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Updated: 10/25/07 11:31 AM |
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| HOME | HEAL | EDUCATE | RESEARCH | DIRECTORY | OUTREACH |
Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
Download Chapter ♦ Download Lecture Slides & Notes
Download Chapter ♦ Download Lecture Slides & Notes
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M. Pathophysiology, Diagnosis and Treatment of Jaundice
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| Jaundice classified according to type of bilirubin retained and specific steps in bilirubin metabolism that are abnormal |
Jaundice may be classified into two broad groups according to the predominant form of bilirubin, conjugated or unconjugated, that is retained in the plasma and tissues (Table 2). As shown in Table 1, unconjugated hyperbilirubinemia is caused by abnormalities in all steps up to and including the conjugation of bilirubin (steps 1 to 5) and alterations in the intestinal handling or enterohepatic recirculation of bilirubin (steps 8 to 10). By contrast, retention of conjugated bilirubins is caused by impairment of canalicular secretion (step 6) or biliary flow
(step 7).
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Table 1 [Click for Larger Image] Specific steps in bilirubin metabolism and abnormalities that affect them |
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Table 2 Unconjugated versus Conjugated Hyperbilirubinemia |
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1. Pathophysiology of Unconjugated Hyperbilirubinemia
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a. Impaired steps in bilirubin metabolism
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Only UCB retained No bilirubinuria Defects in steps 1-5 and 8-10 Mainly functional diseases, so avoid invasive tests |
Unconjugated hyperbilirubinemia, characterized by exclusive retention of UCB in the serum, without bilirubinuria (Table 2), results from insufficient hepatic clearance and/or conjugation of the load of the UCB produced each day, and is subclassified according to the step(s) in bilirubin metabolism that are deranged (Table 1). The most common etiologies are (Step 1) overproduction of unconjugated bilirubin due to disorders of red blood cells; (Step 2) impaired delivery of unconjugated bilirubin due to disturbances in hepatic circulation; and (Steps 3, 4, or 5) functional or hereditary defects in uptake, storage, and/or conjugation of bilirubin. Alterations in the intestinal metabolism and enterohepatic circulation of bilirubin (Steps 8, 9, or 10) may also cause or contribute to unconjugated hyperbilirubinemia.
Although the underlying hematological, circulatory, or functional disorders may also be serious in themselves, the primary hepatic disorders that cause pure unconjugated hyperbilirubinemia are seldom life-threatening per se except in some neonates, and in patients with the Crigler-Najjar syndrome. Therefore, invasive diagnostic studies of the liver, including biopsy, are rarely indicated, except if the cause appears to be porto-systemic shunting.
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1. Overproduction of bilirubin due to accelerated heme catabolism is a very common cause of unconjugated hyperbilirubinemia and often augments jaundice of other causes. Most often caused by hemolytic anemias. Diagnosis rests mainly on hematological studies.
2. Decreased delivery to the liver cells of bilirubin and other substances in plasma is a common cause of unconjugated jaundice. It is most often due to right-sided congestive heart failure and clears as the heart failure is controlled. Another major cause is portosystemic shunting, due to either cirrhosis, surgical anastomosis or TIPS, which diverts the UCB formed in the spleen past the liver directly into the systemic circulation. 3. & 4. Diminished clearance (uptake and storage) of UCB may be due to competitive inhibition of these processes by drugs (e.g., rifampicin). Such jaundice often resolves by 2-3 days after the drug is stopped. Impaired uptake of UCB and other organic anions is present in most patients with Gilbert's syndrome (see below). Pregnancy, hypothyroidism and febrile illnesses may impair hepatic storage capacity for UCB. |
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| Conjugation of UCB preserved in hepatobiliary diseases |
5. Impaired conjugation of bilirubin is usually due to hereditary defects, since the activity of UGT1A1 is preserved in hepatobiliary diseases, except in end-stage cirrhosis or acute hepatic failure.
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b. Hereditary autosomal recessive disorders of UCB conjugation |
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| Gilbert’s syndrome: a combined defect in conjugation plus decreased uptake and/or increased formation of UCB |
i) Gilbert's syndrome is a very common chronic, mild, fluctuating unconjugated hyperbilirubinemia, due to a gene promoter abnormality, causing a 2/3 decrease in the expression and activity of UGT1A1. When combined with overproduction and/or impaired uptake of bilirubin, hyperbilirubinemia occurs, that is often augmented by fasting, stress, or viral infections.
