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MD Consult: Books: Goldman: Cecil Medicine: Chapter 150 – APPROACH TO THE PATIENT WITH JAUNDICE OR ABNORMAL LIVER TEST RESULTS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 150 – APPROACH TO THE PATIENT WITH JAUNDICE OR ABNORMAL LIVER TEST RESULTS

Paul D. Berk   Kevin M. Korenblat

Definition

Jaundice, from the French jaune (yellow), is the yellow-orange discoloration of the skin, conjunctivae, and mucous membranes that results from elevated concentrations of bilirubin in plasma. Mild hyperbilirubinemia may be clinically undetectable, but jaundice becomes evident at plasma bilirubin concentrations of 3 to 4 mg/dL, depending on the patient’s normal pigmentation, the conditions of observation, and the bilirubin fraction that is elevated. Optimal interpretation of an elevated plasma bilirubin concentration is based on an appreciation of its sources and disposition.

Bilirubin Metabolism

Bilirubin Production

Bilirubin is the degradation product of the heme moiety of hemoproteins, a class of proteins involved in the transport or metabolism of oxygen ( Fig. 150-1 ). Normal adults produce about 4 mg of bilirubin per kilogram of body weight per day. Between 70 and 90% of bilirubin is derived from the hemoglobin of erythrocytes that are sequestered and destroyed by mononuclear phagocytic cells of the reticuloendothelial system, principally in the spleen, liver, and bone marrow. The remainder results primarily from the turnover of nonhemoglobin hemoproteins such as myoglobin, the P-450 cytochromes, catalase, and peroxidase, principally in the liver; a minor fraction reflects ineffective erythropoiesis, which is the premature destruction of newly formed erythrocytes within the bone marrow.

FIGURE 150-1  Overview of bilirubin metabolism. Unconjugated bilirubin (UCB) formed from the breakdown of heme from hemoglobin and other hemoproteins is transported in plasma reversibly bound to albumin and converted in the liver to bilirubin monoglucuronide (BMG) and diglucuronide (BDG), the latter being the predominant form secreted in bile. BMG and BDG together usually account for less than 5% of normal serum bilirubin. In patients with hepatobiliary disease, BMG and BDG accumulate in plasma and appear in urine. Bilirubin glucuronides in plasma also react nonenzymatically with albumin and possibly other serum proteins to form protein conjugates, which do not appear in urine and have a plasma half-life similar to that of albumin.

The two-step conversion of heme to bilirubin begins with opening of the heme molecule at its α-bridge carbon by the microsomal enzyme heme oxygenase, a process that results in the formation of equimolar quantities of carbon monoxide and the green tetrapyrrole biliverdin. This nontoxic, water-soluble pigment is the main excretory product of heme in birds, reptiles, and amphibians. However, biliverdin cannot cross the placenta. Accordingly, reduction of biliverdin to bilirubin in mammals by a second enzyme, biliverdin reductase, allows its transplacental removal from the fetus to the maternal circulation. The unconjugated bilirubin produced in the periphery is transported to the liver in plasma. Because of its insolubility in aqueous media, it is kept in solution by tight, but reversible binding to albumin. A number of compounds, including sulfonamides, furosemide, and radiographic contrast agents, competitively displace bilirubin from its binding sites on albumin, a phenomenon that is of little clinical significance except in neonates, in whom the resulting increased concentration of unbound bilirubin raises the risk for kernicterus.

Disposition of Bilirubin by the Liver

Excretion of bilirubin from the body is a major function of the liver (see Fig. 150-1 ), where specialized microanatomy enhances the extraction of tightly protein-bound compounds from the circulation. Hepatic translocation of bilirubin from blood to bile involves four distinct steps: (1) uptake of unconjugated bilirubin, principally by an incompletely characterized, facilitated transport process and, to a lesser extent, by diffusion; (2) intracellular binding, mainly to various cytosolic proteins of the glutathione-S-transferase family; (3) conversion of unconjugated bilirubin to bilirubin monoglucuronides and diglucuronides by a specific uridine diphosphate (UDP)-glucuronosyltransferase isoform designated UGT1A1 encoded by the UGT1 gene complex; and (4) transfer of bilirubin monoglucuronides and diglucuronides into bile by a canalicular membrane adenosine triphosphate (ATP)-dependent transporter designated multidrug resistance–associated protein 2 (MRP2) or canalicular multispecific organic anion transporter (cMOAT). MRP2/cMOAT is a member of the MRP gene family, other members of which pump certain types of drug conjugates, as well as unmodified anticancer drugs, out of cells.

Conjugation of unconjugated bilirubin to bilirubin monoglucuronides and diglucuronides is a critical process that greatly increases the aqueous solubility of bilirubin and thereby enhances its elimination from the body while simultaneously reducing its ability to diffuse across biologic membranes, including the blood-brain barrier. In newborn infants, a decreased capacity to conjugate bilirubin leads to unconjugated hyperbilirubinemia (physiologic jaundice of the newborn). If severe, this hyperbilirubinemia may lead to irreversible central nervous system toxicity. Phototherapy by exposure to blue light converts bilirubin to water-soluble photo-isomers that are readily excreted in bile, thereby protecting the central nervous system from bilirubin toxicity. Gilbert’s syndrome and Crigler-Najjar syndrome types 1 and 2, which result from genetic defects in bilirubin conjugation, are characterized by unconjugated hyperbilirubinemia; in contrast, Dubin-Johnson syndrome, which results from inheritable defects in MRP2/cMOAT (see later), is characterized by conjugated or mixed hyperbilirubinemia.

Bilirubin in Plasma

The total plasma bilirubin concentration in normal adults is less than 1 to 1.5 mg/dL, depending on the measurement method used. Modern analytic techniques show that normal plasma contains principally unconjugated bilirubin, with only traces of conjugates. Clinical laboratories typically quantify plasma bilirubin by a reaction in which bilirubin is cleaved by a diazo reagent, such as diazotized sulfanilic acid, to azodipyrroles, which are readily quantitated spectrophotometrically. Bilirubin conjugates react rapidly (“prompt” or “direct”-reacting bilirubin). Unconjugated bilirubin reacts slowly because the site of attack by the diazo reagent is protected by internal hydrogen bonding. Accordingly, accurate measurement of the total plasma bilirubin concentration requires the addition of an accelerator, such as ethanol or urea, to disrupt this internal hydrogen bonding and to ensure complete reaction of any unconjugated bilirubin. The “indirect”-reacting bilirubin is calculated by subtracting the direct-reacting bilirubin from the total. Even though physicians traditionally equate the direct-reacting fraction of bilirubin in plasma with conjugated bilirubin and the indirect fraction with unconjugated bilirubin, this approach is, at best, a rough approximation. Although 10 to 20% of bilirubin in normal plasma gives a prompt (direct) diazo reaction, this percentage is an artifact of the kinetics of the diazo reaction inasmuch as more than 95% of the total bilirubin in normal plasma is unconjugated. Consequently, unqualified interpretation of the direct and indirect fractions as reflecting conjugated and unconjugated bilirubin, respectively, may lead to diagnostic errors, particularly in the diagnosis of isolated, hereditary hyperbilirubinemia.

