icter

336

CHAPTER OUTLINEBilirubin Metabolism and Measurement ....................................336

Metabolism............................................................................... 336Measurement............................................................................ 337

Differential Diagnosis ................................................................338Isolated.Disorders.of.Bilirubin.Metabolism.................................. 338Liver.Disease............................................................................ 340Bile.Duct.Obstruction................................................................. 342

Diagnostic Approach to Jaundice .............................................342

Jaundice

CHAPTER.

21.

STEVEN D. LIDOFSKY

History.and.Physical.Examination............................................... 343Initial.Laboratory.Studies........................................................... 343Overall.Approach....................................................................... 344Imaging.Studies........................................................................ 344Other.Studies............................................................................ 346

Therapeutic Approaches ...........................................................347Obstructive.Jaundice................................................................. 347Nonobstructive.Jaundice............................................................ 347

Jaundice (also termed icterus) is a condition of yellow discolor-ation of the skin, conjunctivae, and mucous membranes, resulting from widespread tissue deposition of the pigmented metabolite bilirubin. Although jaundice is commonly due to liver and biliary tract disease, it has many causes, so it is not surprising that the diagnosis and management of jaundice have challenged clinicians for centuries.

Clinical and biochemical investigation of the etiology of jaundice has a rich history. Classification of disorders associ-ated with jaundice appeared as early as the treatises of Hip-pocrates. By the late 19th century (e.g., see Osler’s Principles and Practice of Medicine), important distinctions had been made between biliary tract obstruction and nonobstructive causes of jaundice. It was not until the latter part of the 20th century, however, that elucidation of the molecular mechanisms of bili-rubin metabolism and the development of robust imaging technologies made it possible to pinpoint the cause of jaundice in most cases. Despite these advances, an effective manage-ment strategy for the jaundiced patient still requires careful selection of appropriate diagnostic and therapeutic modalities on the basis of an assessment of the likelihood of possible underlying causes.

BILIRUBIN METABOLISM AND MEASUREMENT

MetabolismBilirubin is a tetrapyrrole produced by heme degradation. The metabolism of this hydrophobic and potentially toxic com-pound has been reviewed in depth elsewhere1,2 and is sum-marized briefly in Figure 21-1. On average, a healthy adult produces about 4 mg/kg of bilirubin each day (i.e., almost 0.5 mmol in a 70-kg person). Under physiologic conditions, most bilirubin (70% to 80%) is produced from degradation of hemoglobin from senescent erythrocytes. The remaining 20% to 30% of bilirubin derives primarily from breakdown of other heme-containing proteins (e.g., catalase, cytochrome oxidases) in hepatocytes. Although hemoproteins (e.g., myoglobin) are also present in extrahepatic tissues, their turnover rate is low,

so their overall contribution to bilirubin production under conditions of health is negligible.

Formation of bilirubin from heme involves the actions of 2 enzymes: heme oxygenase, an integral membrane protein of the smooth endoplasmic reticulum, and biliverdin reductase, which is located in the cytosol. Heme oxygenase catalyzes the opening of the heme ring to produce biliverdin. Biliverdin in turn is converted to bilirubin by biliverdin reductase. The major sites of bilirubin production depend on the tissue sources of the hemoprotein precursors. Catabolism of erythrocyte-derived hemoglobin to bilirubin takes place pri-marily in macrophages in the spleen, bone marrow, and liver (Kupffer cells). By contrast, free hemoglobin, haptoglobin-bound hemoglobin, and methemalbumin are predominantly catabolized to bilirubin in hepatocytes.

Bilirubin circulates in plasma tightly but noncovalently bound to albumin. Excretion of bilirubin requires conversion by hepatocytes from the native (unconjugated) form to water-soluble conjugates and subsequent export into bile. Bilirubin metabolism and elimination is a multistep process for which several inherited disorders have been identified (see later). Unconjugated bilirubin is taken up across the sinusoidal (basolateral) membrane of hepatocytes by a carrier-mediated mechanism, but the responsible transport proteins have not been precisely defined. Because the uptake of unconjugated bilirubin is competitively inhibited by certain organic anions (e.g., bromosulfophthalein [BSP], indocyanine), it has been speculated that a member of the organic anion transport protein (OATP) family is involved (see Chapter 64). Support for a role for OATP1B1 (gene symbol SLCO1B1) in the uncon-jugated bilirubin uptake process comes from observations in transfected cells in culture3 and the association of polymor-phisms in the OATP1B1 gene with neonatal jaundice (see Chapter 77)4; however, the importance of OATP1B1 in uncon-jugated bilirubin uptake by hepatocytes has been disputed.5 The subsequent steps of bilirubin metabolism are better understood.

After uptake, unconjugated bilirubin is directed by cyto-solic binding proteins (e.g., glutathione S-transferase B, fatty acid binding protein) to the endoplasmic reticulum, where it is conjugated with bilirubin uridine diphosphate (UDP)– glucuronic acid by the enzyme bilirubin UDP–glucuronyl

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Chapter 21 Jaundice 337

transferase (B-UGT). Conjugated bilirubin is then directed pri-marily toward the canalicular (apical) membrane, where it is transported into the bile canaliculus by an adenosine triphos-phate (ATP)-dependent export pump. The responsible protein, multidrug resistance–associated protein-2 (MRP2, gene symbol ABCC2), can also transport a variety of organic anions, including BSP, glutathione, and conjugated bile salts.6 In addi-tion to canalicular export, small amounts of bilirubin glucuro-nides are secreted across the sinusoidal membrane via a pathway postulated to be mediated by a distinct multispecific organic ion export pump, MRP3 (gene symbol ABCC3).7 Once secreted into plasma, conjugated bilirubin can undergo reup-take by the sinusoidal transporters OATP1B1 and OATP1B3 (gene symbol SLCO1B3),8 or it undergoes renal excretion into urine (see Fig. 21-1). In disorders characterized by cholestasis (impaired bile flow), MRP3-mediated export of conjugated bilirubin can be up-regulated.9 With prolonged cholestasis (or a metabolic disorder of conjugated hyperbilirubinemia [see later]), excess amounts of conjugated bilirubin in plasma become covalently bound to albumin, and this covalently bound bilirubin cannot be excreted into urine.

Under physiologic conditions, virtually all bilirubin in bile is conjugated and only trace amounts are unconjugated. In humans, roughly 80% of bilirubin in bile is in the diglucuro-nide form, and almost all the rest is in the form of monogluc-uronides. Resorption of conjugated bilirubin by the gallbladder and intestine is negligible; the bulk of bilirubin released from the biliary tract enters the intestine in its conjugated form and is eliminated in feces. It should be noted, however, that biliru-bin can be deconjugated by bacteria in the terminal ileum and colon and converted to colorless tetrapyrroles called urobilino-gens. Up to 20% of urobilinogens are resorbed and ultimately excreted in bile and urine.

MeasurementIn adults, the normal bilirubin concentration is lower than 1 to 1.5 mg/dL. Mild hyperbilirubinemia may escape clinical notice, and in general, jaundice is not evident until the serum bilirubin concentration exceeds 3 mg/dL. In healthy persons, most bilirubin circulates in its unconjugated form; less than 5% of circulating bilirubin is present in its conjugated form. In cholestatic conditions, however, the proportion of conju-gated bilirubin in plasma may increase as a consequence of up-regulated MRP3 expression. Therefore, the concentration and composition of bilirubin in plasma can vary widely between health and disease. Accurate measurement of serum bilirubin is of clinical importance in situations that range from managing neonatal jaundice10 to determining priority for liver transplantation.11

Many clinical laboratories measure serum bilirubin con-centration with a colorimetric technique that employs the diazo (van den Bergh) reaction, developed in the early part of the 20th century. In this reaction, bilirubin is cleaved by com-pounds such as diazotized sulfanilic acid to form an azodipyr-role that can be assayed by spectrophotometry. Conjugated bilirubin is cleaved rapidly (directly) by diazo reagents. By contrast, unconjugated bilirubin reacts more slowly because internal hydrogen bonding reduces the accessibility of the diazo reagent to the site of chemical cleavage. Therefore, reli-able measurement of total bilirubin concentration requires addition of another (accelerator) compound (e.g., ethanol, urea) that disrupts this hydrogen bonding and facilitates cleavage of unconjugated bilirubin by the diazo reagent. Using this technique, the “directly” reacting bilirubin, determined in the absence of accelerator compound, is reported as the direct bilirubin concentration, whereas the total bilirubin concentra-tion is reported in the presence of the accelerator compound. The numerical difference between the 2 values is then reported as the indirect bilirubin concentration.

