Inherited disorders associated with conjugated hyperbilirubinemia in adults

INTRODUCTION — Conditions that cause hyperbilirubinemia can be classified into those that result in a predominantly unconjugated hyperbilirubinemia and those that are associated with an elevation of both conjugated and unconjugated forms of bilirubin. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

Excretion of conjugated bilirubin is impaired in a number of acquired conditions (such as alcoholic and viral hepatitis, biliary obstruction, cholestasis of pregnancy) and in inherited disorders (such as Dubin-Johnson syndrome, Rotor syndrome, benign recurrent intrahepatic cholestasis). This topic review will discuss the inherited disorders associated with conjugated hyperbilirubinemia. The other conditions are presented separately. (See appropriate topic reviews).

CLASSIFICATION — Elimination of conjugated bilirubin in bile is affected in several inherited disorders that work through different mechanisms. In all these situations, the abnormality of biliary excretion of bilirubin is shared with excretory defect of all or some other organic anions. Inherited syndromes of intrahepatic cholestasis commonly result from mutations in the following genes: SERPINAI (alpha 1- antitrypsin), JAG1 (causing Alagille syndrome), ATP8B1 (also known as FIC1), ABCB11 (bile salt export pump [BSEP]), MDR3 (ABCB4), and MRP2 (causing Dubin-Johnson syndrome). The genetic basis of Rotor syndrome has not been identified [1].

Although Dubin-Johnson syndrome and Rotor syndrome have similar phenotypes (mild, fluctuating elevation of both unconjugated and conjugated bilirubin in plasma), in Dubin-Johnson syndrome biliary excretion of organic anions, except bile acids, is impaired, while Rotor syndrome is a disorder of hepatic storage. Other inherited conditions, like progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis, cause conjugated hyperbilirubinemia as a consequence of reduced bile flow [2].

DUBIN-JOHNSON SYNDROME — In 1954, Dubin and Johnson [3] and Sprinz and Nelson [4] described patients with predominantly conjugated chronic hyperbilirubinemia that was not associated with hemolysis. The disorder occurs in males and females of all races and nationalities [4-7]. It is rare except in Sephardic Jews in whom the incidence is approximately 1:3000 [7].

Clinical features — Dubin-Johnson syndrome is characterized clinically by mild icterus. Otherwise, patients are asymptomatic, although mild constitutional complaints such as vague abdominal pains and weakness can occur. Icterus can be so mild as to be noted only during intercurrent illnesses, pregnancy, or consumption of oral contraceptives [6]. Pruritus is not seen in this condition. Physical examination is usually normal except for the icterus, although hepatosplenomegaly is seen occasionally.

Laboratory tests — Routine clinical laboratory tests, including the complete blood count, serum albumin, cholesterol, alanine and aspartate aminotransferases, alkaline phosphatase, and prothrombin time, are normal [5-7]. Fasting and postprandial bile acid levels, which are sensitive indices of liver disease, are normal, reflecting the fact that the genetic abnormality does not affect the transport of most bile acids. Serum bilirubin concentrations are usually between 2 and 5 mg/dL but may decline to normal levels or be as high as 20 to 25 mg/dL. Approximately 50 percent of the serum bilirubin is conjugated. Of the conjugated bilirubin, a major fraction is bilirubin diglucuronide. In addition, covalently albumin-bound fraction is found in plasma. Bilirubinuria is common.

Oral cholecystography, using even a double dose of the contrast material is unsuccessful in visualizing the biliary system. Visualization may, however, be possible four to six hours after intravenous administration of Iodipamide [8,9].

Grossly, the liver is black [4]. It is histologically normal except for the presence of a dense pigment (picture 1). Electron microscopy reveals that the pigment is contained in the lysosomes [10]. Electron spin resonance spectroscopy suggests that the pigment is composed of polymers of epinephrine metabolites [11]. Computerized tomography of patients with Dubin-Johnson syndrome shows a significantly higher attenuation as compared with normal subjects [12].

Organic anion transport defect — Uptake of organic anions at the sinusoidal surface of hepatocytes is normal in Dubin-Johnson syndrome, as shown by normal initial plasma clearance of intravenously administered bilirubin [13,14], bromosulfophthalein (BSP) [7,14,15], dibromosulfophthalein (DBSP) [15], indocyanine green (ICG) [14,15], and 125I-labeled rose bengal [15]. However, in 90 percent of patients, plasma BSP concentration shows a secondary increase 90 minutes after intravenous administration [6,7,16]. The secondary rise reflects regurgitation of glutathione-conjugated BSP from hepatocytes to the plasma. A similar secondary rise is seen after intravenous injection of unconjugated bilirubin [11,14], but not after injection of substances, such as DBSP, ICG, and 125I-labeled rose bengal, which are not conjugated prior to excretion [14,15]. Although the secondary rise is characteristic of Dubin-Johnson syndrome, it is not diagnostic by itself, because it is also seen in hepatobiliary cholestatic disorders. In addition, BSP testing is no longer performed.

