Jaundice and Evaluation of Liver Function

JAUNDICE

Definition

Yellow skin pigmentation caused by elevation in serum bilirubin level (also termed icterus); often more easily discernible in sclerae. Scleral icterus becomes clinically evident at a serum bilirubin level of ≥51 μmol/L (≥3 mg/dL); yellow skin discoloration also occurs with elevated serum carotene levels but without pigmentation of the sclerae.

Bilirubin Metabolism

Bilirubin is the major breakdown product of hemoglobin released from senescent erythrocytes. Initially, it is bound to albumin, transported into the liver, conjugated to a water-soluble form (glucuronide) by glucuronosyltransferase, excreted into the bile, and converted to urobilinogen in the colon. Urobilinogen is mostly excreted in the stool; a small portion is reabsorbed and excreted by the kidney. Bilirubin can be filtered by the kidney only in its conjugated form (measured as the “direct” fraction); thus, increased direct serum bilirubin level is associated with bilirubinuria. Increased bilirubin production and excretion (even without hyperbilirubinemia, as in hemolysis) produce elevated urinary urobilinogen levels.

Etiology

Hyperbilirubinemia occurs as a result of (1) overproduction; (2) impaired uptake, conjugation, or excretion of bilirubin; (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts (Table 42-1).

TABLE 42-1: CAUSES OF ISOLATED HYPERBILIRUBINEMIA
  1. Indirect hyperbilirubinemia
    1. Hemolytic disorders
      1. Inherited
        1. Spherocytosis, elliptocytosis, glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies
        2. Sickle cell anemia
      2. Acquired
        1. Microangiopathic hemolytic anemias
        2. Paroxysmal nocturnal hemoglobinuria
        3. Spur cell anemia
        4. Immune hemolysis
        5. Parasitic infections
          1. Malaria
          2. Babesiosis
    2. Ineffective erythropoiesis
      1. Cobalamin, folate, and severe iron deficiencies
      2. Thalassemia
    3. Increased bilirubin production
      1. Massive blood transfusion
      2. Resorption of hematoma
    4. Drugs
      1. Rifampin
      2. Probenecid
      3. Ribavirin
    5. Inherited conditions
      1. Crigler-Najjar types I and II
      2. Gilbert’s syndrome
  2. Direct hyperbilirubinemia
    1. Inherited conditions
      1. Dubin-Johnson syndrome
      2. Rotor syndrome

Evaluation

The initial steps in evaluating the pt with jaundice are to determine whether (1) hyperbilirubinemia is conjugated or unconjugated, and (2) other biochemical liver tests are abnormal (Figs. 42-1 and 42-2, Tables 42-2 and 42-3). Essential clinical examination includes history (especially duration of jaundice, pruritus, associated pain, risk factors for parenterally transmitted diseases, medications, ethanol use, travel history, surgery, pregnancy, presence of any accompanying symptoms), physical examination (hepatomegaly, tenderness over liver, palpable gallbladder, splenomegaly, gynecomastia, testicular atrophy, other stigmata of chronic liver disease), blood liver tests (see below), and complete blood count.

