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(see Metabolic, Electrolyte, and Toxic Disorders in Neonates: Hyperbilirubinemia.)
Jaundice is
yellowing of the skin, sclerae, and other tissues caused by excess
circulating bilirubin.
Overview
of Bilirubin Metabolism
The breakdown of heme produces bilirubin (an insoluble waste product) and other bile pigments. Bilirubin must be made water-soluble to be excreted. This transformation occurs in five steps: formation, plasma transport, liver uptake, conjugation, and biliary excretion.
Formation:
About 250 to 350 mg of unconjugated bilirubin forms daily; 70 to 80% derives from the breakdown of degenerating RBCs, and 20 to 30% (early-labeled bilirubin) derives primarily from other heme proteins in the bone marrow and liver. Hb is degraded to iron and biliverdin, which is converted to bilirubin.
Plasma transport:
Unconjugated (indirect-reacting) bilirubin is not water-soluble and so is transported in the plasma bound to albumin. It cannot pass through the glomerular membrane into the urine. Albumin binding weakens under certain conditions (eg, acidosis), and some substances (eg, salicylates, certain antibiotics) compete for the binding sites.
Liver
uptake:
The liver takes up bilirubin rapidly but does not take up the attached serum albumin.
Conjugation:
Unconjugated bilirubin in the liver is conjugated to form mainly bilirubin diglucuronide, or conjugated (direct-reacting) bilirubin. This reaction, catalyzed by the microsomal enzyme glucuronyl transferase, renders the bilirubin water-soluble.
Biliary excretion:
Tiny canaliculi formed by adjacent hepatocytes progressively coalesce into ductules, interlobular bile ducts, and larger hepatic ducts. Outside the porta hepatis, the main hepatic duct joins the cystic duct from the gallbladder to form the common bile duct, which drains into the duodenum at the ampulla of Vater.
Conjugated bilirubin is secreted into the bile canaliculus with other bile constituents. In the intestine, bacteria metabolize bilirubin to form urobilinogen, much of which is further metabolized to stercobilins, which render the stool brown. In complete biliary obstruction, stools lose their normal color and become light gray (clay-colored stool). Some urobilinogen is reabsorbed, extracted by hepatocytes, and re-excreted in the bile (enterohepatic circulation). A small amount is excreted in the urine.
Because conjugated bilirubin is excreted in urine and unconjugated bilirubin is not, only conjugated hyperbilirubinemia (eg, due to hepatocellular or cholestatic jaundice) causes bilirubinuria.
Etiology
Jaundice can result from increased formation of bilirubin or hepatobiliary disease (hepatobiliary jaundice). Hepatobiliary jaundice can result from hepatocellular dysfunction or cholestasis. Cholestasis can be intrahepatic or extrahepatic.
Increased formation and hepatocellular diseases that impair liver uptake or decrease conjugation cause unconjugated hyperbilirubinemia. Impaired biliary excretion produces conjugated hyperbilirubinemia. Although these mechanisms seem distinct, in clinical practice, jaundice, particularly jaundice due to hepatobiliary disease, almost always produces multiple defects; the result is both unconjugated and conjugated hyperbilirubinemia (mixed hyperbilirubinemia).
Rarely, certain disorders produce predominantly unconjugated or conjugated hyperbilirubinemia. Unconjugated hyperbilirubinemia due to increased bilirubin formation can result from hemolytic disorders; those due to decreased conjugation can result from Gilbert syndrome (mild) and Crigler-Najjar syndrome (severe).
Conjugated hyperbilirubinemia due to impaired excretion can result from Dubin-Johnson syndrome. Conjugated hyperbilirubinemia due to intrahepatic cholestasis can result from hepatitis, drug toxicity, and alcoholic liver disease. Less common causes include primary biliary cirrhosis, cholestasis of pregnancy, and metastatic cancer. Conjugated hyperbilirubinemia due to extrahepatic cholestasis can result from a common bile duct stone or pancreatic cancer. Less common causes include benign stricture of the common duct (usually related to prior surgery), ductal carcinoma, pancreatitis or pancreatic pseudocyst, and sclerosing cholangitis.