Urinary coproporphyrin excretion — The total urinary coproporphyrin is normal in Dubin-Johnson syndrome, but over 80 percent of it is coproporphyrin I, in contrast to normal subjects in whom 75 percent of urinary coproporphyrin is coproporphyrin III [17,18].

Clotting factor VII deficiency — Reduced prothrombin activity, resulting from lower levels of clotting factor VII, is found in 60 percent of the patients with Dubin-Johnson syndrome. Factor VII deficiency is most common among Sephardic Jews originating from Iran, Iraq, and the neighboring areas [19-21]. However, reduced factor VII levels are also found among patients from other communities. In some families, the two disorders segregate independently, indicating that the linkage is not tight.

Animal models — A metabolic defect in Corriedale sheep resembles what is seen in Dubin-Johnson syndrome. Organic anion transport defects and urinary coproporphyrin excretion patterns are similar to patients with Dubin-Johnson syndrome [22-26]. However, the most widely used model is the TR-rat [25-29]. In these rats, biliary excretion of conjugated bilirubin and other organic anions is impaired. The predominant coproporphyrin in urine is coproporphyrin I [17].

Lysosomal accumulation of black pigments in the liver occurs after feeding a diet enriched with amino acids [25]. Breeding studies show an autosomal recessive inheritance pattern and suggest that the abnormality of a single gene is responsible for the disease. The Golden lion tamarin monkey, which manifests conjugated hyperbilirubinemia, is another animal model for Dubin-Johnson syndrome [30].

Molecular mechanism — Non-bile acid organic anions, such as conjugated bilirubin and other glucuronide or glutathione conjugated substances, are transported into the bile canaliculus from the hepatocyte by the multidrug resistance related protein, MRP2 (also known as the canalicular multispecific organic anion transporter, cMOAT), which is encoded by the ABCC2 gene (figure 1) [23,31-34].

The transport is ATP-dependent and is achieved against high concentration gradients. The electrochemical gradient created by the negative intracellular potential of -35 mV also contributes to the transport of bilirubin glucuronides [22,28,35] into the bile canaliculus. MRP2 is one of the ATP-binding cassette (ABC) transporters [36]. Direct evidence for its involvement in canalicular transport came from the discovery of a frameshift mutation in the gene encoding it in the TR-rat [37].

The human MRP2 gene has been localized to chromosome 10q23-q24 [38]. The exon-intron organization has been elucidated [39,40] and the human cDNA has been isolated based upon homology with rat MRP2 [41]. Several different mutations (figure 2) have been identified in this gene in patients with Dubin-Johnson syndrome [39-44]. Mutations in the ATP-binding region, critical for the functioning of the protein, form a significant proportion of the genetic lesions identified [40,42]. One mutation causes impaired maturation and mislocalization of the protein (mutation "h" in the figure) (figure 2) [45]. A mutation at an intronic splice donor site was identified in a patient with Dubin-Johnson syndrome [43]. Autosomal recessive inherence has been confirmed based upon urinary coproporphyrin analysis in families of affected individuals [46,47].

Diagnosis — The diagnosis of Dubin-Johnson syndrome can be made by documenting conjugated hyperbilirubinemia (where at least 50 percent of the total bilirubin is the direct fraction) while the rest of the "liver function profile" (serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, and prothrombin time) are normal, together with the characteristic urinary coproporphyrin excretion. (See 'Urinary coproporphyrin excretion' above and 'Diagnosis and differentiation from Dubin-Johnson syndrome' below.)

Management — Dubin-Johnson syndrome is a benign condition and no treatment is required. However, it is important to recognize the condition so as not to confuse it with other hepatobiliary disorders associated with conjugated hyperbilirubinemia.

ROTOR SYNDROME — Rotor syndrome is a rare disorder, first described in 1948 by Rotor, Manahan, and Florentin. Since then, it has been reported in several nationalities and races.