Although the direct bilirubin concentration is influenced by changes in conjugated bilirubin levels, the 2 are not equiva-lent. Similarly, the indirect bilirubin concentration is not equivalent to the concentration of unconjugated bilirubin. In particular, reliance on direct and indirect bilirubin measure-ments can lead to errors in the diagnosis of isolated disorders of bilirubin metabolism (e.g., suspected Gilbert’s syndrome [see later]). Consequently, a number of clinical laboratories instead employ automated reflectance spectroscopic assays that more accurately estimate conjugated and unconjugated bilirubin concentrations. These assays can provide useful information for the management of neonatal jaundice, in which the therapy of unconjugated hyperbilirubinemia is dis-tinct from that for other conditions (see later discussion). In disorders characterized by prolonged cholestasis, however, such assays may underestimate the conjugated bilirubin concentration because they do not accurately detect albumin-bound conjugated bilirubin (so-called delta bilirubin), although this is not a general limitation in most cases of

FIGURE 21-1. Schematic overview of bilirubin formation, metabolism, and transport. Heme from hemoglobin and other hemoproteins is converted to biliverdin and then to bilirubin (Br), predominantly in macrophages in bone marrow and spleen. Br is released into plasma (in its unconjugated form), where it is tightly but reversibly bound to albumin (Alb). Br is then taken up at the sinusoidal membrane of hepatocytes, possibly via a member of the organic anion transporter (OATP) family. Br is conjugated via the activity of bilirubin uridine diphosphateglucuronyl transferase (B-UGT) to form bilirubin mono and diglucuronides (BrG). Biliary secretion of BrG occurs at the canalicular membrane by the multispecific organic anion transporter MRP2. Under physiologic conditions, the vast majority of BrG is eliminated in bile. Small amounts of BrG are transported at the sinusoidal membrane back into plasma, possibly via the multispecific organic anion transporter MRP3, and are recaptured primarily via uptake by OATP (OATP1B1 and OATP1B3). Remaining plasma BrG enters the renal circulation, where it undergoes glomerular filtration and elimination into urine. Therefore, under normal conditions, at least 95% of bilirubin in plasma is present in the unconjugated form. If abnormally high concentrations of BrG are retained over a prolonged period, BrGAlb complexes, which do not dissociate and cannot undergo glomerular filtration, are formed. MRP, multidrug resistanceassociated protein.

Br

Alb-Br

Br

B-UGTBrG

BrG

MRP2

Plasma

Canalicularmembrane

BrG

Hepatocytes

Bile

MRP3?OATP?

HemoglobinOther hemoproteins

Urine


338 Section III Symptoms, Signs, and Biopsychosocial Issues

practical standpoint, conditions associated with jaundice can be classified under the broad categories of isolated disorders of bilirubin metabolism, liver disease, and bile duct obstruc-tion (Table 21-1).

Isolated Disorders of Bilirubin Metabolism

Unconjugated HyperbilirubinemiaThree basic mechanisms can lead to isolated unconjugated hyperbilirubinemia: (1) increased bilirubin production, (2) decreased hepatocellular uptake of unconjugated bilirubin, and (3) decreased bilirubin conjugation. In each of these condi-tions, global liver function and biochemical markers of hepa-tocellular injury and cholestasis are normal.

Increased Bilirubin Production

Processes that can generate excessive bilirubin production include hemolysis, ineffective erythropoiesis, and resorption

jaundice. There may be special circumstances in which confirmation of the diagnosis of an isolated disorder of biliru-bin metabolism is important. Under these conditions, the diagnosis may require more sophisticated chromatographic techniques that precisely measure concentrations of unconju-gated, monoglucuronidated, and diglucuronidated bilirubin, as well as conjugated bilirubin-albumin complexes.2 In prac-tice, these techniques are not widely used. Even with such accurate methods, determination of conjugated and unconju-gated bilirubin concentrations cannot distinguish hepatic dis-orders from biliary obstruction. Therefore, in most cases precise measurements of conjugated and unconjugated biliru-bin concentrations in serum are of limited use.

DIFFERENTIAL DIAGNOSISJaundice can result from an increase in bilirubin production or a decrease in hepatobiliary elimination of bilirubin. From a

TABLE 21-1 Differential Diagnosis of Jaundice and Hyperbilirubinemia

Disorder Examples

Isolated Disorders of Bilirubin MetabolismUnconjugated Hyperbilirubinemia

Increased bilirubin production Hemolysis, ineffective erythropoiesis, blood transfusion, resorption of hematomasDecreased hepatocellular uptake Drugs (e.g., rifampin), Gilbert’s syndrome (secondary mechanism)Decreased conjugation Gilbert’s syndrome, CriglerNajjar syndrome, physiologic jaundice of the newborn, drugs (e.g.,

indinavir, atazanavir)

Conjugated or Mixed Hyperbilirubinemia

DubinJohnson syndromeRotor’s syndrome

Liver DiseaseHepatocellular Dysfunction

Acute or subacute hepatocellular injury

Viral hepatitis, hepatotoxins (e.g., ethanol, acetaminophen, Amanita phalloides); drugs (e.g., isoniazid, phenytoin); ischemia (e.g., caused by hypotension), vascular outflow obstruction; metabolic disorders (e.g., Wilson disease); pregnancyrelated as in acute fatty liver of pregnancy, preeclampsia

Chronic hepatocellular disease Viral hepatitis; hepatotoxins (e.g., ethanol, vinyl chloride, vitamin A); autoimmune hepatitis; celiac disease; metabolic disorders (e.g., nonalcoholic fatty liver disease, hemochromatosis, Wilson disease, α1antitrypsin deficiency)

Hepatic Disorders with Prominent Cholestasis

Infiltrative diseases Granulomatous diseases such as mycobacterial infections, sarcoidosis, lymphoma, granulomatosis with polyangiitis; amyloidosis; malignancy

Cholangiocyte injury PBC; graftversushost disease; drugs (e.g., erythromycin, trimethoprim/sulfamethoxazole); cystic fibrosis

Miscellaneous conditions Benign recurrent intrahepatic cholestasis; drugs (e.g., estrogens, anabolic steroids); TPN; bacterial infections; paraneoplastic syndromes; intrahepatic cholestasis of pregnancy

Bile Duct ObstructionCholedocholithiasis

Bile Duct Diseases

Inflammation, infection PSC, AIDS cholangiopathy, injury caused by hepatic arterial chemotherapy, postsurgical stricturesNeoplasms Cholangiocarcinoma

Extrinsic Compression

Neoplasms Pancreatic carcinoma, metastatic lymphadenopathy, hepatocellular carcinoma, ampullary adenoma/carcinoma, lymphoma

PancreatitisVascular enlargement Aneurysm, cavernous transformation of the portal vein (portal cavernoma)

AIDS, acquired immunodeficiency syndrome.