Liver disease and biliary obstruction usually cause multiple defects, increasing both conjugated and unconjugated bilirubin.
Evaluation
Evaluation of jaundice should first address whether hepatobiliary disease is present. Hepatobiliary jaundice can result from cholestasis or hepatocellular dysfunction. Cholestasis can be intrahepatic or extrahepatic. Determining the cause of jaundice indicates diagnosis (eg, hemolysis or Gilbert syndrome if there is no hepatobiliary disease; viruses, toxins, hepatic manifestations of systemic diseases, or primary liver diseases in hepatocellular dysfunction; gallstones in extrahepatic cholestasis). Although laboratory and imaging tests are essential, most errors result from inadequate clinical data and overreliance on test results.
History:
Nausea or vomiting preceding jaundice often indicates acute hepatitis or common bile duct obstruction by a stone; abdominal pain or rigors favors the latter. Gradual development of anorexia and malaise is common in alcoholic liver disease, chronic hepatitis, and cancer.
Because urine can darken from hyperbilirubinemia before jaundice is visible, the onset of dark urine indicates the onset of hyperbilirubinemia more accurately than the onset of jaundice.
Physical examination:
Mild jaundice is best seen by examining the sclerae in natural light; it is usually detectable when serum bilirubin reaches 2 to 2.5 mg/dL (34 to 43 μmol/L). Mild jaundice without dark urine suggests unconjugated hyperbilirubinemia (most often caused by hemolysis or Gilbert syndrome); more severe jaundice or jaundice accompanied by dark urine suggests hepatobiliary disease. Signs of portal hypertension or portal-systemic encephalopathy, or skin or endocrine changes, suggest chronic liver disease.
In patients with hepatomegaly and ascites, distended jugular veins suggest heart failure or constrictive pericarditis. Cachexia and an unusually hard or lumpy liver more often indicate metastases than cirrhosis. Diffuse lymphadenopathy suggests infectious mononucleosis in acute jaundice, and lymphoma or leukemia in chronic jaundice. Hepatosplenomegaly without other signs of chronic liver disease may be caused by an infiltrative disorder (eg, lymphoma, amyloidosis, or, in endemic areas, schistosomiasis or malaria), although jaundice is usually minimal or absent in such disorders.
Testing:
(See also Testing for Hepatic and Biliary Disorders: Laboratory Tests.) Aminotransferases and alkaline phosphatase levels should be measured. Mild hyperbilirubinemia (eg, bilirubin < 3 mg/dL [< 51 μmol/L]) with normal aminotransferase and alkaline phosphatase levels is often unconjugated (eg, due to hemolysis or Gilbert syndrome rather than hepatobiliary disease). Moderate or severe hyperbilirubinemia, bilirubinuria, high alkaline phosphatase levels, or high aminotransferase levels suggest hepatobiliary disease. Unconjugated hyperbilirubinemia is usually confirmed by bilirubin fractionation. However, because hyperbilirubinemia produced by any hepatobiliary disease is largely conjugated, bilirubin fractionation is unwarranted if test results reflect hepatobiliary disease.
Other blood tests should be performed selectively. For example, hepatitis serology should be obtained (see Hepatitis: Serology) for suspected acute or chronic hepatitis, PT or INR for suspected hepatic insufficiency, albumin and globulin levels for suspected chronic liver disease, and antimitochondrial antibody levels for suspected primary biliary cirrhosis. In cases of isolated elevation of alkaline phosphatase, γ‑glutamyl transpeptidase (GGT) should be obtained; levels are elevated in hepatobiliary disease but not if the high alkaline phosphatase level is due to a bone disorder.