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| Crigler-Najjar Syndromes due to severe genetic deficiencies in UGT1A1 |
ii) The Crigler-Najjar syndromes are two more severe, rare, hereditary, recessive deficiencies of UGT1A1. In Type I, there is no detectable activity of UGT1A1 in the liver, jaundice is severe from the neonatal period, and bilirubin encephalopathy is the rule if the patients are untreated. In Type II, UGT1A1 activity is detectable at less than 10% of normal levels. Jaundice begins in late childhood, is less severe, and seldom causes brain damage
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2. Unconjugated hyperbilirubinemia of the newborn
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| Neonatal jaundice: impairment of most steps of UCB transport. |
Immaturity of most steps of bilirubin metabolism causes a mild, temporary, retention of UCB in virtually all neonates. Its severity is much influenced by the high rates of production and intestinal reabsorption of UCB in neonates, and the partial starvation of suboptimal breast-feeding. It is usually more marked in infants who are premature and/or have complicating hemolytic disease due to fetal-maternal Rh or ABO antigen incompatibility. Serum UCB levels >15 mg/dL may lead to deposition of unbound UCB diacid in the central nervous system, causing auditory and neurologic dysfunction (bilirubin encephalopathy), which is usually reversible but may be permanent or fatal (kernicterus).
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3. Treatment of Unconjugated Hyperbilirubinemia
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Treatments: Phototherapy Avoid fasting Inhibit UCB formation Trap UCB in gut Exchange transfusion |
The mild jaundice of Gilbert's syndrome does not require treatment, and may protect against oxidant stress. Treatment is only necessary when severe jaundice may cause brain damage. The preferred treatment of neonatal jaundice is phototherapy, which converts UCB to photoisomers that can be excreted in bile and urine without conjugation. In neonates, frequent feeding speeds intestinal transit and limits the reabsorption of UCB. A newly-accepted therapy in newborns is parenteral administration of tin mesoporphyrin IX, a potent competitive inhibitor of heme oxygenase and thus of bilirubin synthesis. Oral administration of calcium phosphate traps UCB in the intestine, interrupting its enterohepatic circulation. When severely jaundiced neonates respond insufficiently to the above therapies, they are treated by exchange transfusion to physically remove UCB from the circulation. Refractory Crigler-Najjar I subjects undergo liver transplantation.
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4. Pathophysiology of Conjugated Hyperbilirubinemia.
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| Both CB and UCB are elevated in plasma |
Conjugated hyperbilirubinemia is characterized by retention principally of conjugated bilirubin in the serum. Plasma UCB concentrations are elevated also, due in part to hydrolysis of retained conjugated bilirubins by tissue β-glucuronidases, as well as by contributions from associated hemolysis and/or impairment of delivery, uptake, and storage of UCB.
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Bilirubinuria is diagnostic of conjugated hyperbilirubinemia. |
Conjugated hyperbilirubinemia results from impairment of the canalicular secretion or biliary flow of conjugated bilirubins. Other organic anions, which share the same MRP2 transporter as conjugated bilirubin, are also excreted poorly. The retained conjugated bilirubins regurgitate through the hepatocytes, cholangiocytes and their weakened tight junctions into the space of Disse and thence via the lymph to the plasma. The small fraction of retained conjugated bilirubins that is not bound to plasma albumin filters at the glomerulus, giving bilirubinuria; this is diagnostic of conjugated hyperbilirubinemia, and also constitutes the major alternate pathway for excretion of conjugated bilirubin and other organic anions when hepatobiliary excretion is reduced.
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| Part of retained conjugates are δ- (delta) bilirubin which is covalently bound to albumin |
With prolonged conjugated hyperbilirubinemia, up to 80% of the conjugated bilirubin can become covalently linked to serum albumin. This δ-bilirubin is not excreted by the liver or kidneys. Therefore, with remission of hepatitis or relief of biliary obstruction, direct-reacting δ-bilirubin persists in the plasma long after urinary excretion of bilirubin conjugates has ended.
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| Conjugated hyper-bilirubinemia indicates significant hepatobiliary disease |
In contrast to unconjugated hyperbilirubinemia, jaundice with bilirubinuria almost always results from significant hepatobiliary disease, and is classified further according to whether canalicular secretion (Step 6) or biliary flow (Step 7) is primarily impaired. Defects in canalicular secretion of bilirubin conjugates and other organic anions secreted by MRP2 are characteristic of the hereditary Dubin-Johnson syndrome, and are common in hepatocellular diseases. Generalized defects in canalicular secretion, or in biliary flow, produce cholestasis, in which there is also marked retention of bile salts. Dislocation of alkaline phosphatase to the basolateral membrane leads to regurgitation of this enzyme into the space of Disse and thence to plasma.
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| Cholestasis causes retention of bile salts, cholesterol & alk. phosphatase |
The retention of bile salts inhibits both hepatic synthesis of cholesterol and (more so) hepatic catabolism of cholesterol to bile salts, but increases hepatic synthesis of alkaline phosphatase. The resultant marked increases in serum cholesterol and alkaline phosphatase levels aid in the clinical distinction of cholestasis from hepatocellular diseases. Cytoxic effects of the retained hydrophobic bile salts may cause the secondary hepatocellular injury that develops with prolonged cholestasis.