Clinical features — The syndrome is characterized by chronic conjugated and unconjugated hyperbilirubinemia without evidence of hemolysis [48]. Although Rotor syndrome had been thought previously to be a variant of Dubin-Johnson syndrome [49], the two conditions are now understood to be different entities [50]. In Rotor syndrome, there is a defect in hepatic reuptake of conjugated bilirubin, which is secreted into the plasma by hepatocytes located upstream to the sinusoidal blood flow, resulting in hyperbilirubinemia. In addition, elevated plasma levels of bile acids glucuronidated at the C‐3 position have been reported [51]. Rotor syndrome is also a benign condition.

Laboratory tests — Serum alkaline phosphatase, alanine aminotransferase, aspartate amino transferase and gamma-glutamyl transpeptidase levels are normal. Plasma clearance of bromophthalein sodium (BSP) is delayed, but unlike in Dubin-Johnson syndrome, biphasic peaks are not seen [52]. Patients exhibit prolonged retention of intravenously injected unconjugated bilirubin and indocyanine green [53]. Transport studies for BSP show a 50 percent reduction in transport maximum of this compound in Rotor syndrome, compared to almost no biliary transport in Dubin-Johnson syndrome [52,53]. In contrast to the finding in Dubin-Johnson syndrome, the gallbladder is usually visualized by oral cholecystography [49].

Liver histology is normal [49]. The absence of dark melanin-like pigments differentiates this disorder from Dubin-Johnson syndrome. However, liver biopsy is not required for the differentiation, which can be done on the basis of urinary coproporphyrin analysis (see below).

Urinary coproporphyrin excretion — The total urinary coproporphyrin excretion is increased to 250 to 500 percent of normal and coproporphyrin I constitutes approximately 65 percent of urinary porphyrins [50,54]. In obligate heterozygotes, the pattern of excretion is intermediate between that of patients with Rotor syndrome and controls. With respect to coproporphyrin excretion, Rotor syndrome is inherited as an autosomal recessive condition and is distinct from Dubin-Johnson syndrome [54]. However, the molecular basis of the hepatic storage defect in Rotor syndrome has not been elucidated.

Molecular mechanism — Bilirubin entering the liver sinusoids is extracted efficiently by hepatocytes that are closest to the points of entry, the portal vein and hepatic artery. As canalicular excretion of conjugated bilirubin is rate limiting in bilirubin excretion, this leads to the possibility of saturation of the excretion process. Bilirubin excretory capacity of the liver is increased by transport of conjugated bilirubin back into the sinusoidal blood through the sinusoidal surface of the hepatocytes via the ATP-hydrolysis dependent pump, ABCC3. Bilirubin undergoes re-uptake by hepatocytes downstream to the sinusoidal blood flow via organic anion transporter proteins 1B1 and 1B3 (OATP1B1 and OATP1B3), encoded by SLCO1B1 and SLCO1B3, respectively. This re-uptake process results in recruitment of additional hepatocytes downstream to the sinusoidal blood flow, thereby increasing the bilirubin excretory capacity of the liver [55]. OATP1B1 and OATP1B3 have functional overlap. Inactivating mutations or deletion of both SLCO1B1 and SLCO1B3 disrupts this re-uptake process, resulting in Rotor syndrome [56].

Notably, mutations of OATP1B1 or OATP1B3 alone do not cause jaundice. However, these transporters mediate the uptake of many other compounds, including several drugs. Reduced-activity OATP1B1 resulting from polymorphisms can result in life-threatening drug toxicities, such as statin-associated myopathy [57]. Therefore, great caution should be used in treating patients with Rotor syndrome with drugs that undergo transport by these proteins.

Diagnosis and differentiation from Dubin-Johnson syndrome — Dubin-Johnson and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-reacting fraction of approximately 50 percent) in the absence of other abnormalities of standard liver function tests. Normal levels of serum alkaline phosphatase and gamma-glutamyltranspeptidase help to distinguish these conditions from disorders associated with biliary obstruction.

The urinary coproporphyrin excretion pattern assists in the diagnosis and in the distinction between these disorders.

In Dubin-Johnson syndrome, the total urinary coproporphyrin excretion is normal but 80 percent is coproporphyrin I (in normal subjects 75 percent of urinary porphyrins are coproporphyrin III). In contrast, in patients with Rotor syndrome, total urinary coproporphyrins are increased to 250 to 500 percent of normal with approximately 65 percent being coproporphyrin I.

The plasma BSP clearance can also be used to aid in the distinction between these disorders, although it is no longer available for routine clinical use. In Dubin-Johnson syndrome, plasma BSP clearance shows a characteristic biphasic peak. Retention of the dye is nearly normal 45 minutes after injection, but there is a secondary peak at 90 minutes. In Rotor syndrome, there is increased retention at 45 minutes and no secondary peak is seen.