4 mg/dL. The molecular basis of Gilbert’s syndrome has been linked to a reduction in transcription of the B-UGT gene UGT1A1 as a result of mutations in the promoter region and, less commonly, in the coding region.1,16 Although Gilbert’s syndrome has generally been thought to be an entirely benign condition, persons with this disorder may be at increased risk for gallstones and for toxicity of selected drugs like ironotecan that require glucuronidation for meta-bolic disposal.16 On the other hand, patients with Gilbert’s syndrome may be at decreased risk for cardiovascular disease, because unconjugated bilirubin has antioxidant properties that are thought to retard atherosclerosis.17

Mutations in the coding region of UGT1A1 appear to be responsible for Crigler-Najjar syndrome.18 In type I Crigler-Najjar syndrome, B-UGT activity is absent, and marked unconjugated hyperbilirubinemia is evident shortly after birth. Because unconjugated bilirubin can cross the blood-brain barrier, patients with type I Crigler-Najjar syndrome accumulate bilirubin in the brain (kernicterus), and the result-ing neurotoxic effects can lead to death in the neonatal period (see Table 21-2). Phototherapy (see later) is required to prevent kernicterus, and liver transplantation can be lifesaving. By contrast, persons with type II Crigler-Najjar syndrome have reduced (but not absent) B-UGT activity, and serum bilirubin levels are lower than in patients with type I Crigler-Najjar syndrome (see Table 21-2). Patients with type II Crigler-Najjar syndrome are not ill during the neonatal period and may not be diagnosed until early childhood. Most patients with type II Crigler-Najjar syndrome can be treated successfully

of a hematoma.2 With these disorders, bilirubin concentration generally does not exceed 4 to 5 mg/dL. Jaundice can also follow massive blood transfusions, because the increased fra-gility of stored erythrocytes leads to excessive hemoglobin release, and this can be a major contributor to hyperbilirubi-nemia in patients with major trauma.12

Decreased Bilirubin Uptake

Selected drugs can interfere with hepatocellular uptake of bilirubin. For example, the antibiotic rifampin and the immu-nosuppressive agent cyclosporine A competitively inhibit the sinusoidal transport protein OATP1B1.13,14 Decreased bilirubin uptake may also exacerbate hyperbilirubinemia in patients with Gilbert’s syndrome (see later), who have impaired bilirubin conjugation resulting from reduced B-UGT activity.15

Decreased Bilirubin Conjugation

Three autosomally inherited disorders of unconjugated hyper-bilirubinemia are due to impaired bilirubin conjugation (Table 21-2). The most common of these is Gilbert’s syndrome, which has a prevalence of approximately 10% in white populations. Patients with Gilbert’s syndrome typically present when iso-lated hyperbilirubinemia is detected as an incidental finding on routine multiphasic biochemical screening, and clinical jaundice is uncommon. Serum bilirubin levels may rise 2- to 3-fold with fasting or dehydration but are generally below

TABLE 21-2 Hereditary Disorders of Bilirubin Metabolism and Transport

Parameter

Syndrome

Gilbert’sType I Crigler-Najjar

Type II Crigler-Najjar Dubin-Johnson Rotor’s

Incidence 6%12% Very rare Uncommon Uncommon Rare

Gene affected UGT1A1 UGT1A1 UGT1A1 MRP2 OATP1B1 and OATP1B3

Metabolic defect

↓Bilirubin conjugation No bilirubin conjugation

↓↓Bilirubin conjugation

Impaired canalicular export of conjugated bilirubin

Impaired canalicular export of conjugated bilirubin

Plasma bilirubin (mg/dL)

≤3 in absence of fasting or hemolysis, almost all unconjugated

Usually >20 (range, 1750), all unconjugated

Usually <20 (range, 645), almost all unconjugated

Usually <7, about half conjugated

Usually <7, about half conjugated

Liver histology Usually normal, occasional ↑lipofuscin

Normal Normal Coarse pigment in centrilobular hepatocytes

Normal

Other distinguishing features

↓Bilirubin concentration with phenobarbital

No response to phenobarbital

↓Bilirubin concentration with phenobarbital

↑Bilirubin concentration with estrogens; ↑↑urinary coproporphyrin I/III ratio

Mild ↑urinary coproporphyrin I/III ratio

Prognosis Normal (theoretical risk of selected drug toxicity)

Death in infancy if untreated

Usually normal Normal (theoretical risk of selected drug toxicity)

Normal (theoretical risk of selected drug toxicity)

Treatment None Phototherapy as a bridge to liver transplantation

Phenobarbital for ↑↑bilirubin concentration

Avoid estrogens None available

MRP2, multidrug resistance–associated protein2 gene; OATP, organic anion transporter; UGTIA1, bilirubin uridine diphosphateglucuronyl transferase gene.



hepatitis is often heralded by anorexia, malaise, and myalgias before jaundice develops (see Chapters 78 to 83). Five hepato-tropic viruses have been isolated: hepatitis A and E viruses, which are transmitted enterally and are generally self-limited, and hepatitis B, C, and D, which are transmitted parenterally and may lead to chronic disease. The diagnosis of each of these disorders is aided by serologic testing (see later).

One of the most common causes of toxic liver injury is ingestion of large quantities of the analgesic acetaminophen (see Chapter 88), which can lead to jaundice and frank liver failure within several days after exposure. In patients who survive, jaundice generally resolves and hepatic function recovers completely in those without preexisting liver disease. Other drugs that produce idiosyncratic (i.e., dose-independent) hepatocellular injury and jaundice are discussed elsewhere in this text (see Chapters 88 and 89). Alcoholic hepatitis should be a diagnostic consideration in the jaundiced patient with ethanol dependency (see Chapter 86). Laboratory studies may help distinguish this entity from most other acute liver diseases.

Jaundice related to hepatic ischemia may result from hypotension, hypoxia, hyperthermia, or obstruction to hepatic outflow secondary to hepatic vein thrombosis (Budd- Chiari syndrome) or sinusoidal obstruction syndrome (see Chapter 85).

Wilson disease, an inherited disorder of hepatobiliary copper secretion, may manifest de novo with clinical features indistinguishable from those of acute viral hepatitis (see Chapter 76). The disease should be a diagnostic consideration in patients younger than age 40, particularly when neurologic abnormalities are present or if examination of the eyes reveals copper-laden (Kayser-Fleischer) rings that surround the iris. Hemolytic anemia is a part of the spectrum of Wilson disease and contributes to disproportionate hyperbilirubinemia in these patients. The diagnosis of Wilson disease is confirmed by biochemical testing and liver copper analysis.

Chronic Hepatocellular DysfunctionIn contrast to acute hepatocellular injury, jaundice does not typically develop in chronic liver disease unless cirrhosis is present. Chronic viral hepatitis should be a diagnostic con-sideration in patients with suspected cirrhosis, especially in the presence of risk factors for parenteral exposure to caus-ative agents. Diagnosis is aided by serologic testing (see later). Cirrhosis is part of the spectrum of fatty liver disease, either in the context of chronic alcohol use (see Chapter 86) or as a component of the metabolic syndrome (nonalcoholic fatty liver disease [see Chapter 87]). Certain hereditary meta-bolic diseases may progress to cirrhosis. Hemochromatosis, a disorder of hepatocellular injury due to excessive iron absorption, is the most common of these (see Chapter 75). Decades of hepatic iron overload are generally required to produce symptoms, and hemochromatosis often is not diag-nosed until middle age. The diagnosis is confirmed by detec-tion of mutations in the HFE gene or by hepatic iron analysis. Copper-induced hepatic injury in Wilson disease may also progress to cirrhosis (see Chapter 76). In a jaundiced patient with chronic lung disease, α1-antitrypsin deficiency should be suspected (see Chapter 77). In this disorder, misfolded mutant α1-antitrypsin accumulates in the endoplasmic reticu-lum of hepatocytes, and liver injury results. The diagnosis can be confirmed by laboratory testing and liver biopsy. Autoimmune hepatitis may be associated with systemic complaints like malaise, fever, and arthralgias (see Chapter 90). The diagnosis is aided by serologic testing and liver biopsy (see later). Although celiac disease characteristically

with phenobarbital, an agonist for the constitutive androstane receptor CAR, which increases UGT1A1 expression,19 and serum bilirubin levels generally fall to the range of 2 to 5 mg/dL.

A related disorder of bilirubin metabolism is physiologic jaundice of the newborn, which results from delayed develop-mental expression of B-UGT and generally resolves rapidly in the neonatal period. A brief course of phototherapy (see later) may be required to prevent kernicterus.