In hepatobiliary disease, neither bilirubin fractionation nor the degree of bilirubin elevation helps differentiate hepatocellular from cholestatic jaundice. Aminotransferase elevations > 500 units suggest a hepatocellular cause such as hepatitis or acute liver hypoxia; disproportionate increases of alkaline phosphatase (eg, alkaline phosphatase > 3 times normal and aminotransferase < 200 units) suggest cholestasis. Liver infiltration can also increase alkaline phosphatase disproportionately to aminotransferases but usually increases bilirubin only slightly or not at all.
Because hepatobiliary disease alone rarely causes bilirubin levels > 30 mg/dL (> 513 μmol/L), higher levels usually reflect a combination of severe hepatobiliary disease and hemolysis or renal dysfunction. Low albumin and high globulin levels suggest chronic rather than acute liver disease. An elevated PT or INR that decreases after giving vitamin K (5 to 10 mg IM for 2 to 3 days) favors cholestasis over hepatocellular disease but is not conclusive.
Imaging is best for diagnosing infiltrative and cholestatic causes of jaundice. Abdominal ultrasound, CT, or MRI is usually performed first. These tests can detect abnormalities within the biliary tree and focal liver lesions but are less accurate in diagnosing diffuse hepatocellular disorders (eg, hepatitis, cirrhosis). In extrahepatic cholestasis, endoscopic or magnetic resonance cholangiopancreatography (ERCP, MRCP) provides a more accurate assessment of the biliary tree; ERCP also permits treatment of the obstruction (eg, stone removal, stenting of strictures).
Liver biopsy is seldom required for diagnosing jaundice but can help in intrahepatic cholestasis and in some kinds of hepatitis. Laparoscopy (peritoneoscopy) permits direct inspection of the liver and gallbladder without the trauma of a full laparotomy. Unexplained cholestatic jaundice warrants laparoscopy occasionally and diagnostic laparotomy rarely.
Cholestatic
Conjugated Hyperbilirubinemia
Cholestasis (obstructive jaundice) can cause conjugated hyperbilirubinemia. Cholestasis results when bile flow is impaired. The term cholestasis is preferred to obstructive jaundice because mechanical obstruction is not always present. Cholestasis in infants differs from cholestasis in other age groups (see Gastrointestinal Disorders in Neonates and Infants: Neonatal Cholestasis).
Etiology
Bile flow may be impaired at any point, from the liver cell canaliculus to the ampulla of Vater.
Intrahepatic causes include hepatitis, drug toxicity, and alcoholic liver disease. Less common causes include primary biliary cirrhosis, cholestasis of pregnancy, and metastatic cancer.
Extrahepatic causes include a common duct stone and pancreatic cancer. Less common causes include benign stricture of the common duct (usually related to prior surgery), ductal carcinoma, pancreatitis or pancreatic pseudocyst, and sclerosing cholangitis.
Pathophysiology
Mechanisms are complex, even in mechanical obstruction. The pathophysiologic effects reflect absence of bile constituents (most importantly, bilirubin, bile salts, and lipids) in the intestines, and their backup, which causes spillage into the systemic circulation. Stools are often pale because less bilirubin reaches the intestine. Absence of bile salts can produce malabsorption, leading to steatorrhea and deficiencies of fat-soluble vitamins (particularly A, K, and D); vitamin K deficiency can reduce prothrombin levels. In long-standing cholestasis, concomitant vitamin D and Ca malabsorption can cause osteoporosis or osteomalacia.
Bilirubin retention produces mixed hyperbilirubinemia. Some conjugated bilirubin reaches and darkens the urine. High levels of circulating bile salts are associated with, but may not cause, pruritus. Cholesterol and phospholipid retention produces hyperlipidemia despite fat malabsorption (although increased liver synthesis and decreased plasma esterification of cholesterol also contribute); triglyceride levels are largely unaffected. The lipids circulate as a unique, abnormal, low-density lipoprotein called lipoprotein X.
Evaluation
Evaluation consists of history, physical examination, and diagnostic tests. Distinguishing between intrahepatic and extrahepatic causes is crucial.