Liver biopsy is not necessary for the diagnosis of either condition. However, if a biopsy is performed for other clinical indications, the dense pigmentation of the liver seen in Dubin-Johnson syndrome (picture 1) distinguishes it from Rotor syndrome.

Pregnancy — In both Dubin-Johnson and Rotor syndromes, serum bilirubin levels may increase during pregnancy, requiring differentiation from cholestasis of pregnancy. The latter is usually associated with pruritus, which is not a feature of Dubin-Johnson or Rotor syndromes [58].

Treatment — As in Dubin-Johnson syndrome, Rotor syndrome does not require treatment. However, the diagnosis is important to avoid confusion with other hepatobiliary diseases.

FAMILIAL HEPATOCELLULAR CHOLESTASIS

Progressive familial intrahepatic cholestasis — Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders, characterized by defective secretion of bile acids or other components of bile. With the exception of benign recurrent cholestasis (BRIC), these disorders usually present during infancy or childhood, and are associated with growth failure and progressive liver disease. Many patients present with a coagulopathy due to vitamin K malabsorption. Intractable pruritus is a dominant feature in the early stages of PFIC I and II.

Progressive familial intrahepatic cholestasis type I — Progressive familial intrahepatic cholestasis type I (PFIC I), also known as Byler disease [59] and Greenland familial cholestasis [60], is caused by a mutation in the P-type ATPase gene (ATP8B1), FIC1, which has been localized to chromosome 18q21 [61]. FIC1 is located in the canalicular membrane of hepatocytes and in cholangiocytes, and couples the hydrolysis of ATP to the translocation of acidic phospholipids [62]. How the mutation of FIC1 causes cholestasis and abnormal bile acid transport is not clear.

Progressive familial intrahepatic cholestasis type II — Progressive familial intrahepatic cholestasis type II (PFIC II) resembles Byler disease clinically but occurs in non-Byler families, mainly in the Middle East and Europe. It is caused by defects in the gene that codes for the sister P-glycoprotein (SPGP) [63], also known as bile salt export pump (BSEP) (figure 1), which is an ATP-dependent transporter of bile acids from the hepatocytes into the bile canaliculus [2]. The SPGP gene (ABCB11) has been localized to chromosome 2q24 [63]. Over 80 different mutations in SPGP have been described in patients with PFIC II [64]. Studies in rats suggest that the mechanisms leading to impaired bile acid transport vary depending upon the specific mutation [65].

PFIC I and PFIC II are both associated with life-threatening cholestasis. Interestingly, despite this, serum gamma-glutamyl transpeptidase levels are normal or nearly so in both these disorders [66].

Hepatocellular carcinoma (HCC), which is rare in young children, has been reported in ten children less than five years of age with PFIC-II. Thus, ABCB11 mutations represent a previously unrecognized risk for HCC in young children [67].

Liver transplantation ameliorates all manifestations of PFIC II, specifically hepatic expression of SPGP. However, in approximately 8 percent of children with PFIC II caused by different ABCB11 mutations, the disease recurred after liver transplantation, probably as a consequence of the development of high titer antibodies against BSEP and deposition of these antibodies, as well as the complement component protein C4d in liver sinusoids [68-71]. Recurrent BSEP disease may be ameliorated by antibody-depletion therapies, such as a monoclonal antibody against the CD20 antigen of B-cells (eg, rituximab) with or without plasmapheresis [71]. As in the case of ATP8B1, some mutations of ABCB11 are associated with a more benign and recurrent course, presenting in adult cases. As in the case of ATP8B1, some mutations of ABCB11 are associated with a more benign and recurrent course, presenting in adult cases. (See 'Benign recurrent intrahepatic cholestasis' below.)

Treatment with 4-phenylbutyrate may be beneficial in the subset of patients with ABCB11 missense mutations that affect BSEP trafficking to the canalicular membrane. In transfected cell lines, 4-phenylbutyrate has been shown to partially correct mistrafficking of BSEP [72,73]. In a study of four patients with this type of mutation, treatment with 4-phenylbutyrate resulted in improvements in pruritus, serum bile acid concentration, and serum liver tests [74]. In addition, canalicular localization of BSEP was demonstrated by immunostaining of liver biopsies obtained in three of the patients after 4-phenylbutyrate therapy.