B-UGT is inhibited competitively by the retroviral protease inhibitors atazanavir and indinavir, which produce hyperbili-rubinemia in more than 25% of patients who receive these agents; patients with Gilbert’s syndrome are at higher risk for this complication.20,21

Conjugated or Mixed HyperbilirubinemiaTwo autosomally inherited disorders, Dubin-Johnson syn-drome and Rotor’s syndrome, are associated with conjugated or mixed hyperbilirubinemia (i.e., increase in serum concen-trations of both conjugated and unconjugated bilirubin). The mechanisms that underlie these disorders are distinct. In Dubin-Johnson syndrome, an absence of expression or altered trafficking of MRP2 impairs secretion of conjugated bilirubin into the bile canaliculus.6 Compensatory up-regulation of the sinusoidal export protein MRP3 may prevent hepatocel-lular overload by potentially toxic organic anions that are normally secreted by MRP2, and this can contribute to the degree of hyperbilirubinemia in the disorder.22 The molec-ular basis of Rotor’s syndrome is more complex. Studies in transgenic mice have demonstrated that conjugated biliru-bin, which is secreted into plasma by MRP3, is taken up by the sinusoidal transport proteins OATP1B1 and OATP1B3.8 Combined deficiency of OATP1B1 and OATP1B3 results in Rotor’s syndrome and impaired re-uptake of conjugated bilirubin.8

Dubin-Johnson and Rotor’s syndromes can be distin-guished biochemically and histologically (see Table 21-2). In Dubin-Johnson syndrome, hepatocytes contain a characteristic black pigment believed to be formed by aromatic amino acid metabolites that are putative MRP2 substrates.6 Liver biopsy is unnecessary in the diagnostic evaluation of patients sus-pected of having Dubin-Johnson or Rotor’s syndrome, because neither disorder is associated with progressive hepatic damage. It has been speculated that patients with Rotor’s syndrome may be at increased risk for toxicity from selected drugs (e.g., statin-induced myopathy) that undergo metabolic disposal via OATP1B-mediated hepatic uptake.8

Liver DiseaseJaundice is a common feature of liver disease, in which hyper-bilirubinemia is generally associated with other biochemical liver test abnormalities. Disorders in which hyperbilirubine-mia and jaundice are manifestations of global acute or chronic hepatocellular dysfunction are distinguished from those for which cholestasis is the predominant problem.

Acute Hepatocellular DysfunctionGeneralized hepatic dysfunction can be caused by acute or chronic hepatocellular injury resulting from a variety of condi-tions that include viral hepatitis, exposure to hepatotoxins, ischemic hepatitis and other causes of hepatic ischemia, and certain metabolic derangements. Serum aminotransferase levels are characteristically elevated (see later). Acute viral



cystic fibrosis transmembrane conductance regulator ion channel protein that is expressed in secretory epithelia.

Cholestasis with Minimal Histologic Abnormalities

Jaundice may accompany conditions characterized by minimal hepatocellular injury and histologic abnormalities. Several mechanisms contribute to cholestasis in these conditions, including mutations in the genes that encode transport pro-teins involved in bile formation and conditions that interfere with the function or expression of such proteins.

Benign recurrent cholestasis is an autosomally inherited disorder associated with mutations in the genes that encode 2 transport proteins that are present on the canalicular membrane of hepatocytes and regulate bile formation: the familial intrahepatic cholestasis 1 protein (FIC1, gene symbol ATP8B1) and the bile salt export pump (BSEP, gene symbol ABCB11 [see Chapters 64 and 77]).28 FIC1 is a P-type ATPase believed to function in hepatocytes as a membrane “flippase” for aminophospholipids, and FIC1 dysfunction appears to cause cholestasis by increasing the susceptibility to canalicular membrane damage by hydrophobic bile acids.29 BSEP is an ATP-dependent bile salt export pump,30 and impaired BSEP activity leads to cholestasis by reduction in bile salt secretion.22 Benign recurrent cholestasis repre-sents 1 end of a spectrum of disorders associated with FIC1 and BSEP mutations; the other end is progressive familial intrahepatic cholestasis (PFIC) types 1 and 2, dis-eases that can lead to liver failure in childhood and neces-sitate liver transplantation.

Patients with benign recurrent cholestasis typically present before the second decade of life with recurrent epi-sodes of malaise and pruritus in association with jaundice; fever and abdominal pain are uncommon.31 When performed during an icteric episode, liver biopsy findings are generally confined to centrilobular cholestasis; portal-based inflam-matory cell infiltrates are uncommon. Cholestatic episodes may last up to several months and are separated by periods of clinical remission. Although quality of life may be adversely affected, the disease does not lead to progressive liver damage and (unlike PFIC) liver failure does not occur.

A number of drugs produce histologically bland intrahe-patic cholestasis (see Chapter 88). Estrogens reduce bile for-mation principally by inhibiting bile salt secretion.22 There are several mechanisms by which this occurs, including down-regulation of the sinusoidal bile salt uptake protein Na+-taurocholate cotransporting peptide (NTCP, gene symbol SLC10A1), competitive inhibition of BSEP, and interference with MRP2 function.32 Jaundice related to the use of oral con-traceptives usually develops within 2 months of initiation of therapy and is generally accompanied by pruritus; these symptoms resolve promptly with discontinuation of the drug. Anabolic steroids can produce a syndrome that is clini-cally indistinguishable from estrogen-induced cholestasis. The clinical features of cholestasis associated with total par-enteral nutrition (possibly related to altered enterohepatic circulation and diminished neuroendocrine stimulation of bile flow) may also resemble those related to estrogen and anabolic steroids, but progressive hepatic fibrosis has also been described.33

Cholestasis and jaundice also may develop during bacte-rial infections, likely because of cytokine-dependent down-regulation of the transporters NTCP, MRP2, and BSEP.9 As in other cholestatic disorders, the clinical features may be diffi-cult to distinguish from biliary obstruction, and imaging studies may be required to resolve this issue.

causes immune-mediated disease in the small intestine (see Chapter 107), it may occasionally present as otherwise unex-plained chronic liver disease, although rarely if ever with jaundice.

Hepatic Disorders with Prominent CholestasisIntrahepatic cholestatic disorders are characterized by impaired bile formation in the absence of widespread hepato-cellular injury or biliary obstruction. The presentation of these disorders and associated biochemical abnormalities may mimic biliary obstruction and can generate diagnostic confu-sion. Intrahepatic cholestatic disorders can be categorized his-tologically as those associated with infiltration of the liver, those associated with injury to cholangiocytes within intrahe-patic bile ductules, and those in which major histologic changes are not evident.

Infiltrative Diseases

Infiltrative diseases of the liver disrupt the network of intra-hepatic bile ductules and are often associated with striking cholestasis. Granulomatous diseases of the liver can be caused by the following: microbial disorders, drugs and industrial toxins, lymphoma, and systemic disorders, including sarcoid-osis and granulomatosis with polyangiitis (see Chapters 31, 36, and 84). The most common of these disorders that produce jaundice are tuberculosis and sarcoidosis.23,24 Granulomatous diseases should be suspected when jaundice accompanies fever of undetermined origin. Physical examination usually reveals hepatosplenomegaly, and lymphadenopathy may be present. Radiographic chest abnormalities often provide a clue to the diagnosis of sarcoidosis or mycobacterial infection. Ultimately, diagnosis may require liver biopsy if other tissue is unavailable. Jaundice is an unusual manifestation of amy-loidosis, but when present is invariably accompanied by marked hepatomegaly.25 The diagnosis of amyloidosis should also be suspected in the jaundiced patient if there are signs of involvement of other organs (e.g., macroglossia, malabsorp-tion, heart failure, peripheral neuropathy, proteinuria). In the absence of other clues, liver biopsy may be necessary. Jaundice due to extensive neoplastic replacement of hepatic paren-chyma is usually heralded by anorexia and weight loss. Non-invasive imaging studies generally lead to the diagnosis (see later).

