in acute viral hepatitis. However, in a patient with acute viral hepatitis,
a prolonged prothrombin time and an international normalized ratio (INR) greater than 1.8 may be the harbinger of submassive necrosis of the liver
and impending liver failure. The prothrombin time and partial thromboplastin time are prolonged in chronic liver disease and cirrhosis. The
prothrombin time may be prolonged in patients with prolonged obstructive jaundice because of failure to absorb vitamin K. In this setting, however,
the prothrombin time will normalize with administration of vitamin K.
Serum cholesterol is frequently low in patients with chronic liver disease. The usual serologies to obtain in patients with jaundice include tests for
hepatitis A, B, and C as well as EpsteinBarr virus and cytomegalovirus.
C. Imaging Studies
Abdominal ultrasound is a very helpful examination in patients with jaundice and obstructivetype chemistries. In a patient with serum bilirubin of 10
mg/dL or higher and in whom the elevation has persisted for more than 2 weeks, ultrasound has a sensitivity and specificity of approximately 95%. The
presence of dilated ducts indicates that the process is extrahepatic. If dilated ducts are not demonstrated, it may indicate that the patient has a
disorder causing intrahepatic cholestasis (Table 38–4).
Table 38–4.
Spectrum of disorders and causes resulting in intrahepatic cholestasis.
Category (see Figure 38–1) Cause
Hepatocellular Viral hepatitis (especially type A)
Alcoholic liver disease
Chronic hepatitis
α1Antitrypsin deficiency
Canalicular Drug induced (phenothiazine, alkylated steroids)
Postoperative
Sepsis
Parenteral nutrition
Hodgkin disease
Sickle cell disease
Toxic shock syndrome
Amyloidosis
Ductule Primary biliary cirrhosis
Sarcoidosis
Ducts Primary sclerosing cholangitis
Caroli disease
Intrahepatic atresia
Recurrent Recurrent cholestasis of pregnancy
DubinJohnson syndrome
Benign recurrent intrahepatic cholestasis
DIFFERENTIAL DIAGNOSIS
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A. Differential Diagnosis of Jaundice
As previously noted, the differential diagnosis of jaundice has changed significantly since the advent of immunization for hepatitis A and B. Prior to
DubinJohnson syndrome Access Provided by:
Benign recurrent intrahepatic cholestasis
DIFFERENTIAL DIAGNOSIS
A. Differential Diagnosis of Jaundice
As previously noted, the differential diagnosis of jaundice has changed significantly since the advent of immunization for hepatitis A and B. Prior to
2000, viral hepatitis was the cause of jaundice in 85–90% of patients younger than age 30. In patients presenting with jaundice who were between the
ages of 40–60, alcoholic liver disease was the most common diagnosis, occurring in 50–70%. In patients 60–80 years of age without a history of blood
transfusion, excessive alcoholic use, contact with a person with jaundice, or use of putative medicines, the diagnosis in over 80% was either gallstones
and their complications or cancer of the pancreas. Chronic hepatitis was the cause of jaundice in 5% of patients across the age spectrum. Drug
induced jaundice occurred in less than 5% of individuals (Table 38–5).
Table 38–5.
Differential diagnosis of jaundice.a
Age
Viral hepatitis 85–90%
Alcoholic liver disease 50–70%
Gallstones and complications 80%
Cancer of the pancreas
Chronic hepatitis 5% 5–10%
Primary biliary cirrhosisb 1% 1%
Primary sclerosing cholangitisb 1% 1%
aReflects incidence of jaundice as reported between 1991 and 2000. That this has changed appreciably is detailed in Table 38–6.
b Data on incidence are insufficient.
Approximately 80% of patients with acute hepatitis C develop chronic infection (viremia) and most of these have chronic hepatitis.