Interpretation of Clinical Measurements of the Plasma Bilirubin Concentration

At virtually any total bilirubin concentration, a direct-reacting fraction of less than 15% of total bilirubin can be considered as essentially being all unconjugated. When the direct-reacting fraction is greater than 15%, a simple dipstick test for bilirubinuria may clarify the situation. Unconjugated bilirubin is not excreted in urine regardless of the height of its plasma concentration because its binding to albumin is too tight for effective glomerular filtration and it is not secreted by the tubules. The canalicular transport mechanism for excretion of bilirubin conjugates is especially sensitive to injury. Accordingly, in hepatocellular disease, as well as with either cholestasis or mechanical bile duct obstruction, bilirubin conjugates within the hepatocyte or biliary tract may reflux into the blood stream and result in a mixed or, less often, a purely conjugated hyperbilirubinemia. Conjugated bilirubin, which is normally loosely bound to albumin, is readily filtered at the glomerulus; even modest degrees of conjugated hyperbilirubinemia result in bilirubinuria, which is always a pathologic finding. With prolonged conjugated hyperbilirubinemia, some of the conjugated bilirubin binds covalently to albumin and produces what is designated the delta (δ) bilirubin fraction. Although δ-bilirubin gives a direct diazo reaction, it is not filterable by the glomerulus and does not appear in urine; it disappears slowly from plasma, with the 14- to 21-day half-life of the albumin to which it is bound. δ-Bilirubin accounts for the sometimes slow rate at which conjugated (direct) hyperbilirubinemia resolves as hepatitis improves or biliary obstruction is relieved. Although δ-bilirubin is not easily measured, its presence can be inferred when an elevated direct-reacting bilirubin persists after bilirubinuria resolves.

Bilirubin in Bile

Normal bile contains an average of less than 5% unconjugated bilirubin, 7% bilirubin monoconjugates, and 90% bilirubin diconjugates. The proportion of monoconjugates increases with either an increased bilirubin load (hemolysis) or reduced bilirubin conjugating capacity (e.g., Crigler-Najjar syndrome type 1).

Posthepatic Aspects of Bilirubin Disposition

Unconjugated bilirubin ordinarily does not reach the gut except in neonates or, by ill-defined alternative pathways, in the presence of severe unconjugated hyperbilirubinemia (e.g., Crigler-Najjar syndrome type 1). In these circumstances, unconjugated bilirubin is reabsorbed from the gut, thereby amplifying the hyperbilirubinemia. After canalicular secretion, conjugated bilirubin traverses the biliary tree, reaches the duodenum, and passes down the gastrointestinal tract without reabsorption by either the gallbladder or intestinal mucosa. Although some bilirubin reaches the feces, most is converted to urobilinogen and to related compounds by bacteria within the ileum and colon, where the urobilinogen is reabsorbed, returns to the liver through the portal circulation, and is re-excreted into bile in a process of enterohepatic recirculation. Any urobilinogen that is not taken up by the liver reaches the systemic circulation, from which it is cleared by the kidneys. Normal urine urobilinogen excretion is 4 mg/day or less. With hemolysis, which increases the load of bilirubin entering the gut and therefore the amount of urobilinogen formed and reabsorbed, or with liver disease, which decreases the hepatic extraction of bilirubin, plasma urobilinogen levels rise, and more urobilinogen is excreted in urine. Severe cholestasis, bile duct obstruction, or broad-spectrum antibiotics that reduce or eliminate the bacterial conversion of bilirubin to urobilinogen markedly decrease the formation and urinary excretion of urobilinogen.

Differential Diagnosis of Hyperbilirubinemia and Jaundice

Hyperbilirubinemia and jaundice ( Fig. 150-2 ) may result from isolated disorders of bilirubin metabolism, liver disease, or obstruction of the biliary tract. Jaundice represents the most visible sign of hepatobiliary disease of many causes ( Table 150-1 ).

FIGURE 150-2  Severe cholestatic jaundice in a patient with primary biliary cirrhosis. The high level of conjugated bilirubin, maintained over a long period, gives a characteristic dark brown-orange pigmentation to the skin and sclerae. Large xanthelasmas and corneal arcus usually develop in patients with primary biliary cirrhosis as a consequence of disordered lipid metabolism.  (From Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003.)