Disorders Involving Cholangiocyte Injury

A variety of disorders can lead to cholangiocyte damage. In many of these, the cholangiocyte is a target of an immune-mediated inflammatory response, as is characteristic of PBC (see Chapter 91). PBC occurs primarily in women. In patients with jaundice, pruritus is also usually present, and fatigue is common. Serologic testing (antimitochondrial antibodies) is generally sufficient, but liver biopsy may be necessary to confirm the diagnosis or extent of hepatic fibrosis in selected cases. The cholangiocyte is a target of graft-versus-host disease (see Chapter 35), and jaundice related to this disorder develops in some 10% of hematopoietic cell transplant recipients.26 Certain drugs also produce cholestasis as a result of cholangiocyte injury (see Chapter 88).27 Examples include erythromycin, trimethoprim/sulfamethoxazole, and amoxicillin–clavulanic acid (see http://www.livertox.nih.gov). In general, cholestasis resolves within several months follow-ing discontinuation of the causative drug. Cholestasis from cholangiocyte injury occurs in about 30% of adults with cystic fibrosis (see Chapters 57 and 77), a genetic disorder of the


http://www.livertox.nih.gov


Bile Duct ObstructionObstructive disorders of the biliary tract include occlusion of the bile duct lumen, intrinsic disorders of the bile ducts, and extrinsic compression.

CholedocholithiasisThe most common cause of biliary obstruction is luminal occlusion by a stone (choledocholithiasis). Three types of stones have been implicated in this process, with cholesterol gallstones responsible for the majority of cases. Cholesterol stones typically originate in the gallbladder and can migrate into the bile duct (see Chapter 65). In patients with uncon-jugated hyperbilirubinemia, calcium bilirubinate stones (so-called black pigment gallstones) form in the gallbladder and may also form in situ at any level of the biliary tract. Brown pigment gallstones, a distinct type of bilirubinate stone, can lead to repeated bouts of cholangitis (recurrent pyogenic cholangitis) in patients from certain regions of Asia (see Chapter 68) and in patients with prior biliary tract surgery or endoscopic intervention (see Chapters 66 and 70).

Bile Duct DiseasesIntrinsic narrowing of the bile ducts occurs in inflammatory, infectious, or neoplastic biliary disease. Congenital disorders of the bile ducts, including cysts and biliary atresia, are dis-cussed in Chapter 62. PSC, a progressive inflammatory disor-der of the bile ducts, is characterized by focal and segmental biliary strictures (see Chapter 68). Focal narrowing and local-ized obstruction of the bile ducts is an unusual complication of acquired immunodeficiency syndrome (so-called AIDS cholangiopathy [see Chapter 34]). Biliary strictures may also follow hepatic arterial infusion of certain chemotherapeutic agents39 or result from surgical injury to the bile duct or hepatic artery (see Chapters 66 and 70). Neoplasms of the biliary tract are discussed in Chapter 69.

Extrinsic CompressionExtrinsic compression of the biliary tract may result from neo-plastic involvement or inflammation of surrounding viscera. Rarely, marked enlargement of the surrounding vasculature (e.g., arterial aneurysms, cavernous transformation of the portal vein [portal cavernoma]) can compress the bile ducts (see Chapter 85).

Painless jaundice is a classic feature of carcinoma of the head of the pancreas (see Chapter 60). Occasionally, hepatocel-lular carcinoma or periportal lymph nodes enlarged by meta-static tumor or lymphoma obstructs the extrahepatic bile ducts. Pancreatitis may also produce extrinsic biliary compression as a result of edema or pseudocyst formation (see Chapters 58 and 59). Rarely, gallstones in the cystic duct or infundibulum of the gallbladder compress the common hepatic duct (Mir-izzi’s syndrome) and produce jaundice (see Chapter 65).40

DIAGNOSTIC APPROACH TO JAUNDICEA general algorithm for evaluating the patient with jaundice is depicted in Figure 21-2. A logical approach involves: (1) a carefully taken patient history, thorough physical examina-tion, and screening laboratory studies; (2) formulation of a working differential diagnosis; (3) selection of specialized tests to narrow the diagnostic possibilities; and (4) develop-ment of a strategy for treatment or further testing if unex-pected diagnostic possibilities arise.

Jaundice due to intrahepatic cholestasis has been reported as a paraneoplastic phenomenon (i.e., in the absence of malig-nant infiltration of the liver) in patients with lymphoma and urologic malignancies. The latter, referred to as Stauffer’s syn-drome, resolves after successful treatment of the primary tumor.34 Pathogenesis may relate to tumor-derived secretion of cytokines35 that interfere with NTCP, MRP2, and BSEP function.9

Atypical Presentations of Cholestasis

Viral hepatitis rarely may cause profound cholestasis with marked pruritus.36 Unless the patient has risk factors for viral hepatitis, no features reliably distinguish this disorder from other cholestatic syndromes or biliary tract obstruction. A high level of suspicion and appropriate serologic tests will help establish the diagnosis. Alcoholic hepatitis manifesting as fever, jaundice, abdominal pain, and leukocytosis may be dif-ficult to distinguish from bile duct obstruction. Liver biopsy may be required to confirm the diagnosis.

Jaundice in PregnancySeveral cholestatic disorders are uniquely encountered in pregnancy (see Chapter 39). Jaundice uncommonly may accompany hyperemesis gravidarum, a generally self-limited disorder of the first trimester, but liver failure is not a feature of this illness.37 Intrahepatic cholestasis of pregnancy typically occurs in the third trimester and presents with pruritus and occasionally with jaundice. Cholestasis generally resolves within 2 weeks of delivery and often recurs with subsequent pregnancies. Polymorphisms in the genes encoding the cana-licular transporters BSEP, FIC1, MRP2, and MDR3 (gene symbol ABCB4) and nuclear receptors that modulate their expression have been associated with this disorder.37 Func-tional alterations in these transporters may enhance their sensitivity to the inhibitory effects of estrogens with respect to bile formation. A far more serious syndrome is acute fatty liver of pregnancy, which typically occurs in the third tri-mester and is associated with hepatocellular injury. Jaundice, when present, is usually accompanied by nausea, abdominal pain, and evidence of liver failure. Liver biopsy (if performed) demonstrates microvesicular steatosis. The disorder may be fatal unless obstetrical delivery is performed promptly. Pre-eclampsia, a microvascular disorder of the third trimester, is heralded by hypertension and proteinuria and affects the liver in about 10% of cases. A particularly severe form, the HELLP (hemolysis, elevated liver enzyme levels, and a low platelet count) syndrome, is treated by prompt obstetric delivery.

Jaundice in the Critically Ill PatientEstablishing the cause of jaundice in the critically ill patient can present a challenge to intensivists and their consultants. The differential diagnosis can be quite broad. Predisposing factors include hepatic ischemia, blood transfusions, hepato-toxic drugs, parenteral nutrition, and occult sepsis,38 and kidney injury may further contribute to impairment of conju-gated bilirubin elimination. The persistence of icterus can be a source of dismay and frustration to concerned relatives and other advocates for the patient, who may view jaundice as the cause rather than a manifestation of the underlying problems. Notably, even if other clinical parameters improve, there may be a lag in the resolution of jaundice. Therefore, the management of jaundice in critical illness requires not only a careful search for reversible causes but also a great deal of patience.



FIGURE 21-2. Algorithm for evaluation and management of jaundice and hyperbilirubinemia. THC, transhepatic cholangiography.

History, physicalexamination,

routine laboratory tests

No

No

Yes

Yes

ERCPor THC

No biliaryobstruction

High Low

Biochemical studiesfor specific causes of

liver disease

Specifictherapy

Positive

Alkaline phosphataseor aminotransferases

elevated?

Evaluate for hemolysis,hereditary

hyperbilirubinemia

Therapeuticintervention

Biliary tract obstructiona consideration?

