A Patient with Persistent Pruritus

• ABSTRACT
• CASE HISTORY
• LIVER BIOPSY FINDINGS
• CLINICAL COURSE
• DISCUSSION
• ABBREVIATIONS
• REFERENCES

ABSTRACT

We present a patient with an initial and acute presentation of jaundice and marked persistent pruritus. Laboratory and radiology test results eliminated the possibility of acute hepatitis A/B/C viral infections, primary biliary cirrhosis, autoimmune hepatitis, Wilson disease, paraneoplastic cholestasis, and obstructive biliary disease. Centrilobular cholestasis was prominent in a liver biopsy specimen. Benign recurrent intrahepatic cholestasis (BRIC) was diagnosed through a review of the clinical history, available data, and the subsequent exclusion of other possible etiologies. The patient's clinical features resolved within 3 months of medical treatment.

CASE HISTORY

The patient is a 21-year-old woman who was initially seen for persistent pruritus of 3 week duration. She had no history of previously having had similar symptoms. Pruritus had been severe enough to affect the patient's sleep and mental concentration at school. Since its onset, relief had not been found with antihistamines, allergy medications, topical corticosteroids, or emollients. No new medications or herbal agents had been taken before the onset of pruritus. Passage of dark-colored urine was noted ~2 weeks before the consultation. Of note was a serum total bilirubin of 4.7 (normal: 0.1 to 1.2) mg/dL, along with mildly elevated liver enzyme activities (Table [1]).

Further test results were negative for acute hepatitis A/B/C viral infections, primary biliary cirrhosis, autoimmune hepatitis (including an anti-LKM antibody), and overt gallbladder disease. Ultrasonography had demonstrated a normal-appearing liver and a contracted gallbladder. Serum copper was mildly elevated; serum ceruloplasmin level and 24-hour urine copper were within the normal range. An evaluation by an ophthalmologist did not find Kayser-Fleischer rings.

The patient recalled having diarrhea 3 months earlier while traveling through Argentina. There was no history of smoking, alcohol abuse, or illicit drug use. The patient had been using a vaginal contraceptive agent (NuvaRing—containing both estrogen and progestin) for the past year.

Family history was negative for jaundice and/or pruritus; the patient's mother had been evaluated for primary biliary cirrhosis (and with negative results) 3 years earlier after being diagnosed with dermatographism. The patient's father underwent a liver biopsy for assessment of elevated liver chemistries 20 years earlier; results demonstrated mild hepatic fibrosis. The patient's brother has cholelithiasis.

LIVER BIOPSY FINDINGS

The core is somewhat disrupted. Only two intact portal tracts are present and one of them lacks a bile duct (Fig. [1A]). Slight portal fibrosis is noted. Portal inflammation and bile ductular reaction are both absent. The hepatic lobules reveal centrilobular canalicular cholestasis (Fig. [1B]), without pronounced rosetting or pseudoacinar change of hepatocytes. The bile is for the most part pallid rather than khaki-colored. A few flecks of bile are seen in the cytoplasm of hepatocytes. Accumulations of bile within Kupffer cells are not identified.

On immunostaining, slight deficiency of canalicular neutral endopeptidase (CD10) expression is noted in some, but not all, centrilobular regions (Fig. [2A]) as compared with control (Fig. [2B]), in which CD10 expression is intact along bile canaliculi throughout most of the lobule. Expression of gamma-glutamyl transpeptidase (GGT) is remarkably deficient throughout the lobule (Fig. [2C]) as compared with control (Fig. [2D]). The transport protein bile salt export pump (BSEP) and its homologue multidrug resistance-associated protein 2 (MRP2) are well-expressed along bile canaliculi throughout the lobule (not shown).

CLINICAL COURSE

Based on the analysis of her signs and symptoms, laboratory and radiologic test results, and liver histopathology findings, a diagnosis of benign recurrent intrahepatic cholestasis (BRIC) was made. Ursodiol 300 mg 3 times daily was added to cholestyramine after the liver biopsy results were known. Due to the difficulty of taking cholestyramine as a prescribed regimen while in school, this agent was substituted with rifampin. A gradual decrease of the patient's pruritus and jaundice was noted; the pruritus resolved 3 months after the consultation. Both ursodiol and rifampin were subsequently discontinued. NuvaRing use was resumed, without recurrence of pruritus or jaundice. Serum total bilirubin and liver enzyme values returned to within normal ranges.

One year later, the patient continued to report the absence of pruritus and jaundice; with her only medication the NuvaRing.