TABLE 150-1   — 
DIFFERENTIAL DIAGNOSIS OF HYPERBILIRUBINEMIA AND JAUNDICE

ISOLATED DISORDERS OF BILIRUBIN METABOLISM
Unconjugated hyperbilirubinemia
  Increased bilirubin production
    Examples: hemolysis, ineffective erythropoiesis, blood transfusion, resorption of hematomas
  Decreased hepatocellular uptake
    Examples: drugs (e.g., rifampin)
  Decreased conjugation
    Examples: Gilbert’s and Crigler-Najjar syndromes, physiologic jaundice of the newborn, breast milk jaundice, HIV protease inhibitors
Conjugated or mixed hyperbilirubinemia
  Decreased canalicular transport: Dubin-Johnson syndrome
  Mechanism uncertain: Rotor’s syndrome
LIVER DISEASE
Acute or chronic hepatocellular dysfunction
  Acute or subacute hepatocellular injury
    Examples: viral hepatitis A, B, C, hepatotoxins (e.g., ethanol, acetaminophen, mushroom [Amanita phalloides] poisoning), drugs (e.g., isoniazid, α-methyldopa), metabolic diseases (e.g., Wilson’s disease, Reye’s syndrome), pregnancy related (e.g., acute fatty liver of pregnancy, preeclampsia), hepatic ischemia (e.g., hypotension, postoperative, hepatic artery thrombosis)
  Chronic hepatocellular disease
    Examples: hepatitis B and C, hepatotoxins (e.g., ethanol, vinyl chloride, vitamin A), autoimmune hepatitis, metabolic disease (Wilson’s disease, hemochromatosis, α1- antitrypsin deficiency)
Hepatic disorders with prominent cholestasis
  Familial cholestatic disorders
  Single-gene disorders
    Examples: benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis types 1–3
  Familial cholestatic disorders of unknown pathogenesis
    Examples: Aagenaes’ syndrome, Navajo neurohepatopathy, North American Indian cholestasis
  Diffuse infiltrative disorders
    Examples: granulomatous diseases (e.g., mycobacterial and fungal infections, sarcoidosis, lymphoma, drugs, Wegener’s granulomatosis), amyloidosis, infiltrative malignancies
  Inflammation of intrahepatic bile ductules and/or portal tracts
    Examples: primary biliary cirrhosis, liver allograft rejection, graft-versus-host disease, drugs (e.g., chlorpromazine, erythromycin)
  Miscellaneous conditions
    Examples: uncommon manifestations of viral or alcoholic hepatitis, intrahepatic cholestasis of pregnancy, contraceptive jaundice, estrogens, anabolic steroids, postoperative cholestasis, total parenteral nutrition, bacterial infections, drugs
OBSTRUCTION OF BILE DUCTS
Choledocholithiasis
  Examples: cholesterol gallstones, pigment gallstones
Diseases of the bile ducts
  Inflammation/infection
    Examples: primary sclerosing cholangitis, AIDS cholangiopathy, hepatic arterial chemotherapy, postsurgical strictures
  Neoplasms (e.g., cholangiocarcinoma)
Extrinsic compression of the biliary tree
  Neoplasms
    Examples: pancreatic carcinoma, metastatic lymphadenopathy, hepatoma
  Pancreatitis with or without pseudocyst formation
  Vascular enlargement (e.g., aneurysm, cavernous transformation of the portal vein)

AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.

DISORDERS OF BILIRUBIN METABOLISM

Pure hyperbilirubinemia may result either from extrahepatic factors or from inherited or acquired defects in specific aspects of hepatic bilirubin disposition.

Unconjugated Hyperbilirubinemia

The plasma unconjugated bilirubin concentration ([UCB]) is determined by a balance between the bilirubin production rate (BRP) and hepatic bilirubin clearance (CBR) according to the relationship

(1) 

CBR is analogous to creatinine clearance in the test of kidney function; it is a measure of the rate at which bilirubin is extracted from plasma, and it is a true quantitative test of liver function. Although BRP and CBR are not easily quantified, investigative measurements have yielded useful pathophysiologic insights. Equation 1 indicates that [UCB] increases linearly with an increase in BRP or hyperbolically with a decrease in CBR, thereby providing a basis for classifying unconjugated hyperbilirubinemias according to their pathogenesis.

Increased Bilirubin Production

Increased production of bilirubin and subsequent unconjugated hyperbilirubinemia can be caused by hemolysis, accelerated destruction of transfused erythrocytes, resorption of hematomas, or ineffective erythropoiesis (e.g., lead poisoning, megaloblastic anemias related to deficiency of either folic acid or vitamin B12, sideroblastic anemia, congenital erythropoietic porphyria, or myeloproliferative or myelodysplastic diseases). In these settings, other liver tests are typically normal and the hyperbilirubinemia is modest, rarely exceeding 4 mg/dL; higher values imply concomitant hepatic dysfunction. However, after brisk blood transfusion or resorption of massive hematomas caused by trauma, the increased bilirubin load may be transiently sufficient to lead to frank jaundice. The causes of hemolysis are numerous ( Chapters 164 to 167 ). Besides specific blood disorders, mild hemolysis accompanies many acquired diseases. In the setting of systemic disease, which may include a degree of hepatic dysfunction, hemolysis may produce a component of conjugated hyperbilirubinemia in addition to an elevated unconjugated bilirubin concentration. Prolonged hemolysis may lead to the formation of bilirubin gallstones, which may cause cholecystitis, obstruction, or any other biliary tract consequence of calculous disease ( Chapter 159 ).

Decreased Hepatic Bilirubin Clearance

Decreased Bilirubin Uptake

Several drugs (e.g., rifampin, flavaspidic acid, novobiocin, and various cholecystographic contrast agents) competitively inhibit the hepatocellular uptake of bilirubin. The resulting unconjugated hyperbilirubinemia resolves with cessation of the medication. Decreased hepatic bilirubin uptake is also believed to contribute to the unconjugated hyperbilirubinemia of Gilbert’s syndrome, although the principal molecular basis for this syndrome is a reduction in the conjugation of bilirubin.

Impaired Bilirubin Conjugation

The most frequent cause of decreased bilirubin clearance is a decrease in bilirubin conjugating activity. Bilirubin conjugation with glucuronic acid is catalyzed by a specific UDP-glucuronosyltransferase that is designated UGT1A1 and encoded by the UGT1 gene complex. The UGT1A1 gene is assembled by alternative splicing of a bilirubin-specific variant of exon 1, designated exon A1, with four common exons (exons 2 to 5) that encode the shared carboxyl-terminal end of all UGT1-encoded proteins. Its promoter region normally contains an A(TA)6TAA TATA box–like construct.

Genetic Disorders of Bilirubin Conjugation

The hereditary hyperbilirubinemias ( Table 150-2 ) are a group of five syndromes in which hyperbilirubinemia occurs as an isolated biochemical abnormality without evidence of either hepatocellular necrosis or cholestasis. The molecular defects have been identified in all but Rotor’s syndrome.