Biliaryobstruction

Dilatedbile ducts Abdominal

US or CTConsider

liver biopsy

Clinical likelihood of biliary obstruction

Intermediate

ConsiderMRCP or EUS

Nondilatedbile ducts

Dilatedbile ducts

Nondilatedbile ducts

Negative

History and Physical ExaminationThe patient’s history and physical examination provide impor-tant clues regarding the cause of jaundice (Table 21-3). A history of biliary surgery, fever (especially when accompanied by rigors), and abdominal pain, particularly in the right upper quadrant, is suggestive of biliary obstruction with cholangitis. On the other hand, symptoms compatible with a viral pro-drome (e.g., anorexia, malaise, myalgias) make acute viral hepatitis a strong diagnostic possibility, especially if there are risk factors for potential infectious exposure. A carefully taken history may suggest that environmental hepatotoxins, ethanol, or medications underlie the patient’s icteric liver disease. A family history of jaundice or liver disease raises the possibility of hereditary hyperbilirubinemia or genetic liver disease. All clues must be interpreted with caution; for example, fever and abdominal pain accompany diseases other than biliary obstruction, and viral hepatitis may occur coincidentally in patients with a history of prior biliary surgery. Moreover, anorexia and malaise are not specific for viral hepatitis, and gallstones can develop in patients with chronic liver disease. Nevertheless, when details from the patient’s history are eval-uated in the context of the physical findings and results of routine laboratory tests, jaundice can be characterized cor-rectly as obstructive or nonobstructive in about 75% of cases, and this rate has yet to be surpassed by computer-based modeling.41

Clues offered by the physical examination are also impor-tant in the patient with jaundice. Fever or abdominal

tenderness (particularly in the right upper quadrant) suggests cholangitis, and a palpable abdominal mass suggests a neo-plastic cause of obstructive jaundice. The presence of cirrhosis may be suggested by signs of portal hypertension (e.g., ascites, splenomegaly, prominent abdominal veins), spider telangiec-tasias, gynecomastia, and asterixis. Some findings may be pathognomonic of a specific disorder (e.g., Kayser-Fleischer rings in Wilson disease).

Initial Laboratory StudiesEssential laboratory tests in the patient with jaundice include serum total bilirubin, alkaline phosphatase, aminotransfer-ases, complete blood count, and prothrombin time (see Chapter 73). Serum alkaline phosphatase activity derives from related isoenzymes expressed on the membranes of multiple cell types, including the apical membranes of hepatocytes and cholangiocytes. In these cells, under physiologic conditions, enzymatic cleavage releases alkaline phosphatase from the apical membrane into bile; small amounts are released from the basolateral membrane into plasma as well. Biliary obstruc-tion and intrahepatic cholestasis increase the basolateral release of alkaline phosphatase, and serum alkaline phospha-tase activity increases under these conditions. Consequently, in a jaundiced patient, a predominant increase in serum alka-line phosphatase (relative to aminotransferase) activity sug-gests the presence of biliary tract obstruction or intrahepatic cholestasis. An increase in serum alkaline phosphatase activity



TABLE 21-3 Clues to the Differential Diagnosis of Jaundice: Biliary Obstruction versus Liver Disease

Parameter Biliary Obstruction Liver Disease

History Abdominal painFever, rigorsPrior biliary surgeryOlder age

Anorexia, malaise, myalgias (viral prodrome)Known viral exposureHistory of blood product receipt or injection drug useExposure to known hepatotoxinFamily history of liver disease

Physical examination FeverAbdominal tendernessPalpable abdominal massAbdominal surgical scar

Spider telangiectasiasStigmata of portal hypertension (e.g., prominent

abdominal veins, splenomegaly, ascites)Asterixis

Laboratory studies Predominant elevation of serum alkaline phosphatase relative to aminotransferases*

Prothrombin time (INR) normal or normalizes with vitamin K administration

LeukocytosisElevated serum amylase or lipase level

Predominant elevation of serum aminotransferase levels relative to alkaline phosphatase

Prolonged prothrombin time that does not normalize with vitamin K administration

ThrombocytopeniaSerologies indicative of specific liver disease

*Except early after acute obstruction when the opposite pattern may be seen transiently.

(especially if aminotransferase activity is normal), however, may reflect release of alkaline phosphatase isoenzymes from extrahepatic tissues. If there is diagnostic uncertainty, elevated serum activities of other proteins (e.g., gamma glutamyl trans-peptidase, 5′-nucleotidase, alkaline phosphatase isoenzymes) confirm the presence of hepatobiliary disease (see Chapter 73).

The aminotransferases—alanine aminotransferase (ALT), a cytosolic enzyme found predominantly in hepatocytes, and aspartate aminotransferase (AST), isozymes of which are found within hepatocytes and cells from several other tissues—are ordinarily detected in serum in low concentrations. Condi-tions that produce hepatocellular injury (e.g., viral hepatitis, toxic liver injury, hepatic ischemia [see earlier]) increase plasma membrane permeability and release of aminotransfer-ases into plasma. A predominant elevation of serum amino-transferase levels (relative to alkaline phosphatase) suggests that jaundice is due to hepatocellular injury. There are excep-tions to this generalization, however; for example, transient biliary obstruction from choledocholithiasis may cause a brief but dramatic elevation (>10 to 20 times normal) of serum ami-notransferase activity.42

A complete blood count provides complementary informa-tion. Leukocytosis may be a clue to the presence of biliary tract obstruction or another inflammatory disorder that may be associated with cholestasis. The presence of anemia raises the possibility that a hemolytic disorder is responsible for jaun-dice, especially if isolated hyperbilirubinemia (without other abnormalities in biochemical liver tests) is detected. Thrombo-cytopenia is a characteristic finding in cirrhosis and appears to result from reduced synthesis of the platelet production regulator thrombopoietin or from increased splenic sequestra-tion associated with portal hypertension.

Prothrombin time reflects the activities of coagulation factors I, II, V, VII, and X. With impaired hepatic synthesis of these proteins, prothrombin time is prolonged (often reported as an increase in the international normalized ratio [INR]), but this finding is not specific for conditions associated with hepatocellular injury. Prolongation of prothrombin time can also be seen with intrahepatic cholestasis or prolonged biliary obstruction, as a result of impaired absorption of vitamin K, a fat-soluble cofactor required for synthesis of factors II, VII, IX,

and X. Exogenously administered vitamin K will generally normalize the prothrombin time in intrahepatic cholestasis or prolonged biliary obstruction but not in conditions associated with hepatocellular injury.

Overall ApproachIntegration of the patient’s history, physical examination, and laboratory study results will provide an estimate of the likeli-hood that jaundice is due to a disorder of bilirubin production or metabolism, intrinsic liver disease, or biliary obstruction. At 1 extreme is the asymptomatic patient with no abnormali-ties (other than jaundice) on physical examination. Under these conditions, if the serum alkaline phosphatase and ami-notransferase activities, platelet count, and prothrombin time are normal, liver disease or biliary obstruction is highly unlikely. In this situation, further testing for specific disorders, such as an isolated defect in bilirubin metabolism or hemoly-sis, is warranted (see Fig. 21-2). Alternatively, if the history, physical examination, and laboratory study results raise the possibility of biliary obstruction, hepatobiliary imaging is appropriate. Selection of the appropriate imaging study depends on the likelihood of bile duct obstruction and the diagnostic accuracy, cost, complication rate, and availability of each test (see later), especially if therapeutic intervention at the time of the study is anticipated.

Imaging Studies

Abdominal USAbdominal US is usually the initial imaging test in jaundiced patients with suspected hepatobiliary disease.43-47 US can also demonstrate cholelithiasis (although bile duct stones may not be well seen) and intrahepatic lesions more than 1 cm in diam-eter. US has the advantages of being noninvasive, portable, and less expensive than other imaging studies (Table 21-4). Disadvantages include dependence on the skill of the operator for the procedure and potential technical difficulty in obese patients or patients with excessive bowel gas that overlies some organs like the pancreas.