DISCUSSION

Benign recurrent intrahepatic cholestasis (BRIC) is an extremely rare clinical entity that is characterized by: recurrent episodes of jaundice, severe pruritus due to cholestasis, laboratory test values consistent with intrahepatic cholestasis, normal-to-minimally elevated GGT level, normal biliary system on imaging, liver histology showing centrilobular cholestasis, and absence of other factors associated with cholestasis.[1] Despite recurrent episodes, there is no evidence of permanent, progressive hepatic injury. In this patient's case, a diagnosis of BRIC was achieved after an exhaustive search for more common illnesses that would explain her symptoms. Because this was her first prolonged episode of pruritus, we did not initially consider BRIC as her diagnosis.

BRIC was first described in two patients from England in 1959,[2] but other reports of BRIC have been made in patients from various parts of the world (e.g., Europe, Africa, North and South America, and Japan).[3] [4] [5] [6] [7] [8] [9] Three subtypes of BRIC are now recognized. The prototypical variant, BRIC1, is the one initially described by Summerskill and Walshe.[2] It results from a particular mutation in the gene for the phosphatidyl serine flippase PFIC1 (ATP8B1), other mutations that are associated with progressive familial intrahepatic cholestasis type 1 and several other cholestatic syndromes.[10] BRIC2 is the consequence of mutations in the bile salt excretory pump (BSEP, or ABCB11)[11] while BRIC3 results from the loss of MDR3 or ABCB4, a phosphatidyl choline floppase.[12] Although most cases of BRIC are sporadic, an autosomal recessive type of inheritance has been described.[9]

The first attack of pruritus and jaundice in BRIC generally occurs during the patient's late teens or early twenties,[3] [13] [14] [15] although the diagnosis can be made at an earlier age in families with a history of BRIC.[8] Each attack can last for a few weeks up to 18 months; the mean duration is ~3 months.[3] The average frequency of attacks is slightly more than once every 2 years. In between attacks, the patient remains completely asymptomatic.

These initial clinical episodes in female patients with BRIC have sometimes been related to pregnancy or to the use of oral contraceptives. However this association has been weak or absent in most cases,[3] [13] [14] and is obviously not relevant in male BRIC patients. Nevertheless, it is now recognized that the three syndromes of intrahepatic cholestasis of pregnancy (ICP) (ICP1, 2, and 3) are associated with mutations in the same genes associated with BRIC, and BRIC and ICP may occur in the same kindred.

Abnormal bile acid physiology is noted in patients with BRIC. The concentration of serum bile acids increases during the period of pruritus, continues to increase as patients develop jaundice and scleral icterus, and then returns to normal levels as the attack resolves.[16] [17] [18] [19] A correlation has not been found between the severity of the pruritus and the concentration of bile acids.[20] [21] The hepatic metabolism of organic anions appears to be affected during attacks of BRIC; after attacks, the secretion of these anions either returns to normal levels or remains slightly higher than seen in unaffected persons.[4] [18] The total bile acid pool is contracted in patients with BRIC due to increased fecal bile acid loss, resulting in a compensatory increase in bile acid synthesis.[17] [22] However, the contracted bile acid pool and increased fecal bile acid loss persist in BRIC patients who are asymptomatic.

Improvement in appetite is often followed by the sudden and complete resolution of pruritus and the gradual resolution of jaundice.[23] Our patient's history of diarrhea ~3 months prior to the onset of pruritus and jaundice is something to be considered since gastroenteritis has been considered as a precipitant of a BRIC attack. The association with diarrhea is most often noted in BRIC type 1.

Laboratory test abnormalities are commonly noted during BRIC attacks. Our patient presented with elevated total bilirubin, mildly-elevated liver enzymes, and normal GGT levels (Table [1]). Most reported cases demonstrated significantly elevated alkaline phosphatase levels, which were absent in our patient even during her attack. A persistently normal GGT level largely eliminated the possibility of drug toxicity, Alagille syndrome, α1-antitrypsin deficiency, and cystic fibrosis.[24] Normal bile ducts on imaging also eliminated other entities affecting the major biliary system. Marked pruritus with normal GGT levels and the absence of known malignancy limits the differential diagnoses to the progressive familial intrahepatic cholestasis syndromes (PFIC1, PFIC2], and the sub-types of BRIC. Since PFIC1 and PFIC2 both manifest with severe disease in patients at extremely young ages, BRIC stands as the most plausible reason for the patient's clinical ailment. However, which variant of BRIC remains an incompletely resolved issue.

Centrilobular cholestasis, the most prominent histologic feature in BRIC, was present in our patient. Other features were minimal fibrosis of portal tracts and a questionable deficiency of interlobular bile ducts, in the setting of deficiency or decreased expression of canalicular ectoenzymes GGT and CD10 and normal expression of BSEP and MRP2. While the normal expression of BSEP on immunostaining mitigates against BRIC2, normal transporter expression does not completely exclude this gene defect, because a mutation may induce a loss of function with preservation of normal synthesis and trafficking.[25] Since an elevated GGT is a frequent finding in BRIC3, this diagnosis cannot be made based on the available data. However, absence or mild deficiency of canalicular ectoenzyme expression may be in favor of a defect in ATP8B1.[26] These findings suggest that deficiency of the familial intrahepatic cholestasis 1 protein (FIC1), encoded by ATP8B1, caused hepatobiliary disease in this patient. Sequencing of her ATP8B1 may demonstrate a mutation that can be associated with impairment of FIC1 synthesis or function.