TABLE 42-2: HEPATOCELLULAR CONDITIONS THAT MAY PRODUCE JAUNDICE
Viral hepatitis
 Hepatitis A, B, C, D, and E
 Epstein-Barr virus
 Cytomegalovirus
 Herpes simplex
Alcoholic hepatitis
Drug toxicity
 Predictable, dose dependent, (e.g., acetaminophen)
 Unpredictable, idiosyncratic, (e.g., isoniazid)
Environmental toxins
 Vinyl chloride
 Jamaica bush tea—pyrrolizidine alkaloids
 Kava Kava
 Wild mushrooms—Amanita phalloides or A. verna
Wilson’s disease
Autoimmune hepatitis
TABLE 42-3: CHOLESTATIC CONDITIONS THAT MAY PRODUCE JAUNDICE
  1. Intrahepatic
    1. Viral hepatitis
      1. Fibrosing cholestatic hepatitis—hepatitis B and C
      2. Hepatitis A, Epstein-Barr virus infection, cytomegalovirus infection
    2. Alcoholic hepatitis
    3. Drug toxicity
      1. Pure cholestasis—anabolic and contraceptive steroids
      2. Cholestatic hepatitis—chlorpromazine, erythromycin estolate
      3. Chronic cholestasis—chlorpromazine and prochlorperazine
    4. Primary biliary cirrhosis
    5. Primary sclerosing cholangitis
    6. Vanishing bile duct syndrome
      1. Chronic rejection of liver transplants
      2. Sarcoidosis
      3. Drugs
    7. Congestive hepatopathy and ischemic hepatitis
    8. Inherited conditions
      1. Progressive familial intrahepatic cholestasis
      2. Benign recurrent cholestasis
    9. Cholestasis of pregnancy
    10. Total parenteral nutrition
    11. Nonhepatobiliary sepsis
    12. Benign postoperative cholestasis
    13. Paraneoplastic syndrome
    14. Veno-occlusive disease
    15. Graft-versus-host disease
    16. Infiltrative disease
      1. TB
      2. Lymphoma
      3. Amyloidosis
    17. Infections
      1. Malaria
      2. Leptospirosis
  2. Extrahepatic
    1. Malignant
      1. Cholangiocarcinoma
      2. Pancreatic cancer
      3. Gallbladder cancer
      4. Ampullary cancer
      5. Malignant involvement of the porta hepatis lymph nodes
    2. Benign
      1. Choledocholithiasis
      2. Postoperative biliary strictures
      3. Primary sclerosing cholangitis
      4. Chronic pancreatitis
      5. AIDS cholangiopathy
      6. Mirizzi’s syndrome
      7. Parasitic disease (ascariasis)
FIGURE 42-1

Evaluation of the pt with jaundice. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatogram; MRCP, magnetic resonance cholangiopancreatography; SMA, smooth-muscle antibody; SPEP, serum protein electrophoresis.

FIGURE 42-2

Algorithm for evaluation of abnormal liver tests. α AT, α1 antitrypsin; AlkP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ERCP, endoscopic retrograde cholangiopancreatogram; GGT, γ-Glutamyl transpeptidase; HAV, hepatitis A virus; HBc, hepatitis B core; HBsAG, hepatitis B surface antigen; HCV, hepatitis C virus; MRCP, magnetic resonance cholangiopancreatography; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; SMA, smooth-muscle antibody.

Gilbert Syndrome

Impaired conjugation of bilirubin due to reduced bilirubin UDP glucuronosyltransferase activity. Results in mild unconjugated hyperbilirubinemia, almost always <103 μmol/L (<6 mg/dL). Affects 3–7% of the population; males/females 2–7:1.

BLOOD TESTS OF LIVER FUNCTION

Used to detect presence of liver disease (Fig. 42-2), discriminate among different types of liver disease (Table 42-4), gauge the extent of known liver damage, and follow response to treatment.

TABLE 42-4: LIVER TEST PATTERNS IN HEPATOBILIARY DISORDERS
Type of DisorderBilirubinAminotransferases
Hemolysis/Gilbert’s syndromeNormal to 86 μmol/L (5 mg/dL)Normal
 85% due to indirect fractions 
 No bilirubinuria 
Acute hepatocellular necrosis (viral and drug hepatitis, hepatotoxins, acute heart failure)

Both fractions may be elevated

Peak usually follows aminotransferases

Bilirubinuria

Elevated, often >500 IU ALT >AST
Chronic hepatocellular disordersBoth fractions may be elevatedElevated, but usually <300 IU
 Bilirubinuria 
Alcoholic hepatitis, cirrhosis

Both fractions may be elevated

Bilirubinuria

AST:ALT > 2 suggests alcoholic hepatitis or cirrhosis
Intra- and extra-hepatic cholestasisBoth fractions may be elevatedNormal to moderate elevation
(Obstructive jaundice)BilirubinuriaRarely >500 IU
Infiltrative diseases (tumor, granulomata); partial bile duct obstructionUsually normalNormal to slight elevation
Alkaline PhosphataseAlbuminProthrombin Time
NormalNormalNormal
Normal to <3 times normal elevationNormalUsually normal. If >5 × above control and not corrected by parenteral vitamin K, suggests poor prognosis
Normal to <3 times normal elevationOften decreased