TABLE 21-4 Imaging Studies for Evaluation of Jaundice

TestSensitivity (%)

Specificity (%) Morbidity (%)

Mortality (%) Advantages and Disadvantages

Abdominal US 5591 8295 0 0 Advantages: noninvasive, portableDisadvantages: bowel gas may obscure bile duct;

difficult in obese persons, operator dependent

Abdominal CT 6396 93100 See disadvantages 0 Advantages: noninvasive, higher resolution than US, not operator dependent

Disadvantages: potential for contrastinduced nephrotoxicity, anaphylaxis

MRCP 82100 9498 See disadvantages Advantages: noninvasive, imaging of bile ducts superior to US and CT

Disadvantages: requires breath holding, may miss smallcaliber bile duct disease

ERCP 8998 89100 5 0.2 Advantages: provides direct imaging of bile ducts; permits direct visualization of periampullary region and acquisition of tissue distal to bifurcation of hepatic ducts; permits simultaneous therapeutic intervention, especially useful for lesions distal to the bifurcation of the hepatic ducts

Disadvantages: requires sedation, cannot be performed if altered anatomy precludes endoscopic access to the ampulla (e.g., RouxenY loop); may cause complications (e.g., pancreatitis)

Percutaneous THC 98100 89100 3.5 0.2 Advantages: provides direct imaging of the bile ducts, permits simultaneous therapeutic intervention, especially useful for lesions proximal to the common hepatic duct

Disadvantages: more difficult with nondilated intrahepatic bile ducts; may cause complications

EUS 8997 6798 See disadvantages 0 Advantages: imaging of the bile ducts is superior to US and CT; permits needle aspiration of suspected neoplasms

Disadvantages: requires sedation

THC, transhepatic cholangiography.

CTCT of the abdomen with intravenous contrast is an alter-native noninvasive means of evaluating hepatobiliary disease. Abdominal CT permits accurate measurement of the caliber of the biliary tract, with sensitivity and specificity rates com-parable to those for ultrasonog raphy.43-45,47 Abdominal CT detects intrahepatic space-occupying lesions as small as 5 mm, is not operator dependent, and provides technically superior images in obese persons. However, it lacks portability, exposes the patient to ionizing radiation, and is more expensive than ultrasonography. The requirement for the use of intravenous contrast may be problematic in the setting of kidney injury (see Table 21-4).

MRCPMRCP is a technical refinement of standard MRI that permits rapid clear-cut delineation of the biliary tract. MRCP appears

to be superior to conventional ultrasonography or CT for the detection of biliary tract obstruction48-51 and plays an impor-tant role as a diagnostic test in this setting (see Table 21-4). Moreover, standard MRI can be performed during the same examination if there is a question of a hepatobiliary mass or if a contrast allergy precludes CT. It is more expensive than ultrasonography or CT.

ERCPERCP permits direct visualization of the biliary tract. ERCP is more invasive than ultrasonography, CT, and MRCP (see Table 21-4) and comparable in cost to MRCP.52 After endo-scopic identification of the ampulla of Vater, insertion of a catheter permits contrast injection into the biliary tract; sedation and analgesia are necessary. ERCP is highly accurate in the diagnosis of biliary obstruction.47,53 If a focal cause of biliary obstruction (e.g., choledocholithiasis, biliary stric-ture) is identified, maneuvers to relieve obstruction (e.g.,



sphincterotomy, stone extraction, stricture dilation, stent placement) can be performed during the same session (see Chapter 70). Similarly, if there is concern about a neoplasm, biopsy and brushings for cytology can be performed. Acquisi-tion of biopsy specimens and therapeutic interventions via ERCP are limited largely to lesions distal to the bifurcation of the right and left hepatic bile ducts. The technical success rate of diagnostic ERCP is higher than 90%; the technique fails when the ampulla of Vater cannot be cannulated, as may be the case in patients with prior abdominal surgery and altered anatomy (e.g., gastric bypass, choledochojejunostomy). The major complication of ERCP is pancreatitis, which occurs in at least 5% of cases,54 and the mortality rate is approximately 0.2%.55 These rates are influenced in part by the patient’s base-line characteristics and need for therapeutic instrumentation during the procedure.

Percutaneous Transhepatic CholangiographyPercutaneous transhepatic cholangiography (THC) is a proce-dure that complements ERCP. Percutaneous THC requires passage of a needle through the skin and subcutaneous tissues into the hepatic parenchyma and advancement into a periph-eral bile duct. When bile is aspirated, a catheter is introduced through the needle, and radiopaque contrast medium is injected. Sensitivity and specificity of percutaneous THC for the diagnosis of biliary tract disease are comparable with those for ERCP.56,57 Like ERCP, interventional procedures like balloon dilation and stent placement can be performed at the time of percutaneous THC to relieve focal obstructions of the biliary tract (see Chapter 70). Percutaneous THC is potentially techni-cally advantageous when the level of biliary obstruction is proximal to the common hepatic duct or altered anatomy pre-cludes ERCP (see earlier). Percutaneous THC may be techni-cally challenging in the absence of dilatation of the intrahepatic bile ducts; in this situation, multiple passes may be required, and visualization of the biliary tract may be unsuccessful in up to 10% of attempts.58 With percutaneous THC, about 2% of patients experience complications as a result of bleeding, per-foration, and infection; death is rare.59 Percutaneous THC is more expensive than abdominal ultrasonography and CT (see Table 21-4).

Endoscopic USEUS can also detect obstruction of the bile duct and major intrahepatic bile ducts, with sensitivity and specificity com-parable to those for MRCP.60-62 EUS has the potential advan-tage of permitting biopsy of suspected malignant lesions, and under appropriate circumstances, the operator can proceed directly to ERCP for definitive biliary decompression (see Table 21-4). The risk of diagnostic EUS is comparable with that of diagnostic upper endoscopy; when needle biopsy is used, the mortality rate is roughly 0.1%.63 EUS may be most useful in circumstances in which the patient is thought to be at high risk for complications of ERCP or percutaneous THC.

Nuclear Imaging StudiesNuclear scintigraphy of the biliary tract, although helpful in the diagnosis of cholecystitis, is not sufficiently sensitive to justify its routine use in the diagnostic evaluation of adults with jaundice.64 Furthermore, hepatic uptake of radiolabeled derivatives of iminodiacetic acid (e.g., HIDA) is limited when the serum bilirubin level exceeds 7 to 10 mg/ dL.65 One exception to this generalization is in the evaluation of a poten-tial bile leak, an uncommon cause of jaundice following

biliary surgery, in which scintigraphy has an accuracy rate as high as 87%.66

Suggested Strategies for ImagingThe order of imaging studies depends largely on the clinical likelihood of obstructive jaundice (see Fig. 21-2). Several diag-nostic strategies have been compared by clinical decision analysis in the era that predated MRCP and EUS67; no subse-quent refinements to this comparison have been published. Based on the analysis, if the probability of biliary obstruction is approximately 20%, the positive and negative predictive values of a strategy that uses ultrasonography as the initial test are estimated to be 96% and 98%, respectively. If the prob-ability of biliary obstruction is 60%, a strategy that uses ultra-sonography as the first test would yield a positive predictive value of 99%, whereas the negative predictive value would fall to 89%. The implication is that if the level of suspicion for biliary tract obstruction is high and ultrasonography does not show dilated bile ducts, further studies to visualize the biliary tract should be pursued.

Therefore, in jaundiced patients in whom biliary obstruc-tion is a possibility, abdominal ultrasonography (or CT) is an appropriate initial approach. If the bile ducts are dilated, the biliary tract should be imaged directly with ERCP (or percu-taneous THC) and appropriate therapy undertaken if biliary obstruction is found. If the bile ducts are not dilated on abdominal ultrasonography (or CT), the next step depends on the clinical likelihood of biliary obstruction. If the likelihood of biliary obstruction is thought to be low, the patient should be evaluated for intrinsic liver disease (see later). If the likeli-hood of biliary obstruction is believed to be intermediate, EUS or MRCP is a reasonable next step prior to biliary intervention or evaluation for a hepatic disorder.68 Among patients in whom biliary obstruction is believed to be likely, ERCP (or percutaneous THC) should be considered as the next step. If ERCP or percutaneous THC does not show biliary obstruc-tion, the patient should be evaluated for cholestatic liver disease. The choice between ERCP and percutaneous THC will be influenced by various factors (see Table 21-4), includ-ing the availability of each procedure at a particular institu-tion, presence or absence of dilated bile ducts on initial imaging, and suspected level of biliary obstruction. Under most circumstances, ERCP should be the procedure of choice because it is comparable to percutaneous THC in accuracy, technical success rate, and frequency of major complications; tends to be more widely available; and may offer better post-procedure tolerability (e.g., no need for an external biliary drainage tube).