History:
Cholestasis produces jaundice, dark urine, pale stools, and generalized pruritus. If chronic, cholestasis may produce bleeding (due to vitamin K malabsorption) or bone pain (due to osteoporosis from vitamin D and Ca malabsorption). Abdominal pain and systemic symptoms (eg, anorexia, vomiting, fever) reflect the underlying cause rather than cholestasis itself. Symptoms of hepatitis, heavy alcohol ingestion, or recent use of potentially cholestatic drugs suggest intrahepatic cholestasis. Rigors, biliary colic, or pain typical of pancreatic disorders (eg, pancreatic cancer) suggests extrahepatic cholestasis.
Physical examination:
If chronic, cholestasis may produce muddy skin pigmentation, excoriations (from pruritus), or cutaneous lipid deposits (xanthelasmas or xanthomas). Signs of chronic hepatocellular disease (eg, spider angiomas, splenomegaly, ascites) suggest intrahepatic cholestasis. Signs of cholecystitis (see Gallbladder and Bile Duct Disorders: Treatment) suggest extrahepatic cholestasis.
Testing:
Regardless of etiology, alkaline phosphatase levels characteristically increase, more from increased synthesis than from impaired excretion. Aminotransferase levels are usually only moderately elevated. Bilirubin levels are variable. To help confirm hepatic origin of high levels of alkaline phosphatase if other liver tests are normal, γ‑glutamyl transpeptidase (GGT) is measured. If hepatic insufficiency is suspected, PT (usually reported as the INR) is measured. Neither alkaline phosphatase, GGT, nor bilirubin levels, however, indicate the cause of cholestasis.
Other laboratory tests may reveal the cause of cholestasis, but only occasionally. Marked elevations in aminotransferase levels suggest a hepatocellular cause but occasionally occur in extrahepatic cholestasis, especially with acute obstruction by a common duct stone. High serum amylase levels are uncommon but suggest common bile duct obstruction. Correction of a prolonged PT or INR after administration of vitamin K suggests extrahepatic obstruction, but hepatocellular disorders may also respond. Presence of antimitochondrial antibodies strongly suggests primary biliary cirrhosis.
Imaging tests of the biliary tract are essential (see Testing for Hepatic and Biliary Disorders: Imaging Tests). Ultrasound, CT, and MRI reliably detect bile duct dilation, which usually occurs after the first several hours of symptoms due to mechanical obstruction. The underlying cause of obstruction may also be shown; in general, gallstones are more reliably seen on ultrasound and pancreatic lesions on CT. Ultrasound is usually preferred because of its lower cost and lack of ionizing radiation. If ultrasound demonstrates extrahepatic obstruction but not its cause, a more definitive study, usually endoscopic or magnetic resonance cholangiopancreatography (ERCP, MRCP), is indicated. Diagnostic laparoscopy or laparotomy is rarely indicated if extrahepatic obstruction is progressive and no cause can be found with imaging tests.
Liver biopsy is indicated for suspected intrahepatic cholestasis if the diagnosis is not clear from noninvasive studies. Because it predisposes to puncture of the biliary tree, which can cause peritonitis, ductal dilation should be ruled out (by ultrasound or CT) before biopsy.
Treatment
Extrahepatic biliary obstruction requires mechanical decompression. Other goals include treatment of the underlying cause, symptoms, and complications (eg, vitamin malabsorption).
Decompression of extrahepatic biliary obstruction usually requires laparotomy, endoscopy (eg, for removal of ductal stones) or, for strictures or partially obstructed areas, insertion of stents and drainage catheters. For obstruction due to inoperable cancers, stents can usually be placed transhepatically or endoscopically to provide drainage.