TABLE 150-2   — 
PRINCIPAL FEATURES OF HEREDITARY DISORDERS OF BILIRUBIN METABOLISM

  Crigler-Najjar Syndrome      
Feature TYPE I TYPE II Gilbert’s Syndrome Dubin-Johnson Syndrome Rotor’s Syndrome
Incidence Very rare Uncommon Up to 12% of the population Uncommon Rare
Total serum bilirubin (mg/dL) 18–45 (usually >20), unconjugated 6–25 (usually ≤20), unconjugated Typically ≤4 in the absence of fasting or hemolysis; mostly unconjugated Typically 2–5, less often ≤25; about 60% direct reacting Usually 3–7, occasionally ≤20; about 60% direct reacting
Defect(s) in bilirubin metabolism Bilirubin UDPGT activity markedly reduced: trace to absent Bilirubin UDPGT activity reduced: ≤10% of normal Bilirubin UDPGT activity typically reduced to 10–33% of normal; reduced bilirubin uptake in some cases; mild hemolysis in up to 50% of patients Impaired canalicular secretion of conjugated bilirubin because of MRP2/cMOAT mutation Impaired hepatic secretion or storage of conjugated bilirubin; molecular defect not known
Routine liver tests Normal Normal Normal Normal Normal
Serum bile acids Normal Normal Normal Usually normal Normal
Plasma sulfobromophthalein removal (% retention of a 5-mg/kg dose at 45 min)[*] Normal Normal Usually normal (<5%); mild 45-min retention (<15%) in some patients Slow initial decline in plasma concentration (retention ≤20% at 45 min) with secondary rise at 90–120 min Very slow initial decline in plasma concentration (45-min retention = 30–45%) without secondary rise
Oral cholecystography Normal Normal Normal Faint or nonvisualization of the gallbladder Usually normal
Pharmacologic responses/special features No response to phenobarbital Phenobarbital reduces bilirubin by ≤75% Phenobarbital reduces bilirubin, often to normal Increased bilirubin concentration with estrogens; diagnostic urine coproporphyrin isomer pattern (total is normal, with isomer I increased to ≤80% of total) Characteristic urine coproporphyrin excretion pattern (total is increased ≥2.5-fold in ≈65% of cases, but isomer I always <80% of total)
Major clinical features Kernicterus in infancy if untreated; may occur later despite therapy Rare late-onset kernicterus with fasting None Occasional hepatosplenomegaly None
Hepatic morphology/histology Normal Normal Normal; occasionally increased lipofuscin pigment Liver grossly black; coarse, dark centrilobular pigment Normal
Bile bilirubin fractions[] >90% unconjugated Largest fraction (mean 57%) is monoconjugates Mainly diconjugates, but monoconjugates are increased (mean 23%) Mixed conjugates, reported increase in diconjugates Increased conjugates
Inheritance (all autosomal) Recessive Recessive Promoter mutation is recessive; missense mutation often dominant Recessive; rare kindred appears dominant Recessive
Diagnosis Clinical and laboratory findings; lack of response to phenobarbital Clinical and laboratory findings; response to phenobarbital Clinical and laboratory findings; promoter genotyping; liver biopsy rarely necessary Clinical and laboratory findings; liver biopsy unnecessary if coproporphyrin studies available; BSP disappearance Clinical and laboratory findings; urine coproporphyrin analysis; BSP disappearance
Treatment Phototherapy or tin protoporphyrin as short-term therapy; liver transplantation definitive Consider phenobarbital if baseline bilirubin ≥8 mg/dL None necessary Avoid estrogens; no other therapy necessary No treatment necessary

BSP = sulfobromophthalein; cMOAT = canalicular multispecific organic anion transporter; MRP2 = multidrug resistance–associated protein 2; UDPGT = uridine diphosphate glucuronosyltransferase.

* Sulfobromophthalein studies may be useful in distinguishing the Dubin-Johnson and Rotor syndromes if coproporphyrin isomer studies are not available.
Bilirubin in normal bile: less than 5% is unconjugated bilirubin, with an average of 7% bilirubin monoconjugates and 90% bilirubin diconjugates.

Crigler-Najjar syndrome types 1 and 2 and Gilbert’s syndrome are hereditary forms of unconjugated hyperbilirubinemia that result from mutations in UGT1A1. In Crigler-Najjar type 1, essentially no functional enzyme activity is present, whereas patients with Crigler-Najjar type 2 have up to 10% of normal and patients with Gilbert’s syndrome have 10 to 33% of normal activity, which leads to bilirubin concentrations of 18 to 45, 6 to 25, and 1.5 to 4 mg/dL, respectively (see Table 150-2 ). Because total UGT1A1 enzymatic activity must be reduced to less than 50% of normal to produce unconjugated hyperbilirubinemia, phenotypic expression of mutations in this enzyme requires either homozygosity or double heterozygosity. Thus, despite earlier reports to the contrary, each of these disorders is inherited as an autosomal recessive trait. Patients with types 1 and 2 Crigler-Najjar syndrome are either homozygotes or double heterozygotes for structural mutations within the coding region. In Western countries, patients with Gilbert’s syndrome are typically homozygous for an A(TA)7TAA promoter mutation. Structural mutations causing modest reductions in UGT1A1 enzymatic activity have been reported in some Japanese patients with Gilbert’s syndrome.

Crigler-Najjar syndrome type 1 is characterized by striking unconjugated hyperbilirubinemia that appears in the neonatal period, persists for life, and is unresponsive to phenobarbital. The majority of patients (type 1A) exhibit defects in glucuronide conjugation of a spectrum of substrates in addition to bilirubin as a result of mutations in one of the common exons (2 to 5) of the UGT1 complex. In a smaller subset (type 1B), a mutation in the bilirubin-specific exon A1 limits the defect to bilirubin conjugation. More than 30 structurally diverse UGT1A1 mutations can cause type 1 Crigler-Najjar syndrome; their common feature is that they all encode proteins with absent or, at most, traces of enzymatic activity. Before the availability of phototherapy, most patients with Crigler-Najjar type 1 died of bilirubin encephalopathy (kernicterus) in infancy or early childhood. Optimal treatment for a neurologically intact patient includes (1) about 12 hr/day of phototherapy from birth throughout childhood, perhaps supplemented by exchange transfusion in the neonatal period; (2) use of tin-protoporphyrin to blunt transient episodes of increased hyperbilirubinemia; and (3) early liver transplantation, before the onset of brain damage. Transplantation with isolated allogeneic hepatocytes is being evaluated as an experimental therapeutic approach.

Bilirubin concentrations are typically lower in type 2 Crigler-Najjar syndrome, and plasma bilirubin levels can be reduced to 3 to 5 mg/dL by phenobarbital. At least 10 different mutations in UGT1A1 have been associated with Crigler-Najjar type 2; all encode a bilirubin-UDP-glucuronosyltransferase with markedly reduced but detectable enzymatic activity. Though uncommon in Crigler-Najjar type 2, kernicterus has occurred at all ages and is typically associated with factors that temporarily raise the plasma bilirubin concentration above baseline (e.g., fasting, intercurrent illness). For this reason, phenobarbital therapy is often recommended; a single bedtime dose usually maintains clinically safe plasma bilirubin concentrations.