Other Studies

Serologic TestingWhen imaging studies do not suggest biliary obstruction, jaundiced patients with biochemical evidence of hepatocellu-lar dysfunction or cholestasis should be evaluated for underly-ing liver disease. Depending on the disorder suspected, screening laboratory studies may include viral serologies; serum levels of iron, transferrin, and ferritin (for hemochro-matosis); ceruloplasmin (for Wilson disease); antimitochon-drial antibodies (for PBC); antinuclear antibodies, smooth muscle antibodies, and serum immunoglobulins (for autoim-mune hepatitis); and tissue transglutaminase antibodies (for celiac disease). Confirmation of these diagnoses, as well as elucidation of diagnoses not revealed by serologic analysis, may be made by liver biopsy (or small bowel biopsy in the case of celiac disease).



infants (e.g., physiologic jaundice of the newborn, type I Crigler-Najjar syndrome). In these disorders, the risk of neu-rotoxicity can be reduced with phototherapy, in which expo-sure to blue or green light produces photoisomerization of bilirubin to more water-soluble enantiomers that do not require conjugation for excretion in bile.10,70 One study has suggested that orlistat, which increases intestinal fat excretion, traps unconjugated bilirubin intraluminally and can augment phototherapy- or phenobarbital-induced reduction of uncon-jugated hyperbilirubinemia in children with type I or type II Crigler-Najjar syndrome, respectively,71 but this observation has not yet been confirmed.

Ursodeoxycholic acid (ursodiol), a bile acid that potently stimulates bile flow, has been studied as a treatment for several cholestatic disorders.72 Ursodeoxycholic acid improves biochemical indices and appears to slow disease progression in PBC (see Chapter 91). Ursodeoxycholic acid has also been shown to improve biochemical markers and clinical outcomes in patients with intrahepatic cholestasis of pregnancy,73 and pilot studies have suggested that it is helpful in improving biochemical indices of cholestasis related to parenteral nutri-tion74,75 and in preventing cholestasis following hematopoietic cell transplantation.76,77 By contrast, although initial pilot studies suggested that ursodeoxycholic acid reversed cho-lestasis in PSC, a long-term benefit of this agent in this disorder has not been demonstrated to date in randomized controlled trials (see Chapter 68). Additional treatments for cholestatic disorders are directed toward complications other than hyperbilirubinemia. One complication is impaired absorption of fat-soluble vitamins (A, D, E, K), and supple-mentation of the deficient vitamins is recommended. Management of pruritus caused by cholestasis is discussed in Chapter 91.

KEY REFERENCESFull references for this chapter can be found on www.expertconsult.com.

1. Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol 2003; 38:107-17.

2. Fevery J. Bilirubin in clinical practice: A review. Liver Int 2008; 28:592-605.

6. Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 2007; 453:643-59.

Liver BiopsyLiver biopsy provides precise information regarding lobular architecture and the extent and pattern of hepatic inflamma-tion and fibrosis and is most helpful for patients with persis-tent and undiagnosed jaundice. With special histologic stains (and if appropriate, quantification of iron or copper content), liver biopsy permits the diagnosis of viral hepatitis, fatty liver disease, hemochromatosis, Wilson disease, PBC, granuloma-tous hepatitis, and neoplasms. Occasionally, liver biopsy spec-imens provide clues to otherwise unsuspected biliary tract obstruction, the histologic features of which are shown in Figure 21-3; however, liver histology may be entirely normal in acute biliary obstruction. Liver biopsy is associated with a low but definite complication rate, predominantly from bleed-ing and perforation, and the need for hospitalization in 1% of cases; the mortality rate is about 0.01%.69

THERAPEUTIC APPROACHES

Obstructive JaundiceIn the patient with bile duct obstruction, therapy is typically directed at relieving the obstruction. Interventional endo-scopic or radiologic approaches include sphincterotomy, balloon dilation of focal strictures, and placement of drains or stents (see Chapter 70); the alternative approach is surgery (see Chapters 66 and 69). The therapeutic strategy chosen depends in part on the location and likely cause of the obstructing lesion. Focal intrahepatic strictures may be ame-nable to an interventional radiologic approach, whereas lesions distal to the bifurcation of the hepatic ducts may be more suitably managed endoscopically (e.g., sphincterotomy for choledocholithiasis); neoplasms generally require surgery if feasible.

Nonobstructive JaundiceWhen jaundice is due to liver disease, optimal treatment is directed toward the underlying cause (e.g., cessation of ethanol, discontinuation of the offending drug, administration of antiviral therapy for hepatitis B, immunosuppressive agents for autoimmune hepatitis). Therapy for hyperbilirubinemia per se is generally unnecessary in adults because the neuro-toxicity of bilirubin is limited to disorders characterized by extreme elevations of unconjugated bilirubin in neonates and

FIGURE 21-3. Liver histology in biliary tract obstruction. A, Prominent bile duct proliferation (arrows) and a mixed portalbased inflammatory infiltrate are evident. Periportal hepatocytes show feathery degeneration (arrowheads) indicative of cholate stasis, cytologic changes caused by prolonged cholestasis (H&E, ×200). B, The periportal bilirubinstained region (arrow) surrounded by necrotic cells represents a bile infarct (H&E, ×40).

A B


http://www.expertconsult.com


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27. Padda MS, Sanchez M, Akhtar AJ, et al. Drug-induced cholestasis. Hepatology 2011; 53:1377-87.

28. van der Woerd WL, van Mil SW, Stapelbroek JM, et al. Familial cholestasis: Progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol 2010; 24:541-53.

30. Lam P, Soroka CJ, Boyer JL. The bile salt export pump: Clinical and experimental aspects of genetic and acquired cholestatic liver disease. Semin Liver Dis 2010; 30:125-33.

38. Brienza N, Dalfino L, Cinnella G, et al. Jaundice in critical illness: Promoting factors of a concealed reality. Intensive Care Med 2006; 32:267-74.

72. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006; 3:318-28.

7. Borst P, de Wolf C, van de Wetering K. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 2007; 453:661-73.

8. van de Steeg E, Stranecky V, Hartmannova H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122:519-28.

9. Geier A, Wagner M, Dietrich CG, et al. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta 2007; 1773:283-308.

10. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008; 358:920-8.

12. Labori KJ, Raeder MG. Diagnostic approach to the patient with jaundice following trauma. Scand J Surg 2004; 93: 176-83.

16. Geier A, Wagner M, Dietrich CG, et al. Principles glucuronidation. Hepatology 2012; 55:1912-21.


Chapter 21 Jaundice 348.e1

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J Hepatol 2003; 38:107-17.2. Fevery J. Bilirubin in clinical practice: A review. Liver Int

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4. Buyukkale G, Turker G, Kasap M, et al. Neonatal hyperbilirubinemia and organic anion transporting polypeptide-2 gene mutations. Am J Perinatol 2011; 28:619-26.

5. Wang P, Kim RB, Chowdhury JR, et al. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J Biol Chem 2003; 278:20695-9.

6. Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 2007; 453:643-59.

7. Borst P, de Wolf C, van de Wetering K. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 2007; 453:661-73.

8. van de Steeg E, Stranecky V, Hartmannova H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122:519-28.

9. Geier A, Wagner M, Dietrich CG, et al. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta 2007; 1773:283-308.

10. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008; 358:920-8.

11. Kamath PS, Kim WR. The Model for End-stage Liver Disease (MELD). Hepatology 2007; 45:797-805.

12. Labori KJ, Raeder MG. Diagnostic approach to the patient with jaundice following trauma. Scand J Surg 2004; 93:176-83.

13. Vavricka SR, Van Montfoort J, Ha HR, et al. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 2002; 36:164-72.

14. Campbell SD, de Morais SM, Xu JJ. Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol Interact 2004; 150:179-87.

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