Recent studies call attention to changing trends in the differential diagnosis of jaundice (Table 38–6). In a review of 732 patients with serum bilirubin
levels greater than 3 mg/dL, the most common cause was decompensation of chronic liver disease, occurring in 20.5% of the patients. Alcoholic
hepatitis was present in 16.5%. Acute viral hepatitis was less frequently a cause of acute onset jaundice in 8.8% of the patients, a decline in incidence
that is attributed to increased immunization of children and pregnant women against hepatitis A and B. Other hepatic causes of jaundice included
acute autoimmune hepatitis and druginduced jaundice. An extrahepatic etiology was evident in nearly half the patients, with sepsis, gallstone disease,
hemolysis, and malignancy accounting for the bulk of cases.
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Table 38–6.
Chapter 38: Approach to the Patient with Jaundice &; Abnormal Liver Tests, Norton J. Greenberger
Causes of jaundice identified in one recent survey.
Page 8 / 12
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Cause Percentage of Cases
levels greater than 3 mg/dL, the most common cause was decompensation of chronic liver disease, occurring in 20.5% of the patients. Alcoholic
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hepatitis was present in 16.5%. Acute viral hepatitis was less frequently a cause of acute onset jaundice in 8.8% of the patients, a decline in incidence
that is attributed to increased immunization of children and pregnant women against hepatitis A and B. Other hepatic causes of jaundice included
acute autoimmune hepatitis and druginduced jaundice. An extrahepatic etiology was evident in nearly half the patients, with sepsis, gallstone disease,
hemolysis, and malignancy accounting for the bulk of cases.
Table 38–6.
Causes of jaundice identified in one recent survey.
Cause Percentage of Cases
Hepatic Etiology (n = 406; 55%)
Decompensation preexisting chronic liver disease 20.5%
Alcoholic hepatitis 16.5%
Acute viral liver disease 8.8%
HBV [5.0]
HCV [2.0]
HAV [1.0]
EBV [0.5]
HIV [0.3]
Acute autoimmune hepatitis 0.3%
Drug induced 3.9%
Acetaminophen [3.3]
HAART [0.4]
Valproate [0.1]
Metabolite [0.1]
Extrahepatic Etiology (n = 326; 45%)
Sepsis/abnormal hemodynamic state 22%
Gallstone disease 14%
Hemolysis 2.5%
Malignancy 6.2%
Pancreatic biliary [2.9]
Metastatic [3.5]
EBV, EpsteinBarr virus; HAART, highly active antiretroviral therapy; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency
virus.
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Adapted with permission from Vuppalanchi R, Liangpunsakul S, Chalasani N: Etiology of newonset jaundice: how often is it caused by idiosyncratic druginduced
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
liver injury in the United States? Am J Gastroenterol. 2007 Mar;102(3):558–562.
Sepsis is a cause of jaundice due to intrahepatic cholestasis (see Table 38–4 and Figure 38–1). Sickle cell anemia, which is common among African
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Metastatic [3.5]
EBV, EpsteinBarr virus; HAART, highly active antiretroviral therapy; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency
virus.
Adapted with permission from Vuppalanchi R, Liangpunsakul S, Chalasani N: Etiology of newonset jaundice: how often is it caused by idiosyncratic druginduced
liver injury in the United States? Am J Gastroenterol. 2007 Mar;102(3):558–562.
Sepsis is a cause of jaundice due to intrahepatic cholestasis (see Table 38–4 and Figure 38–1). Sickle cell anemia, which is common among African
Americans, also may be characterized by intrahepatic cholestasis (see Table 38–4).
Gilbert syndrome, or chronic idiopathic unconjugated hyperbilirubinemia, occurs in 2–7% of the population and is associated with entirely normal
liver tests and absence of bilirubinuria. The importance of making this diagnosis is that patients are so identified and unnecessary testing is avoided.
Primary biliary cirrhosis and primary sclerosing cholangitis are being increasingly recognized as important causes of jaundice, although in both of
these disorders the diagnosis is being made earlier with the use of biochemical tests, liver biopsy, and imaging studies.