Progressive familial intrahepatic cholestasis type III — Progressive familial intrahepatic cholestasis type III (PFIC III), involves mutations in the ABCB4 gene (also known as multidrug resistance protein-3 P-glycoprotein [MDR3 or PGY3]) (figure 1) [75]. MDR3 is thought to replenish the phosphatidylcholine in the outer lipid membrane of the bile canaliculus by translocating it from the inner lipid layer. However, bile salt secretion remains normal. In the absence of phosphatidylcholine translocation, bile acids are thought to damage the canalicular membrane, causing progressive destruction of small bile ducts [76,77]. PFIC III, which is caused by mutations on both alleles, is distinguished from PFIC I, BRIC, and PFIC II by the markedly elevated gamma-glutamyl transpeptidase activity in the serum [66].

Heterozygous mutations in ABCB4 can reduce biliary phospholipid concentration, resulting in increased risk for cholesterol stones, microlithiasis, or sludge, a syndrome known as low phospholipid-associated cholestasis (LPAC). LPAC should be suspected in patients presenting with cholelithiasis before age 40, recurrence after cholecystectomy, and intrahepatic hyperechogenic foci compatible with sludge or microlithiasis [78]. Many patients have a family history of cholelithiasis in first-degree relatives or a clinical history of intrahepatic cholestasis of pregnancy [79]. (See "Intrahepatic cholestasis of pregnancy".)

Approximately one-third of adult patients presenting with unexplained cholestasis have mutations in the coding region of at least one ABCB4 allele [80]. ABCB4 mutations also cause acute recurrent biliary pancreatitis, biliary cirrhosis, and fibrosing cholestatic liver disease in adults with or without biliary symptoms [80,81].

Progressive familial intrahepatic cholestasis type IV — Severe chronic cholestatic liver disease, with serum GGT levels that were low for the degree of cholestasis (similar to that found in PFIC I and II) were reported in 33 children from 29 families [82]. Genetic analysis showed protein-truncating mutations in the TJP2 gene that expresses tight junction protein 2. The truncation of TJP2 protein resulted in failure of its incorporation in tight junctions delimiting the bile canaliculi. This causes the failure of claudin1 (CLDN1) to localize in the cholangiocyte-cholangiocyte borders and margins of bile canaliculi. Interestingly, the pathology appears to be limited to the liver. There were no mutations of ABCB11 or ATP8B1 genes that are responsible for PFIC I and PFIC II, respectively. As in many other rare monogenic disorders, there was a high incidence of consanguinity, which was observed in 18 parents in the 29 families. Two infants with PFIC IV have been reported to develop hepatocellular carcinoma [83]. One had a single tumor and the other had a large number of multifocal tumors.  

Treatment — Initial care for patients with PFIC addresses the nutritional problems and pruritus caused by chronic cholestasis. Fat-soluble vitamin supplementation and monitoring is necessary, as for other forms of chronic cholestasis. Initial therapy for patients with all forms of PFIC is ursodeoxycholic acid, which may improve liver function in some patients, especially those with PFIC III who often have less severe disease [84-86].

Pruritus may be the predominant symptom in many patients with PFIC. Although the mechanism of pruritus of cholestasis is not fully understood, several classes of pruritogens have been recognized: bile acids; the enzyme autotaxin, which cleaves lysophosphatidylcholine, forming lysophosphatidic acid [87]; endogenous opioids; the neurotransmitter serotonin; and unidentified pruritogens. A sequential approach is recommended for the treatment of pruritus [88].

The first line of treatment consists of modification or depletion of the bile salt pool. Ursodeoxycholic acid (UCDA), 15 mg/kg daily, a natural hydrophilic bile acid, should be tried to partially replace the endogenous bile acid pool by competition for ilial bile acid absorption [89]. If pruritus is not relieved by UCDA, depletion of the bile acid pool should be attempted. Conventionally, this has been done by administering cholestyramine (1 to 4 g/day), an oral bile acid binding resin that forms non-absorbable micelles with the bile acids in the intestines, thereby disrupting the enterohepatic recycling of bile acids [90]. Cholestyramine can cause constipation and can interfere with the absorption of fat-soluble vitamins and certain drugs. Therefore, it should be administered at least one hour before or four to six hours after meals or other drugs.