Gilbert’s syndrome is the most common of the hereditary hyperbilirubinemias, with a genotypic prevalence of up to 12% and a phenotypic prevalence of up to 7%. Its high prevalence may explain the frequent appearance of mild unconjugated hyperbilirubinemia in liver transplant recipients. Plasma bilirubin concentrations are most often less than 3 mg/dL, although both higher and lower values are frequent, with increases of two- to three-fold commonly occurring with fasting and intercurrent illness. The phenotypic distinction between mild Gilbert’s syndrome and a normal state is often blurred. Phenobarbital normalizes both the bilirubin concentration and CBR. Oxidative drug metabolism and the disposition of most xenobiotics that are metabolized by glucuronidation appear to be normal in Gilbert’s syndrome. A critical exception is the antitumor agent irinotecan (CPT-11), whose active metabolite (SN-38) is glucuronidated specifically by UGT1A1. In patients with Gilbert’s syndrome, CPT-11 can cause intractable diarrhea, myelosuppression, and other serious toxicities. Unconjugated hyperbilirubinemia related to selective inhibition of UGT1A1 also occurs with several human immunodeficiency virus (HIV) protease inhibitors (e.g., indinavir). Abnormal disposition of menthol, estradiol benzoate, acetaminophen, tolbutamide, rifamycin SV, and other agents has not been associated with significant complications, but prudence should be exercised in prescribing agents that are metabolized by glucuronidation to patients with Gilbert’s syndrome.

Unconjugated Hyperbilirubinemia in the Newborn Period

Mild unconjugated hyperbilirubinemia develops in most neonates between days 2 and 5 after birth because of hepatic immaturity and low levels of UGT1A1. Peak bilirubin levels are typically less than 5 to 10 mg/dL, and levels return to normal within 2 weeks as mechanisms of bilirubin disposition mature. Prematurity, with hemolysis or hepatic immaturity, is associated with higher bilirubin levels that may require phototherapy. The progestational steroid 3α,20β-pregnanediol and certain fatty acids found in the breast milk (but not serum) of some mothers inhibit bilirubin conjugation and can cause excessive neonatal hyperbilirubinemia (breast milk jaundice). By comparison, transient familial neonatal hyperbilirubinemia (Lucey-Driscoll syndrome) is caused by a UGT1A1 inhibitor that is found in maternal serum.

Acquired Conjugation Defects

A modest reduction in bilirubin conjugating capacity occurs in patients with advanced hepatitis or cirrhosis ( Chapters 157 and 158 ). However, in this setting, conjugation is better preserved than other aspects of bilirubin disposition, such as canalicular excretion. Pharmacologic and metabolic perturbations may also lead to acquired reductions in bilirubin conjugation. Various drugs (e.g., pregnanediol, novobiocin, chloramphenicol, gentamicin, and several HIV protease inhibitors) may cause unconjugated hyperbilirubinemia by inhibiting UGT1A1. In all settings in which UGT1A1 inhibitors cause unconjugated hyperbilirubinemia, the hyperbilirubinemia is greater in patients with underlying Gilbert’s syndrome.

Conjugated or Mixed Hyperbilirubinemia

Two phenotypically similar, but mechanistically distinct inherited disorders, Dubin-Johnson syndrome and Rotor’s syndrome, are characterized by conjugated or mixed hyperbilirubinemia with normal values for other standard liver tests (see Table 150-2 ). Dubin-Johnson syndrome results from any of several mutations in the gene encoding the ATP-dependent canalicular organic anion transporter MRP2/cMOAT (see Fig. 150-1 ). The molecular defect in Rotor’s syndrome remains unknown, although some data suggest that it is precanalicular. Despite the conjugated hyperbilirubinemia, patients with these syndromes are not cholestatic and can be distinguished noninvasively by analysis of urine coproporphyrins (see Table 150-2 ), so liver biopsy is not required. Both syndromes carry a benign prognosis without specific therapy.

LIVER AND BILIARY TRACT DISEASE

Jaundice is a common sign of generalized hepatobiliary dysfunction, both acute and chronic. Icteric hepatobiliary disease is readily distinguished from the isolated disorders of bilirubin metabolism because the increase in plasma bilirubin concentration occurs in association with abnormalities in other standard liver tests. Liver diseases can be categorized as those in which the primary injury results from inflammation and hepatocellular necrosis versus those in which the central feature is inhibition of bile flow (cholestasis) and retention of bile constituents, some of which (e.g., bile acids) may be toxic. Although an accurate classification into one of these two broad categories is possible in most patients on the basis of clinical findings and standard biochemical studies (see later), further classification of patients with a predominantly cholestatic picture into those with decreased hepatocellular bile secretion and those with mechanical obstruction of the biliary tree may be more difficult. These diagnostically challenging conditions include several familial cholestatic syndromes; infiltrative disorders, particularly those involving the intrahepatic biliary tree; certain other inflammatory or neoplastic conditions; and drug reactions (see Table 150-1 and Chapters 151 to 157 ).

Familial Cholestasis Syndromes

Benign recurrent intrahepatic cholestasis is a rare, autosomal recessive disorder characterized by recurrent attacks of malaise, pruritus, and jaundice beginning in either childhood or adulthood and varying in duration from weeks to months. Intervals between attacks may vary from months to years. This benign disorder does not progress to chronic liver disease or cirrhosis, and there is complete resolution between episodes; treatment during the cholestatic episodes is symptomatic. The familial intrahepatic cholestasis 1 (FIC1) gene, which is mutated in this condition, encodes a protein that transports aminophospholipids from the outer to the inner leaflet of various cell membranes. The gene is expressed strongly in the small intestine but only weakly in the liver. Progressive familial intrahepatic cholestasis describes three phenotypically related syndromes of cholestasis during infancy and end-stage liver disease during childhood. In contrast to the selective bilirubin transport defect in Dubin-Johnson syndrome, the conjugated hyperbilirubinemia in these syndromes is caused by generalized bile secretory failure.

Postoperative Jaundice

This multifactorial syndrome can be caused by increased bilirubin production (e.g., breakdown of transfused erythrocytes, resorption of hematomas), by decreased hepatic clearance (e.g., bacteremia, endotoxemia, parenteral nutrition, perioperative hypoxia), or by both. Hyperbilirubinemia, which is the main biochemical feature, is often accompanied by a several-fold increase in levels of alkaline phosphatase, γ-glutamyl transpeptidase (GGT), or both. Aminotransferases are, at most, minimally elevated, and synthetic function is typically normal. The differential diagnosis includes biliary obstruction ( Chapter 159 ) or hepatocellular injury related to shock, anesthetic injury ( Chapter 153 ), or post-transfusion hepatitis ( Chapter 151 ). Postoperative jaundice per se is not a threat to the patient, and it usually resolves in parallel with the patient’s overall condition.