B. Differential Diagnosis of Intrahepatic Cholestasis
The spectrum of disorders causing intrahepatic cholestasis is summarized in Table 38–4. At every site in the intrahepatic biliary tree, there are
disorders associated with jaundice (see Figure 38–1). Thus, hepatocellular causes, including viral hepatitis (especially type A), alcoholic liver disease,
chronic hepatitis, and α1antitrypsin deficiency can be associated with intrahepatic cholestasis. Canalicular cholestasis may be drug induced (eg,
caused by phenothiazines or alkylated steroids), or associated with the postoperative state, sepsis, parenteral nutrition, Hodgkin disease, sickle cell
disease, toxic shock syndrome, or amyloidosis. The ductules are the source of jaundice in primary biliary cirrhosis and sarcoidosis; the larger ducts in
primary sclerosing cholangitis, Caroli disease, and intrahepatic biliary atresia. Recurrent jaundice occurs with recurrent cholestasis of pregnancy,
benign recurrent intrahepatic cholestasis and DubinJohnson syndrome. Jaundice can occur in patients with sepsis, especially gramnegative sepsis,
because gramnegative bacilli elaborate toxins that interfere with canalicular function (ie, canalicular membrane ATPases). It should also be
remembered that patients with intrathoracic or intraabdominal bleeding may develop jaundice because of the large bilirubin pigment load. Every 50
mL of blood loss produces up to 250 mg of bilirubin; thus, a patient who has experienced a 5unit intraperitoneal or intrathoracic bleed may have 2500
mg of bilirubin presented for excretion, overwhelming the body’s uptake, conjugation, and excretion mechanisms for handling bilirubin.
C. Differential Diagnosis of Chronic Hepatitis
The differential diagnosis of chronic hepatitis is depicted using a mnemonic device in Table 38–7. The letters in the lefthand column—A, B, C, D1, D2,
E1, E2, F, and H—correspond to the categories of possible causes of chronic hepatitis.
Table 38–7.
Differential diagnosis of chronic hepatitis.
A Autoimmune
• ANASMA positive
• Antiactin positive
• Anti–LKM1 positive
• AntiSLA positive
B Hepatitis B
C Hepatitis C
D(1) Hepatitis D (only with hepatitis B)
D
(2) Drugs (αmethyldopa, isoniazid, nitrofurantoin)
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E(1) Wilson disease
E(2) α1Antitrypsin
C. Differential Diagnosis of Chronic Hepatitis Access Provided by:
The differential diagnosis of chronic hepatitis is depicted using a mnemonic device in Table 38–7. The letters in the lefthand column—A, B, C, D1, D2,
E1, E2, F, and H—correspond to the categories of possible causes of chronic hepatitis.
Table 38–7.
Differential diagnosis of chronic hepatitis.
A Autoimmune
• ANASMA positive
• Antiactin positive
• Anti–LKM1 positive
• AntiSLA positive
B Hepatitis B
C Hepatitis C
D(1) Hepatitis D (only with hepatitis B)
D(2) Drugs (αmethyldopa, isoniazid, nitrofurantoin)
E(1) Wilson disease
E(2) α1Antitrypsin
F Nonalcoholic fatty liver disease (NAFLD)
H Hemochromatosis
ANA, antinuclear antibody; SLA, soluble liver antigen.
Chronic hepatitis may be due to autoimmune disease in which the subtypes are anti–nuclear body smooth muscle positive, antiactin positive, anti–
LKM1 positive, and anti–liver surface antigen positive. The most common entity in the United States is anti–nuclear and smooth muscle (Factin)–
positive disease. Approximately 5% of patients with acute hepatitis B develop chronic hepatitis. Approximately 80% of patients with acute hepatitis C
develop chronic infection (viremia) and most of them will have chronic hepatitis. Hepatitis D occurs only with hepatitis B. Various drugs, including α
methyldopa, isoniazid, Augmentin, and nitrofurantoin, are associated with jaundice. In the United States, the drug most frequently associated with
jaundice is amoxicillin and its various derivatives. Wilson disease is a rare cause of jaundice but needs to be considered because it is eminently
treatable. α1Antitrypsin deficiency also needs to be considered. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver test
abnormalities and is discussed in detail in Chapter 44. Hemochromatosis is another important cause of liver disease and is detailed in Chapter 42.