De Koning et al[9] described the pedigree analysis of a Dutch family, with four affected members spanning five generations, and demonstrated that BRIC can be inherited as an autosomal recessive disorder. Microsatellite haplotype analysis has identified the defective gene, ATP8B1, and has located it on the long arm of chromosome 18:18q21–22.[9] [27] [28]

Due to the currently unknown precipitating cause for the cholestatic episodes in BRIC, treatment options are limited to symptomatic relief until spontaneous resolution of pruritus, jaundice, and other related symptoms occur. Agents and treatment modalities that may be effective for pruritus management include antihistamines, cholestyramine, phenobarbital, rifampin, ursodeoxycholic acid (UDCA), opiate antagonists, and plasmapheresis.[29] In patients who develop coagulopathy secondary to malabsorption of fat-soluble vitamins, vitamin K rapidly corrects the prolonged prothrombin time.[30] [31] The continued use of UDCA after an attack may be effective in preventing future attacks[27]; however, the appropriate dose regimen for patients with BRIC is unknown. Treatment with temporary nasobiliary drainage has been described in 3 patients who experienced complete and long-lasting resolution of pruritus, along with normalization of serum bile salt concentrations, within 24 hours post-drainage.[32] In our patient's case, her pruritus and jaundice resolved within 3 months after treatment with ursodiol and rifampin. It remains to be seen if these features will recur.

In contrast to PFIC1, BRIC, although significantly symptomatic during attacks, is a benign clinical entity and does not lead to permanent hepatic damage. Due to the extreme rarity of this ailment, it has not been possible to devise randomized controlled drug and treatment trials in patients with BRIC. Future knowledge will continue to be culled from case reports and series, pedigree analysis of new cases, and further understanding of bile acid physiology.

In conclusion, we present a patient with an initial, acute presentation of jaundice and marked persistent pruritus in whose case we arrived at a diagnosis of BRIC through a meticulous review of her clinical history after embarking on an exhaustive laboratory evaluation for other diseases and subsequently eliminating them systematically. An ultimate final diagnosis awaits our ability to obtain a detailed analysis of her ATP8B1 gene.