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5. Differential Diagnosis of Conjugated Hyperbilirubinemia
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| Hepatocellular vs. cholestatic jaundice |
Once the presence of conjugated hyperbilirubinemia has been established, the next steps in diagnosis are to determine whether jaundice is hepatocellular or cholestatic and to determine the level of the block (canalicular, or ductal) to biliary flow if cholestasis is present (Table 3).
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Itching virtually diagnostic of cholestatic jaundice
>3X elevation of serum alkaline phosphatase |
Itching, especially on the palms and soles, is virtually diagnostic of cholestasis but occurs in only 75% of cases. Retention of endogenous opioids is thought to cause the itching. In those who do not itch, the presence of cholestasis may be surmised from a >3X elevation of the serum alkaline phosphatase level, increased serum cholesterol level, milder elevations of serum transaminases, and response of an abnormal prothrombin time to Vitamin K. Steatorrhea may occur due to low concentrations of bile salts and mixed micelles in the intestine.
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Table 3 [Click for Larger Image] Hepatocellular versus Cholestatic Jaundice |
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6. Overlap of Syndromes of Hepatocellular & Cholestatic Jaundice |
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Agents may damage canaliculi as well as hepatocytes
Chronic cholestasis damages hepatocytes. |
a) agents that typically cause hepatocellular disease (e.g., alcohol and hepatitis viruses) sometimes also affect bile canaliculi; b) some drugs that characteristically cause intrahepatic cholestasis (e.g., chlorpromazine) may also damage hepatocytes; c) prolonged cholestasis, especially extrahepatic obstruction, secondarily damages the liver cells, due to the toxic effects of retained bile salts; and d) prolonged cholestasis and hepatocellular disease often progress to cirrhosis and portal hypertension.
The criteria in Table 3 are not infallible. Serum alkaline phosphatase values less than 3x normal are common in cholestasis due to infection or estrogens. Alkaline phosphatase levels, moreover, may be increased due to bone or kidney disease, or pregnancy; thus, the hepatic origin of the enzyme elevation may need verification by measurement of alkaline phosphatase isoenzymes, or determination of serum 5'-nucleotidase, which is hepato-specific though less sensitive. Serum transaminase and lactic dehydrogenase levels may be markedly elevated in patients with primary or metastatic hepatic cancer, or when cholangitis complicates biliary obstruction. |
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7. Distinguishing Intra- and Extra-Hepatic Cholestasis
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| All forms of cholestasis produce similar laboratory abnormalities. |
a. Routine liver function tests are of no assistance in locating the site of a cholestatic lesion because all forms of cholestasis produce similar clinical, histological, and biochemical abnormalities. A careful history and physical examination, plus routine blood chemistry tests, can appropriately classify cholestatic jaundice in 80% to 90% of patients.
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| Younger age, larger liver, substance abuse, and low serum cholesterol favor intrahepatic cholestasis |
b. Findings that suggest a diagnosis of intrahepatic cholestasis (often associated with hepatocellular disease) include: a) age less than 40 years (viral and drug hepatitis are most common in this age group); b) liver span of more than 15 cm on percussion, especially if the liver is tender (this sign most often indicates alcoholic or nonalcoholic fatty liver disease, or malignancy); c) drug addiction or homosexuality (high risk of transmission of hepatitis); d) history of alcoholism or recent treatment with drugs or hormones, especially estrogens, known to cause jaundice; and e) a decreased serum cholesterol level with an otherwise typical cholestatic syndrome suggests viral or alcoholic hepatitis as the etiology.
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| Older age, acholic stools, colicky pain, lack of systemic symptoms favor extrahepatic cholestasis |
c. Findings that favor a diagnosis of extrahepatic obstruction include: a) age greater than 60 years (in males in this age group, the obstruction is usually due to malignancy); b) acholic (pale) stools persisting for more than 2 weeks; c) colicky right upper quadrant pain and/or shaking chills compatible with choledocholithiasis and cholangitis; d) severe jaundice without systemic symptoms (hepatocellular diseases with severe jaundice are almost always associated with systemic symptoms); and e) a palpable gallbladder, which is most often associated with a malignant obstruction of the common bile duct.
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| Non-invasive imaging followed by ERCP if indicated |
d. Other Diagnostic Tests. When classification of cholestasis is uncertain, upper abdominal ultrasonography is advised, followed by computerized tomographic X-rays (CT scan) if the sonogram is undiagnositc. If intrahepatic cholestasis is suspected clinically and ultrasonography reveals no dilated ducts, liver biopsy is often helpful in establishing the etiology. If extrahepatic obstruction seems most likely clinically and noninvasive imaging reveals dilated ducts, endoscopic ultrasound can be useful in identifying tumor, and ERCP can be used to visualize, and even relieve, the obstructing lesion(s).
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