DIAGNOSTIC CONSIDERATIONS IN PATIENTS WITH ELEVATED SERUM AMINOTRANSFERASES
An elevation in aminotransferase in asymptomatic individuals is common, occurring in over 8% of the US population. Recent surveys by the National
Health and Nutrition Examination Survey (NHANES) have provided important information on aminotransferase elevations in asymptomatic individuals
in the United States. The third annual NHANES survey reported on 15,676 adults over the age of 17 years. Aminotransferase elevation was defined by an
aspartate aminotransferase (AST) value greater than 37, and an alanine aminotransferase (ALT) value greater than 42 and was classified as explained if
there was (1) evidence of hepatitis B, (2) hepatitis C, (3) iron overload (ie, transferrin saturation >50%), or (4) alcohol consumption greater than two
drinks per day for men and greater than one drink per day for women. Aminotransferase elevation was classified as unexplained if any of the
preceding four factors were absent.
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Prevalence of aminotransferase elevation in the United States was 7.9%. If lower values for the upper limit for both serum AST and ALT (>19 for women
Chapter 38: Approach to the Patient with Jaundice &; Abnormal Liver Tests, Norton J. Greenberger Page 11 / 12
and >30 for men) are used the prevalence of aminotransferase elevations would increase to 26%. Aminotransferase elevations were more common in
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men (9.3%) compared with women (6.6%), and in Mexican Americans (14.9%) and nonHispanic blacks 8.1% compared with nonHispanic whites
(7.1%). Known causes occurred in 31% of the patients, with the most common causes being alcohol, hepatitis C virus, hemochromatosis, and hepatitis
in the United States. The third annual NHANES survey reported on 15,676 adults over the age of 17 years. Aminotransferase elevation was defined by an
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aspartate aminotransferase (AST) value greater than 37, and an alanine aminotransferase (ALT) value greater than 42 and was classified as explained if
there was (1) evidence of hepatitis B, (2) hepatitis C, (3) iron overload (ie, transferrin saturation >50%), or (4) alcohol consumption greater than two
drinks per day for men and greater than one drink per day for women. Aminotransferase elevation was classified as unexplained if any of the
preceding four factors were absent.
Prevalence of aminotransferase elevation in the United States was 7.9%. If lower values for the upper limit for both serum AST and ALT (>19 for women
and >30 for men) are used the prevalence of aminotransferase elevations would increase to 26%. Aminotransferase elevations were more common in
men (9.3%) compared with women (6.6%), and in Mexican Americans (14.9%) and nonHispanic blacks 8.1% compared with nonHispanic whites
(7.1%). Known causes occurred in 31% of the patients, with the most common causes being alcohol, hepatitis C virus, hemochromatosis, and hepatitis
B virus. The cause was unexplained in twothirds of cases but was associated with higher body mass index, dyslipidemia, diabetes, hypertension, and
insulin resistance. Among patients with a body mass index greater than 40, over half had NAFLD. Many patients with these findings have the metabolic
syndrome. Fifteen percent of such patients may already have cirrhosis.
Uncommon but important causes of asymptomatic aminotransferase elevations included chronic acetaminophen use greater than 4 g/day, celiac
sprue, and use of statins. Elevations in aminotransferase values in statin users ranged from 0.5% to 3% and were dependent in large part on the dose
of statin. It bears emphasizing that despite the aminotransferase elevations noted in users of statins, only rare cases of significant liver disease have
been reported in such patients, and in those cases another cause was usually identified.
Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol .
2003;98:960–967.
[PubMed: 12809815]
Greenberger NJ. History taking and physical examination for the patient with liver disease. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s
Diseases of the Liver . 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007:3–18.
Vuppalanchi R, Liangpunsakul S, Chalasani N. New onset jaundice: how often is it caused by idiosyncratic druginduced liver injury in the United
States. Am J Gastroenterol . 2007;102:558–562.
[PubMed: 17156142]
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Chapter 38: Approach to the Patient with Jaundice &; Abnormal Liver Tests, Norton J. Greenberger Page 12 / 12
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