Often prolonged

Fails to correct with parenteral vitamin K

  
Normal to <3 times normal elevationOften decreased

Often prolonged

Fails to correct with parenteral vitamin K

Elevated, often >4 times normal elevationNormal, unless chronic

Normal

If prolonged, will correct with parenteral vitamin K

Elevated, often >4 times normal elevation

Fractionate, or confirm liver origin with 5′ nucleotidase or γ-glutamyl transpeptidase

NormalNormal

Bilirubin

Provides indication of hepatic uptake, metabolic (conjugation) and excretory functions; conjugated fraction (direct) distinguished from unconjugated by chemical assay (Table 42-1).

Aminotransferases (Transaminases)

Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT); sensitive indicators of liver cell injury; greatest elevations seen in hepatocellular necrosis (e.g., viral hepatitis, toxic or ischemic liver injury, acute hepatic vein obstruction), occasionally with sudden, complete biliary obstruction (e.g., from gallstone); milder abnormalities in cholestatic, cirrhotic, and infiltrative disease; poor correlation between degree of liver cell damage and level of aminotransferases; ALT more specific measure of liver injury, because AST also found in striated muscle and other organs; ethanol-induced liver injury usually produces modest increases with more prominent elevation of AST than ALT.

Alkaline Phosphatase

Sensitive indicator of cholestasis, biliary obstruction (enzyme increases more quickly than serum bilirubin), and liver infiltration; mild elevations in other forms of liver disease; limited specificity because of wide tissue distribution; elevations also seen in normal childhood, pregnancy, and bone diseases; tissue-specific isoenzymes can be distinguished by fractionation or by differences in heat stability (liver enzyme activity stable under conditions that destroy bone enzyme activity).

5′-Nucleotidase (5′-NT)

Pattern of elevation in hepatobiliary disease similar to alkaline phosphatase; has greater specificity for liver disorders; used to determine whether liver is source of elevation in serum alkaline phosphatase, esp. in children, pregnant women, pts with possible concomitant bone disease.

γ-Glutamyl transpeptidase (GGT)

Correlates with serum alkaline phosphatase activity. Elevation is less specific for cholestasis than alkaline phosphatase or 5′-NT.

Coagulation Factors

Measure of clotting factor activity; prolongation results from clotting factor deficiency or inactivity; all clotting factors except factor VIII are synthesized in the liver, and deficiency can occur rapidly from widespread liver disease as in hepatitis, toxic injury, or cirrhosis; single best acute measure of hepatic synthetic function; helpful in diagnosis and prognosis of acute liver disease (See Also Chap. 64). Clotting factors II, VII, IX, X function only in the presence of the fat-soluble vitamin K; PT prolongation from fat malabsorption distinguished from hepatic disease by rapid and complete response to vitamin K replacement.

Albumin

Decreased serum levels result from decreased hepatic synthesis (chronic liver disease or prolonged malnutrition) or excessive losses in urine or stool; insensitive indicator of acute hepatic dysfunction, because serum half-life is 2–3 weeks; in pts with chronic liver disease, degree of hypoalbuminemia correlates with severity of liver dysfunction.

Globulin

Mild polyclonal hyperglobulinemia often seen in chronic liver diseases; marked elevation frequently seen in autoimmune chronic active hepatitis.

Ammonia

Elevated blood levels result from deficiency of hepatic detoxification pathways and portal-systemic shunting, as in fulminant hepatitis, hepatotoxin exposure, and severe portal hypertension (e.g., from cirrhosis); elevation of blood ammonia does not correlate well with hepatic function or the presence or degree of acute encephalopathy.

HEPATOBILIARY IMAGING PROCEDURES

Ultrasonography (US)

Rapid, noninvasive examination of abdominal structures; no radiation exposure; relatively low cost, equipment portable; images and interpretation strongly dependent on expertise of examiner; particularly valuable for detecting biliary duct dilation and gallbladder stones (>95%); much less sensitive for intraductal stones (~60%); most sensitive means of detecting ascites; moderately sensitive for detecting hepatic masses but excellent for discriminating solid from cystic structures; useful in directing percutaneous needle biopsies of suspicious lesions; Doppler US useful to determine patency and flow in portal, hepatic veins and portal-systemic shunts; imaging improved by presence of ascites but severely hindered by bowel gas; endoscopic US less affected by bowel gas and is sensitive for determination of depth of tumor invasion through bowel wall.