Jaundice in Pregnancy

Jaundice in pregnancy ( Chapter 259 ) may result from any liver disease that also affects nonpregnant women or from conditions unique to pregnancy. The unique conditions include a generally modest and self-limited elevation in aminotransferase and bilirubin levels during the first trimester, often in patients with hyperemesis gravidarum; intrahepatic cholestasis of pregnancy, which occurs during the second and third trimesters and resolves spontaneously after delivery; or acute fatty liver or the HELLP syndrome (h emolysis, e levated l iver enzymes, and l ow p latelets) in association with preeclampsia in the third trimester ( Chapters 154 , 181 , and 259 ). Acute fatty liver may resemble fulminant hepatic failure, with early delivery being a prerequisite to maternal recovery; a defect in the oxidation of fatty acids is found in some infants born after these pregnancies.

Diagnostic Tools for the Evaluation of Liver Disease

Accurate diagnosis and the distinction between acute and chronic disease are often dependent on appropriate selection and interpretation of a spectrum of laboratory and imaging studies.

Tests used for the initial evaluation of liver disease fall into two categories: (1) tests that indicate injury, such as release of intracellular enzymes, and (2) tests that measure, or at least reflect, actual function. Tests that reflect injury do not measure liver function and should not be called liver function tests.

The important functions of the liver include clearance, biotransformation and detoxification of potentially toxic metabolites and exogenous compounds, synthesis and export of various plasma proteins, and a critical integrative role in the intermediary metabolism of carbohydrates, amino acids, and lipids ( Chapter 149 ). In specific diseases, some of these functions may be markedly compromised, whereas others are little affected. Liver tests must be chosen with care and interpreted within the total clinical context. In specific situations, serial determinations are often helpful to assess the course of disease or the effects of therapy.

Serum Enzyme Tests

The levels of hepatic enzymes found in plasma are a measure of hepatocyte turnover or injury. Enzymes released during normal hepatocyte turnover are believed to be the basis for normal circulating levels. Cell injury and cell death activate phospholipases that create holes in the plasma membrane, thereby increasing the release of intracellular contents.

Aminotransferases

The aminotransferases (formerly called transaminases) catalyze transfer of the α-amino group of aspartate (aspartate aminotransferase [AST]) or alanine (alanine aminotransferase [ALT]) to the α-keto group of ketoglutarate. Serum levels are normally 40 IU/L or less (see Appendix ) but can exceed 1000 IU/L in acute hepatocyte injury, such as from viral infection ( Chapter 151 ) or toxins ( Chapter 153 ). ALT is a purely cytosolic enzyme. Distinct isoforms of AST are present in the cytosol and mitochondria. Expression of the mitochondrial isoform and its physiologic export from the hepatocyte are upregulated by ethanol. Circulating levels of AST and ALT are elevated in most hepatic diseases, and the degree of aminotransferase activity found in plasma roughly reflects the current activity of the disease process. There are, however, critical exceptions. In even the most severe cases of alcoholic hepatitis, aminotransferase levels of 200 to 300 IU/L or greater are uncommon ( Chapter 156 ). By contrast, aminotransferase activity of 1000 IU/L or greater is often present in even mild acute viral hepatitis ( Chapter 151 ) or shortly after acute biliary obstruction, such as during passage of a gallstone ( Chapter 159 ). Conversely, aminotransferase levels may decline during the course of massive hepatic necrosis because the liver injury is so extensive that little enzyme activity remains ( Chapter 158 ).

Aminotransferase levels are useful in several distinct ways. First, they provide a relatively specific screening test for hepatobiliary disease. Although AST levels may be increased with disease of other organs (notably myocardial and skeletal muscle), values equal to or greater than 10 times the upper limit of normal almost invariably indicate hepatobiliary pathology. Moreover, in the total clinical context, the source of increased aminotransferase activity is usually obvious. Aminotransferase levels are also used to monitor the activity of acute or chronic parenchymal liver disease and its response to therapy. However, levels in a given patient may correlate poorly with severity of the disease as assessed by liver biopsy, particularly in chronic hepatitis C ( Chapter 152 ). Aminotransferases are also often normal in advanced cirrhosis ( Chapter 157 ), in which they are of limited prognostic value. Finally, aminotransferase levels may provide diagnostic clues. AST levels 15 or more times normal are unusual in chronic bile duct obstruction without cholangitis, and AST levels 6 or more times normal are uncommon in alcoholic liver disease in the absence of other causes. In most liver diseases, the ratio of AST to ALT is usually 1 or less. However, ratios are typically 2 or higher in alcoholic fatty liver and alcoholic hepatitis ( Chapters 156 and 157 ) as a result of increased synthesis and secretion of mitochondrial AST into plasma and selective loss of ALT activity because of the pyridoxine deficiency commonly seen in alcoholism. An elevated AST/ALT ratio also occurs in fulminant hepatitis related to Wilson’s disease ( Chapter 230 ).

Alkaline Phosphatase

Alkaline phosphatases are widely distributed enzymes (e.g., liver, bile ducts, intestine, bone, kidney, placenta, and leukocytes) that catalyze the release of orthophosphate from ester substrates at an alkaline pH. The normal activity level in adult serum is highly dependent on the measurement method, age, and sex. Two methods in current use have upper limits of normal in adults of 85 and 110 IU/L (see Appendix ). Higher levels are normal in children and in pregnancy. Results must always be compared with the appropriate normal range. In bone, alkaline phosphatase participates in the deposition of hydroxyapatite in osteoid. In other sites, including the liver, phosphatase activity may facilitate movement of molecules across cell membranes. Serum alkaline phosphatase activity usually reflects the hepatic and bone isozymes principally, but the intestinal form may account for 20 to 60% of the total after a fatty meal. There is a substantial placental contribution to the alkaline phosphatase level late in pregnancy; the Regan isozyme, a variant that appears identical to the placental form, is associated with hepatoma, lung cancer, and other tumors ( Chapter 206 ).

Elevations in serum alkaline phosphatase activity in cholestatic hepatobiliary disease result from two distinct mechanisms: increased synthesis and secretion of the enzyme and solubilization from the apical (canalicular) surface of hepatocytes and the luminal surface of biliary epithelial cells by the increased local concentrations of bile acids that occur with cholestasis. Serum alkaline phosphatase activity may also be increased in bone disorders (e.g., Paget’s disease [ Chapter 268 ], osteomalacia [ Chapter 265 ], bone metastases [ Chapters 201 , 208 , and 211 ]), during rapid bone growth in children, in the later stages of pregnancy, with chronic renal failure ( Chapter 131 ), and occasionally, in the presence of malignancy not involving bones or the liver. The source is often obvious, but when it is not, methods such as heat stability and electrophoretic separation can distinguish hepatobiliary alkaline phosphatase from other forms. A simpler alternative is to measure serum levels of GGT or 5′-nucleotidase (5-NT), which tend to parallel levels of alkaline phosphatase in hepatobiliary disease but are not usually increased in bone disease. With a serum half-life of approximately 1 week, serum alkaline phosphatase levels may remain elevated for days to weeks after resolution of the biliary obstruction. This delay may be especially misleading when it is accompanied by prolonged direct-reacting hyperbilirubinemia because of delayed clearance of δ-bilirubin.