Pruritus usually subsides with correction of the underlying disorder or with cholestyramine 2 to 8 g po bid, which binds bile salts in the intestine. However, cholestyramine is ineffective in complete biliary obstruction. Unless severe hepatocellular damage is present, hypoprothrombinemia usually subsides after use of phytonadione (vitamin K1) 5 to 10 mg sc once/day for 2 to 3 days. Ca and vitamin D supplements, with or without a bisphosphonate, slow the progression of osteoporosis only slightly in long-standing irreversible cholestasis. Vitamin A supplements prevent deficiency, and severe steatorrhea can be minimized by replacing some dietary fat with medium-chain triglycerides.
Noncholestatic
Conjugated Hyperbilirubinemia
Disorders of bilirubin metabolism causing conjugated hyperbilirubinemia without cholestasis produce no symptoms or sequelae other than jaundice. In contrast to unconjugated hyperbilirubinemia in Gilbert syndrome, bilirubin may appear in the urine. Aminotransferase and alkaline phosphatase levels are usually normal. Treatment is unnecessary.
Dubin-Johnson
syndrome:
This rare autosomal recessive disorder involves impaired excretion of bilirubin glucuronides. It is usually diagnosed by liver biopsy; the liver is deeply pigmented as a result of an intracellular melanin-like substance but is otherwise histologically normal.
Rotor's
syndrome:
This rare disorder is clinically similar to Dubin-Johnson syndrome, but the liver is not pigmented, and other subtle metabolic differences are present.
Unconjugated Hyperbilirubinemia
Unconjugated hyperbilirubinemia is a disorder of bilirubin metabolism consisting of overproduction or defective conjugation of bilirubin.
Hemolysis:
RBC hemolysis is the most frequent clinically important cause of increased bilirubin formation. Although the normal liver can conjugate excess bilirubin, hemolysis may increase bilirubin to an unmanageable amount. Still, even in brisk hemolysis, serum bilirubin is rarely > 5 mg/dL (> 86 μmol/L). However, hemolysis combined with liver disease may cause higher levels; in these cases, canalicular bile excretion also becomes impaired, producing some conjugated hyperbilirubinemia (discussed in Anemias Caused by Hemolysis).
Gilbert
syndrome:
Gilbert syndrome is a presumably lifelong disorder whose only significant abnormality is asymptomatic, mild, unconjugated hyperbilirubinemia. It can be mistaken for chronic hepatitis or other liver disorders. Gilbert syndrome may affect as many as 5% of people. Although family members may be affected, a clear genetic pattern is difficult to establish.
Pathogenesis may involve complex defects in the liver's uptake of bilirubin. Glucuronyl transferase activity is low, though not as low as in Crigler-Najjar syndrome type II. In many patients, RBC destruction is also slightly accelerated, but this acceleration does not explain hyperbilirubinemia. Liver histology is normal.
Gilbert syndrome is most often detected in young adults serendipitously by finding an elevated bilirubin level, which usually fluctuates between 2 and 5 mg/dL (34 and 86 μmol/L) and tends to increase with fasting and other stresses.
Gilbert syndrome is differentiated from hepatitis by fractionation that shows predominantly unconjugated bilirubin, otherwise normal liver function test results, and absence of urinary bilirubin. It is differentiated from hemolysis by the absence of anemia and reticulocytosis. Treatment is unnecessary. Patients should be reassured that they do not have liver disease.
Crigler-Najjar
syndrome:
This rare inherited disorder is caused by deficiency of the enzyme glucuronyl transferase. Patients with autosomal recessive type I (complete) disease have severe hyperbilirubinemia. They usually die of kernicterus by age 1 yr but may survive into adulthood. Treatment may include phototherapy and liver transplantation. Patients with autosomal dominant type II (partial) disease (which has variable penetrance) often have less severe hyperbilirubinemia (< 20 mg/dL [< 342 μmol/L]) and usually live into adulthood without neurologic damage. Phenobarbital 1.5 to 2 mg/kg po tid, which induces the partially deficient glucuronyl transferase, may be effective.
Primary
shunt hyperbilirubinemia:
This rare, familial, benign condition is associated with overproduction of early-labeled bilirubin.
Last full review/revision November 2005
Content last modified November 2005
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