CT

Particularly useful for detecting, differentiating, and directing percutaneous needle biopsy of abdominal masses, cysts, and lymphadenopathy; imaging enhanced by intestinal or intravenous contrast dye and unaffected by intestinal gas; somewhat less sensitive than US for detecting stones in gallbladder but more sensitive for choledocholithiasis; may be useful in distinguishing certain forms of diffuse hepatic disease (e.g., fatty infiltration, iron overload).

MRI

Most sensitive detection of hepatic masses and cysts; allows easy differentiation of hemangiomas from other hepatic tumors; most accurate noninvasive means of assessing hepatic and portal vein patency, vascular invasion by tumor; useful for monitoring iron, copper deposition in liver (e.g., in hemochromatosis, Wilson’s disease). Magnetic resonance cholangiopancreatography (MRCP) can be useful for visualizing the head of the pancreas and the pancreatic and biliary ducts.

Radionuclide Scanning

Using various radiolabeled compounds, different scanning methods allow sensitive assessment of biliary excretion (HIDA, PIPIDA, DISIDA scans), parenchymal changes (technetium sulfur colloid liver/spleen scan), and selected inflammatory and neoplastic processes (gallium scan); HIDA and related scans particularly useful for assessing biliary patency and excluding acute cholecystitis in situations where US is not diagnostic; CT, MRI, and colloid scans have similar sensitivity for detecting liver tumors and metastases; CT and combination of colloidal liver and lung scans sensitive for detecting right subphrenic (suprahepatic) abscesses.

Cholangiography

Most sensitive means of detecting biliary ductal calculi, biliary tumors, sclerosing cholangitis, choledochal cysts, fistulas, and bile duct leaks; may be performed via endoscopic (transampullary) or percutaneous (transhepatic) route; allows sampling of bile and ductal epithelium for cytologic analysis and culture; allows placement of biliary drainage catheter and stricture dilation; endoscopic route (endoscopic retrograde cholangiopancreatogram [ERCP]) permits manometric evaluation of sphincter of Oddi, sphincterotomy, and stone extraction.

Angiography

Most accurate means of determining portal pressures and assessing patency and direction of flow in portal and hepatic veins; highly sensitive for detecting small vascular lesions and hepatic tumors (esp. primary hepatocellular carcinoma); “gold standard” for differentiating hemangiomas from solid tumors; most accurate means of studying vascular anatomy in preparation for complicated hepatobiliary surgery (e.g., portal-systemic shunting, biliary reconstruction) and determining resectability of hepatobiliary and pancreatic tumors. Similar anatomic information (but not intravascular pressures) can often be obtained noninvasively by CT- and MR-based techniques.

Percutaneous Liver Biopsy

Most accurate in disorders causing diffuse changes throughout the liver; subject to sampling error in focal infiltrative disorders such as metastasis; should not be the initial procedure in the diagnosis of cholestasis. Contraindications to performing a percutaneous liver biopsy include significant ascites and prolonged international normalized ratio (INR). In such settings, the biopsy can be performed via the transjugular approach.

For a more detailed discussion

For a more detailed discussion, see John S, Pratt DS: Jaundice, Chap. 58, p. 279; Ghany MG, Hoofnagle JH: Approach to the Patient with Liver Disease, Chap 357, p. 1989; and Pratt DS: Evaluation of Liver Function, Chap. 358, p. 1995, in HPIM-19.

Jaundice and Evaluation of Liver Function is a sample topic from the Harrison's Manual of Medicine.

To view other topics, please or purchase a subscription.

Harrison’s Manual of Medicine 19th edition provides 600+ internal medicine topics in a rapid-access format. Download Harrison’s App to iPhone, iPad, and Android smartphone and tablet. Learn more.

Citation

* When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Jaundice and Evaluation of Liver Function ID - 623179 Y1 - 2017 PB - Harrison's Manual of Medicine UR - https://harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623179/all/Jaundice_and_Evaluation_of_Liver_Function ER -