Modest increases in serum alkaline phosphatase activity (three times normal or less) occur in many hepatic parenchymal disorders, including hepatitis and cirrhosis. In the absence of bone disease, larger increases (3 to 10 times normal) generally indicate obstruction of bile flow. Although the highest levels usually reflect obstruction of the common bile duct, major elevations also occur with intrahepatic cholestasis and with infiltrative or mass lesions (primary or metastatic cancer, lymphoma, leukemia, sarcoidosis, or infection with Mycobacterium avium-intracellulare). A normal serum bilirubin level in the setting of chronic elevation of the alkaline phosphatase level can occur early in primary biliary cirrhosis ( Chapter 157 ), but this combination also suggests localized infiltrative disease or obstruction of a portion of the biliary tree related to other localized lesions, such as stricture or tumor ( Chapter 159 ). Alkaline phosphatase is a relatively sensitive screening test for primary or metastatic tumors of the liver, but up to a third of patients with isolated elevations in hepatobiliary alkaline phosphatase have no detectable liver or biliary disease.

Other Hepatic Enzymes

5′-NT is a plasma membrane enzyme that cleaves orthophosphate from the 5′ position on the pentose sugar of adenosine or inosine phosphate. Leucine aminopeptidase (LAP) is a ubiquitous cellular peptidase. The serum levels of both usually increase in cholestasis. Accordingly, their major use is to confirm whether an elevated serum alkaline phosphatase level is hepatic in origin. Both enzymes may be increased in the latter stages of a healthy pregnancy.

GGT is present in many tissues. Its serum activity increases in hepatobiliary disease but also after myocardial infarction; in neuromuscular diseases, pancreatic disease (even in the absence of biliary obstruction), pulmonary disease, and diabetes; and during the ingestion of ethanol and other inducers of microsomal enzymes. Nevertheless, because serum GGT levels are generally normal in bone disease, the enzyme may be helpful in confirming the hepatic origin of alkaline phosphatase. Measurement of GGT has been proposed as a sensitive screening test for hepatobiliary disease and for monitoring abstinence from ethanol. Because of its low specificity, many persons who test positive have no identifiable liver disease on further study. GGT offers no clear advantage over LAP or 5′-NT for identifying the source of increased serum alkaline phosphatase activity except in pregnancy. Serum GGT levels may be normal despite elevated hepatobiliary alkaline phosphatase levels in certain rare disorders, including benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis types 1 and 2 (see earlier and Chapter 154 ).

Lactate dehydrogenase levels are often elevated in liver disease but are not usually helpful diagnostically because this enzyme is also found in most other body tissues.

Tests Based on Clearance of Metabolites and Drugs

A major function of the liver is to remove various metabolites and toxins from blood. In liver disease, clearance of such molecules may be impaired because of loss of parenchymal cells, diminished bile secretion, biliary obstruction, decreased cellular uptake or metabolism, or reduced or heterogeneous hepatic blood flow. When a metabolite is produced at a relatively constant rate (e.g., bilirubin), its serum level can be a sensitive indicator of liver function. The rate of removal of certain exogenous drugs and dyes from plasma can be similarly interpreted.

Bilirubin

The differential diagnosis of hyperbilirubinemia (see earlier) includes generalized liver disease, inherited disorders of bilirubin metabolism (e.g., Gilbert’s and Crigler-Najjar syndromes), and nonhepatic conditions (e.g., hemolysis). Higher bilirubin levels correlate with a poorer prognosis in alcoholic hepatitis ( Chapter 156 ), primary biliary cirrhosis ( Chapter 157 ), and fulminant hepatic failure ( Chapter 158 ).

Ammonia

Ammonia, a byproduct of amino acid metabolism, is removed from blood by the liver, converted to urea in the Krebs-Henseleit cycle, and excreted by the kidneys ( Chapters 116 and 226 ). In the setting of portosystemic shunting or severe hepatic dysfunction (e.g., fulminant hepatic failure), ammonia levels rise. Measurements of blood ammonia are principally used to confirm a diagnosis of hepatic encephalopathy and to monitor the success of therapy, but the correlation of ammonia levels with the degree of encephalopathy is only approximate ( Chapter 158 ). Correlations may be somewhat better if the measurement is made rapidly on an iced arterial blood sample. Elevated ammonia levels also occur when ammonia production is increased by intestinal flora (e.g., after a high-protein meal or gastrointestinal bleeding), by the kidney (in response to metabolic alkalosis or hypokalemia), or in rare genetic diseases that affect the pathway of urea synthesis ( Chapter 226 ).

Drug Clearance

The rate of hepatic clearance of compounds such as sulfobromophthalein, lidocaine, and aminopyrine from the circulation can be measured chemically or with radiolabeled tracers. Although such tests can quantify hepatic function, they are rarely used in clinical practice.

Tests Reflecting Hepatic Synthetic Function

Coagulation Tests ( Chapters 35 , 178 , and 181 )

 

Prothrombin Time

The prothrombin time (PT) reflects the plasma concentrations of both extrinsic and common pathway factors, that is, factors VII, X, and V, prothrombin, and fibrinogen. A prolonged PT most often results from vitamin K deficiency, liver disease, or both. Vitamin K, a fat-soluble vitamin, is found in many foods and is also synthesized by gut bacteria ( Chapter 178 ). Vitamin K deficiency can be caused by poor dietary intake and malabsorptive states, including the fat malabsorption that results from cholestasis, and it also occurs with antibiotic suppression of gut flora, particularly in patients who receive inadequate vitamin K replacement.

The half-lives of clotting factors are typically less than 1 day. Factor VII, which has the shortest half-life, is usually the earliest and most severely depressed during periods of defective hepatic synthesis. Because the PT is dependent on the level of factor VII, it responds rapidly with changes in hepatic synthetic function; it is useful for monitoring the course of acute liver diseases, with a significant or growing prolongation of the PT possibly indicating a poor prognosis ( Chapter 151 ). An abnormal PT that is due solely to vitamin K deficiency generally becomes normal within 24 to 48 hours after parenteral repletion. However, if decreased synthesis of clotting factors reflects hepatocyte dysfunction, there may be little or no response to vitamin K. Finally, prolongation of the PT may also reflect disseminated intravascular coagulation ( Chapter 181 ), which should always be considered in the context of both acute liver failure and end-stage chronic liver disease.