In patients who are not adequately relieved of pruritus by cholestyramine, an alternative approach to reduce serum bile acid levels consists of pharmacologic inhibition of ileal sodium/bile acid transport by the non-absorbable small molecule drugs, odevixibat [91] or maralixibat [92], which are reversible inhibitors of the ilial sodium/bile acid transporter. Both drugs have been approved for the treatment of pruritus in patients with PFIC, with the exception of a subgroup of PFIC-2, whose ABCB11 mutation leads to a severe bile acid/salt transport defect, so that bile acid secretion into the bile is negligible. Diarrhea is a significant side effect of these drugs because of the effect of the unabsorbed bile acids on the colonic epithelium. Bile acid depletion can result in the deficiency of fat-soluble vitamins (A,D, E, and K), causing coagulation disorders and bone fracture. Therefore, baseline serum levels of these vitamins should be established before starting the treatment and followed up intermittently to determine the need for supplementation and possible treatment interruption. Both drugs can cause hepatotoxicity. Therefore, serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, bilirubin levels, and prothrombin time (INR) should be determined before initiation of treatment and every six to eight months during the course of the treatment for potential dose adjustment or discontinuation of these drugs. Odevixibat is stated at 40 mcg/kg, orally once daily in the morning with a meal. If after three months the clinical response remains inadequate, the dose may be increased in 40 mcg/kg increments up to 120 mcg/kg once daily, not exceeding 6 mg daily. Maralixibat is administered orally 30 minutes before a meal in the morning, starting at 190 mcg/kg orally once daily for a week, and then increasing to 380 mcg/kg once daily, as tolerated, not exceeding 28.5 mg. If cholestyramine needs to be used in addition to either odevixibat or maralixibat, it should be administered at least four hours apart from these drugs.

The second line of therapy aims at increasing the metabolism and excretion of pruritogens using rifampicin, a pregnane X-receptor (PXR) agonist and a potent inducer of key enzymes in hepatic and intestinal detoxification, and the export pump MRP2 [93]. Rifampicin reduces serum autotaxin levels. Because of an approximately 5 percent incidence of drug-induced liver injury in children, rifampicin should be initiated at a low dose (150 mg/day), with serial monitoring of serological liver tests and blood count, before escalating the dose to maximum of 600 mg/day [93]. If rifampin therapy fails to reduce itching, the third line of therapy should be naltrexone, the oral opioid antagonist, at a dose of 50 mg daily [94]. Naltrexone should be started at a low dose of 12.5 mg and increased by one-quarter every three to seven days to avoid the self-limited withdrawal-like syndrome in the first days of treatment caused by dissociation of endogenous opioids from their receptors [95]. To prevent a "break-through" phenomenon during long-term therapy, naltrexone may be withheld two days a week. Finally, the selective serotonin reuptake inhibitor sertraline, which increases neurotransmitter concentrations within the central nervous system [96], may be considered as a fourth-line treatment for patients resistant to above mentioned treatments. Sertraline is started at 25 mg/day, increasing gradually to 75 to 100 mg/day, and can be also used in addition to rifampicin therapy.

In some patients, pruritus may be refractory to pharmacologic intervention. In these patients, surgical procedures to interrupt the enterohepatic circulation of bile acids are often successful. This can be done by diverting part of the bile flow to an external fistula, where it is discarded [97-99]. Biochemical improvements are often seen, suggesting that the diversion procedure might slow the progression of liver disease [99-101]. Liver transplantation is generally curative for patients with PFIC I, II, and IV. However, patients with PFIC I may have ongoing disease due to the extrahepatic expression of FIC I [102,103].

Liver transplantation is an important option for patients with end-stage liver disease due to PFIC and for some patients with pruritus that is unresponsive to the measures described above [104]. Liver transplantation is generally curative for patients with PFIC. However, patients with PFIC I may have ongoing disease due to the extrahepatic expression of FIC I [105]. In a case report, post-liver transplantation steatohepatitis in a two-year-old patient with PFIC I was ameliorated after performing a total internal biliary diversion [106]. About 8 percent of patients receiving liver transplantation for PFIC-II develop recurrence of BSEP deficiency due to the development of anti-BSEP antibody [107]. Antibody-induced BSEP deficiency (AIBD) is treated with increased immunosuppression, but a second liver transplantation may be needed, which is associated with a high mortality rate. AIBD has been reported to be reversed by allogeneic bone marrow transplantation in a PFIC II patient who had received liver transplantation [107].

Transplantation of normal hepatocytes to repopulate the liver and replace the dying cells has been tried in a mouse model of PFIC III, with partial restoration of phospholipid secretion in the bile [108,109].

Patients presenting with cholelithiasis associated with ABCB4 mutations may require endoscopic or surgical removal of gallstones. Replacement of endogenous lithogenic bile acids with hydrophilic bile acids, such as ursodeoxycholic acid, has been proposed for prevention of cholelithiasis in these patients. Ursodeoxycholic acid (15 mg/kg body weight daily) has been used successfully in several adult patients [79,80].

Benign recurrent intrahepatic cholestasis — Benign recurrent intrahepatic cholestasis (BRIC), first described in 1959, is characterized by intermittent cholestatic episodes [110]. Age at first presentation ranges from infancy to late adulthood. The number of attacks can range from several episodes per year to one episode in a decade [111-114]. During the attacks, the patients present with conjugated hyperbilirubinemia, malaise, anorexia, pruritus, weight loss, and malabsorption. Laboratory tests reveal biochemical evidence of cholestasis without severe hepatocellular injury [112,115,116]. Such episodes last for weeks to months followed by a complete clinical, biochemical, and histologic normalization. In a given patient, recurrent attacks resemble each other in symptoms, signs, and duration, although the severity and frequency of the episodes appear to decrease with age. BRIC has long been thought to be associated with intrahepatic cholestasis of pregnancy and cholestasis associated with use of oral contraceptives. In one study, 11 members of kindred of whom three members had been affected by BRIC developed intrahepatic cholestasis of pregnancy, cholestasis associated with oral contraceptives, or both [111].

Liver histology reveals noninflammatory intrahepatic cholestasis without fibrosis, regardless of the number and severity of attacks. During remission, liver histology returns to normal whether examined by light or electron microscopy [117].

Family studies suggest a recessive inheritance pattern. Surprisingly, this relatively benign disorder was also found to be associated with mutations of ATP8B1 (FIC I) and ABCB11 (BSEP) genes, which are associated with PFIC-1 and PFIC-II respectively. Mutations in ABCB11 (BSEP gene) have been also associated with BRIC [118]. As an example, a patient with clinical features of BRIC was found to have two different mutations on the two alleles of the ABCB11: A E186G substitution (previously described in a BRIC-2 case) and a V444A substitution (linked to intrahepatic cholestasis of pregnancy). The compound heterozygosity led to the absence of BSEP in bile canaliculi of hepatocytes. Bile salt excretion was reduced [119].

It has been proposed that BRIC caused by mutations of ATP8B1 and ABCB11 should be termed BRIC-1 and BRIC-2, respectively [118]. There are clinical differences between these two subtypes suggesting that it may be appropriate to subclassify BRIC into at least two distinct disorders (BRIC type 1 and 2). Pancreatitis is a known extrahepatic manifestation in BRIC caused by the ATPB1 mutations but not in BRIC patients with mutations in ABCB11. Similarly, cholelithiasis has been described in patients with the ABCB11 mutation but not in those with the ATP8B1 mutation [120].

Treatment — There is no specific treatment for BRIC. Liver transplantation is generally not considered because of the episodic and non-progressive nature of the disease, although the pruritus can be severe enough for the patient to seek liver transplantation. Short-term nasobiliary drainage has been reported to improve pruritus in a patient with BRIC, presumably by normalizing serum bile salt concentrations [121]. Rapid termination of cholestatic episode was reported in a 34-year-old man with BRIC and secondary renal impairment, following extracorporeal albumin dialysis in a molecular absorbent recycling system (MARS) [122]. Administration of colestimide, an anion exchange resin that inhibits intestinal bile acid absorption, resulted in rapid remission of the cholestatic episode in one patient [123].

BILE CANALICULAR AND STRUCTURAL ANOMALIES OF KNOWN GENETIC BASIS — The genetic basis of two disorders involving bile canalicular and structural anomalies has been described: Alagille syndrome and abnormalities of Villin gene expression.

Alagille syndrome — Alagille syndrome is characterized by the paucity of interlobular bile ducts and the following associated features [124-127]:

●Chronic cholestasis (approximately 90 percent)

●Cardiac anomalies, most commonly peripheral pulmonic stenosis (85 to 91 percent)

●Butterfly vertebrae (39 to 87 percent)

●Posterior embryotoxon (prominent Schwalbe line) of the eye (61 to 88 percent)

●Dysmorphic facies, consisting of broad nasal bridge, triangular facies, and deep-set eyes (77 to 95 percent)

Other minor abnormalities seen in these patients consist of growth and intellectual disability, developmental delay, renal disease, and pancreatic insufficiency. The syndrome is inherited as an autosomal dominant characteristic. The gene responsible for the condition (JAG 1) has been mapped to chromosome 20p12 [128].

Severe liver disease is a major cause of morbidity in patients with Alagille syndrome. The clinical manifestations and management of Alagille syndrome are discussed in detail separately. (See "Causes of cholestasis in neonates and young infants", section on 'Alagille syndrome' and "Alagille syndrome", section on 'Clinical features'.)

Chronic neonatal cholestasis due to ZFYVE19 deficiency — This neonatal onset chronic cholestatic disease is characterized by hepatosplenomegaly pruritus and elevation of serum GGT, ALT and AST, but hepatic protein synthetic function is retained [129-132]. The diagnosis was made by whole exon sequencing.