Partial Thromboplastin Time

This test reflects both the intrinsic and common pathway factors, that is, all of the classic clotting factors except factor VII, and is therefore complementary to the PT. It is especially useful in detecting circulating anticoagulants ( Chapter 181 ) but adds little to the PT in evaluating hepatic synthetic function.

Albumin

Albumin is produced solely by the liver. Its plasma concentration reflects a balance between its synthetic rate of about 100 to 200 mg/kg/day and its plasma half-life of about 21 days. The synthetic rate is affected by the patient’s nutritional state, thyroid and glucocorticoid hormone levels, plasma colloid osmotic pressure, exposure to hepatotoxins (e.g., alcohol), and presence of systemic disorders or liver disease (or both). Many conditions increase albumin loss and shorten its plasma half-life, including nephrotic syndrome ( Chapter 122 ), protein-losing enteropathy ( Chapter 143 ), severe burns ( Chapter 113 ), exfoliative dermatitis, and major gastrointestinal bleeding ( Chapter 137 ). In cirrhosis with ascites ( Chapter 157 ), hypoalbuminemia indicates diminished synthesis or redistribution into ascitic fluid. Thus, a reduced serum albumin concentration can be considered an indicator of decreased hepatic synthetic function only when these factors are not involved.

Examination of Urine and Stool

Bilirubinuria always indicates a pathologic increase in plasma conjugated bilirubin levels and is frequently seen with plasma conjugated bilirubin concentrations of 2 to 3 mg/dL; it often appears before the onset of clinical jaundice and persists after the jaundice has resolved. Quantification of urobilinogen in urine or feces is of limited clinical value. By contrast, stool culture or examination for ova and parasites may provide important information in selected patients. Testing of stool for occult blood may lead to discovery of a gastrointestinal lesion related to hepatobiliary disease (e.g., tumors metastatic to the liver, ulcerative colitis associated with sclerosing cholangitis) or may explain the onset or worsening of hepatic encephalopathy.

Hematologic Tests for Liver Disease

In moderate to severe acute liver disease, mild anemia may reflect low-grade hemolysis or marrow depression; modest leukopenia, often with atypical lymphocytes, and mild thrombocytopenia are also common. Bone marrow suppression may be caused by ethanol or drugs, and aplastic anemia may sometimes complicate acute viral hepatitis ( Chapters 151 and 171 ). Zieve’s syndrome (hemolytic anemia and hypertriglyceridemia) is a rare, but well-characterized complication of alcoholic liver disease ( Chapters 156 and 157 ). Coagulopathy frequently complicates both acute and chronic liver failure as a result of depressed hepatic synthesis of clotting factors or disseminated intravascular coagulation, or both ( Chapters 180 and 181 ).

Chronic liver disease, especially if cholestatic, may be accompanied by target cells in the peripheral blood smear. Target cells are erythrocytes with an expanded cell membrane that reflects abnormalities in serum lipids. Spur cells (acanthocytes), most often found in advanced alcoholic cirrhosis, reflect a still greater increase in membrane cholesterol. Red blood cells, white blood cells, and platelets may all be decreased in the presence of portal hypertension related to hypersplenism ( Chapters 157 and 174 ).

Tests for Specific Liver Diseases

Patients with findings of acute or chronic parenchymal liver disease are most likely to fall into one of three categories: viral or toxic hepatitis, including alcoholic liver disease; autoimmune liver disease; or an inherited metabolic disorder ( Chapters 151 to 154 , 156 , and 397 , 399 , and 400 ). Specific tests for viral antigens, nucleic acids, and antibodies are available for the conventional hepatitis viruses ( Chapter 151 ), as well as for Epstein-Barr virus ( Chapter 400 ), cytomegalovirus ( Chapter 399 ), and herpesviruses ( Chapter 397 ), which are well-established but less common causes of liver disease. The major autoimmune diseases of the liver include primary biliary cirrhosis ( Chapter 157 ), autoimmune hepatitis ( Chapter 152 ), and various overlap syndromes. The starting point for establishing a specific diagnosis within this category is a search for specific autoantibodies in serum, including antimitochondrial antibodies against epitopes of the pyruvate dehydrogenase complex, which are virtually diagnostic of primary biliary cirrhosis ( Chapter 157 ), and antinuclear, anti–smooth muscle, and anti–liver microsomal antibodies, which suggest a diagnosis of one of the subtypes of autoimmune hepatitis ( Chapters 152 , 157 , and 159 ). The most prevalent of the hereditary metabolic disorders affecting the liver include hemochromatosis ( Chapter 231 ), α1-antitrypsin deficiency ( Chapter 154 ), and Wilson’s disease ( Chapter 230 ).

Liver Biopsy

Liver biopsy can be of great help in the diagnosis of diffuse or localized parenchymal diseases, including chronic hepatitis, cirrhosis, and primary or metastatic malignancy in the liver. The value of liver biopsy in acute hepatitis or acute cholestatic jaundice may be primarily prognostic because the histologic changes in these settings may be nonspecific. However, toxic hepatitis ( Chapter 153 ) related to certain medications may display diagnostic features. Liver biopsy for assessment of diffuse disease can be performed percutaneously after localization of the liver by physical examination or ultrasonographic visualization. When specific lesions such as tumors must be sampled, the biopsy can be guided by ultrasonographic or radiographic imaging or performed under direct visualization during laparoscopy or laparotomy. Relative or absolute contraindications include coagulopathy, high-grade biliary obstruction, biliary sepsis, ascites, and right pleural disease. Although liver biopsy remains the standard for assessment of hepatic histology in diffuse disease ( Chapter 149 ), the procedure’s invasiveness and concern for sampling error have generated interest in noninvasive measures of hepatic fibrosis. Transient elastography uses ultrasound to assess tissue stiffness as a measure of hepatic fibrosis. Commercially available biomarker panels have also been developed to provide a noninvasive assessment of hepatic fibrosis by blood testing alone. These panels typically include standard laboratory measures of hepatic injury (GGT, total bilirubin) and other serum markers (e.g., haptoglobin, hyaluronic acid, apolipoprotein A-I). However, the ability of currently available noninvasive markers to assess the extent of hepatic fibrosis across the clinically relevant histologic spectrum remains to be established.

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