Liver histology reveals features seen in congenital hepatic fibrosis, and the condition often progresses to micronodular cirrhosis.

ANCHR (Abscission/NoCut Checkpoint Regulator), the protein product of ZFYVE19, is important in protein sorting to appropriate cellular sites. This zinc-finger protein mediates communication between proteins of the endosomal sorting complexes for transport-III (ESCRT-III) and the vacuolar protein sorting 4 (VPS4). ESCRT-III is required for polarized trafficking of ABCB11 (BSEP) to hepatocyte canalicular membrane [133]. ABCB11 deficiency causes PFIC-II. However, in contrast to PFIC-II, serum GGT levels are elevated consistently in patients with chronic cholestasis caused by ZFYVE19 mutation, suggesting the presence of additional pathogenetic mechanisms. Interestingly, during interphase and early mitosis, ANCHR is located mainly in centrosomes, which stabilize the primary cilium of bile duct epithelial cells. Destabilization of these primary cilia has been proposed as an additional mechanism of high-GGT cholestasis and hepatic fibrosis [133].

Treatment — Ursodeoxycholic acid has been useful in ameliorating pruitus in many cases. Odevixibat (an ileal sodium-bile acid co-transport inhibitor) has been reported to relieve pruritus and partially ameliorate serum GGT, ALT, and AST elevation in a single case report [131]. Several of the children have required liver transplantation [129]. Longer term follow-up is required to determine prognosis and to evaluate which patients will need liver transplantation.

Abnormal villin expression — This inherited disease is characterized by a biliary atresia-like presentation with special ultrastructural features. In a review of 50 children who underwent orthotopic liver transplantation for a clinical diagnosis of biliary atresia, three were found to have aberrant ultrastructural findings and a lack of villin expression in the bile canaliculi, as determined by immunohistochemical staining [134]. Each of these patients had clinical features of cholestasis including elevations in serum alkaline phosphatase (356 to 788 international units), gamma-glutamyl transpeptidase (76 to 203 U/L) and bilirubin (16 to 26 mg/dL). All patients had cirrhosis at the time of liver transplantation at the age of two to five years. Histologic examination of the liver showed paucity or absence of bile ducts and only a moderate degree of portal fibrosis at the age of three months, which distinguished these cases from classic biliary atresia. Electron microscopy revealed disordered canalicular microvilli, which were often inverted (ie, projected into the cytoplasm, rather than the canalicular lumen).

Absence of villin gene expression is thought to be the mechanism causing this disorder. Villin is a protein involved in binding actin and arranging actin fibers in bundles, which are necessary for generating and maintaining anatomically normal microvilli. The human villin gene has been mapped to chromosome 2q35-36 [135]. The protein is expressed in the microvilli of brush-border surfaces in the gastrointestinal tract and kidney [136]. Interestingly, patients with abnormal villin gene expression do not exhibit clinical features of malabsorption, pancreatic abnormality, or renal disease.

Villin gene knockout mice show an abnormal response to intracellular calcium and develop colonic ulcers when fed with dextran sulfate [137]. However, in contrast to the human cases, no obvious liver phenotype was found. The mechanistic basis of these discrepancies is unknown.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited liver disease".)

SUMMARY

●Elimination of conjugated bilirubin in bile is affected in several inherited disorders that work through different mechanisms. In all these situations, the abnormality of biliary excretion of bilirubin is shared with excretory defect of all or some other organic anions, bile salts, or phospholipids. (See 'Classification' above.)

●Dubin-Johnson syndrome is characterized clinically by mild icterus and is caused by defective canalicular excretion of conjugated bilirubin and many other organic anions. The liver is black. Otherwise, patients are asymptomatic, although mild constitutional complaints such as vague abdominal pains and weakness can occur. (See 'Dubin-Johnson syndrome' above.)

●Rotor syndrome is a rare disorder characterized by chronic conjugated and unconjugated hyperbilirubinemia without evidence of hemolysis. The defect is in the reuptake of the fraction of conjugated bilirubin, which is secreted into the sinusoidal blood by hepatocytes. (See 'Rotor syndrome' above.)

●Familial hepatocellular cholestasis includes several inherited disorders including progressive familial intrahepatic cholestasis (subclassified into three types) and benign recurrent intrahepatic cholestasis. (See 'Familial hepatocellular cholestasis' above.)

●Three genetic disorders characterized by bile canalicular and structural anomalies have been described: ZFYVE19 mutation, Alagille syndrome, and abnormal villin expression. (See 'Bile canalicular and structural anomalies of known genetic basis' above.)