ABBREVIATIONS

• Anti-LKM antibodies to liver and kidney microsomes

• BRIC benign recurrent intrahepatic cholestasis

• BSEP transport protein bile salt export pump

• FIC1 familial intrahepatic cholestasis 1 protein

• GGT gamma-glutamyl transpeptidase

• MRP2 multidrug resistance-associated protein 2

• PFIC1 progressive familial intrahepatic cholestasis type 1

• PFIC2 progressive familial intrahepatic cholestasis type 2

• UDCA ursodeoxycholic acid

REFERENCES

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• 4 Da Silva L C, de Brito T. Benign recurrent intrahepatic cholestasis in two brothers.  Ann Intern Med. 1966;  65 330-341
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• 5 Kuhn H A. Intrahepatic cholestasis in two brothers.  Ger Med Mon. 1963;  8 185-188
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• 6 Stathers G, Reed C SH, Hirst E. Idiopathic recurrent cholestasis.  Gastroenterology. 1967;  52(3) 536-543
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• 7 Tygstrup N. Intermittent possibly familial intrahepatic cholestatic jaundice.  Lancet. 1960;  1(7135) 1171-1172
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  PubMedSearch in Google Scholar
• 13 de Pagter A GF, van Berge Henegouwen G P, ten Bokkel Huinink J A, Brandt K H. Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?.  Gastroenterology. 1976;  71(2) 202-207
  PubMedSearch in Google Scholar
• 14 Lesser P B. Benign familial recurrent intrahepatic cholestasis.  Am J Dig Dis. 1973;  18(4) 259-264
  CrossrefPubMedSearch in Google Scholar
• 15 Tang X, Halleck M S, Schlegel R A, Williamson P. A subfamily of P-type ATPases with aminophospholipid transporting activity.  Science. 1996;  272(5267) 1495-1497
  CrossrefPubMedSearch in Google Scholar
• 16 Biempica L, Gutstein S, Arias I M. Morphological and biochemical studies of benign recurrent cholestasis.  Gastroenterology. 1967;  52(3) 521-535
  PubMedSearch in Google Scholar
• 17 Endo T, Uchida K, Amuro Y, Higashino K, Yamamura Y. Bile acid metabolism in benign recurrent intrahepatic cholestasis. Comparative studies on the icteric and anicteric phases of a single case.  Gastroenterology. 1979;  76(5 Pt 1) 1002-1006
  PubMedSearch in Google Scholar
• 18 Spiegel E L, Schubert W, Perrin E, Schiff L. Benign recurrent intrahepatic cholestasis, with response to cholestyramine.  Am J Med. 1965;  39(4) 682-688
  CrossrefPubMedSearch in Google Scholar
• 19 van Berge Henegouwen G P, Brandt K-H, de Pagter A GF. Is an acute disturbance in hepatic transport of bile-acids the primary cause of cholestasis in benign recurrent intrahepatic cholestasis?.  Lancet. 1974;  1(7869) 1249-1251
  PubMedSearch in Google Scholar
• 20 Freedman M R, Holzbach R T, Ferguson D R. Pruritus in cholestasis: no direct causative role for bile acid retention.  Am J Med. 1981;  70(5) 1011-1016
  CrossrefPubMedSearch in Google Scholar
• 21 Ghent C N, Bloomer J R, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and topruritus.  Gastroenterology. 1977;  73(5) 1125-1130
  PubMedSearch in Google Scholar
• 22 Bijleveld C MA, Vonk R J, Kuipers F et al.. Benign recurrent intrahepatic cholestasis: altered bile acid metabolism.  Gastroenterology. 1989;  97(2) 427-432
  PubMedSearch in Google Scholar
• 23 Tygstrup N, Jensen B. Intermittent intrahepatic cholestasis of unknown etiology in five young males from the Faroe Islands.  Acta Med Scand. 1969;  185(6) 523-530
  CrossrefPubMedSearch in Google Scholar
• 24 Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis.  Orphanet J Rare Dis. 2009;  4 1-12
  CrossrefPubMedSearch in Google Scholar
• 25 Strautnieks S S, Byrne J A, Pawlikowska L et al.. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.  Gastroenterology. 2008;  134(4) 1203-1214
  CrossrefPubMedSearch in Google Scholar
• 26 Paulusma C C, Groen A, Kunne C et al.. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.  Hepatology. 2006;  44(1) 195-204
  CrossrefPubMedSearch in Google Scholar
• 27 Carlton V EH, Knisely A S, Freimer N B. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.  Hum Mol Genet. 1995;  4(6) 1049-1053
  CrossrefPubMedSearch in Google Scholar
• 28 Oude Elferink R PJ, van Berge Henegouwen G P. Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis.  J Hepatol. 1998;  29(2) 317-320
  CrossrefPubMedSearch in Google Scholar
• 29 Shiffman M L, Heuman D H. Pathophysiology and pharmacology of cholestasis. In: McCallum RW, Friedman G, Jacobson ED Gastrointestinal Pharmacology and Therapeutics. New York; Raven Press 1996: 401-416
  Search in Google Scholar
• 30 Summerskill W HJ. The syndrome of benign recurrent cholestasis.  Am J Med. 1965;  38 298-305
  CrossrefPubMedSearch in Google Scholar
• 31 Williams R, Cartter M A, Sherlock S, Scheuer P J, Hill K R. Idiopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases.  Q J Med. 1964;  33 387-399
  PubMedSearch in Google Scholar
• 32 Stapelbroek J M, van Erpecum K J, Klomp L WJ et al.. Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis.  Hepatology. 2006;  43(1) 51-53
  CrossrefPubMedSearch in Google Scholar

Lawrence U LiuM.D. 

Division of Liver Diseases, The Mount Sinai Medical Center

One Gustave L. Levy Place, Box 1104, New York, NY 10029

Email: Lawrence.Liu@mountsinai.org

REFERENCES

• 1 Luketic V A, Shiffman M L. Benign recurrent intrahepatic cholestasis.  Clin Liver Dis. 2004;  8(1) 133-149, vii
  CrossrefPubMedSearch in Google Scholar
• 2 Summerskill W HJ, Walshe J M. Benign recurrent intrahepatic “obstructive” jaundice.  Lancet. 1959;  2(7105) 686-690
  PubMedSearch in Google Scholar
• 3 Brenard R, Geubel A P, Benhamou J P. Benign recurrent intrahepatic cholestasis. A report of 26 cases.  J Clin Gastroenterol. 1989;  11(5) 546-551
  CrossrefPubMedSearch in Google Scholar
• 4 Da Silva L C, de Brito T. Benign recurrent intrahepatic cholestasis in two brothers.  Ann Intern Med. 1966;  65 330-341
  PubMedSearch in Google Scholar
• 5 Kuhn H A. Intrahepatic cholestasis in two brothers.  Ger Med Mon. 1963;  8 185-188
  PubMedSearch in Google Scholar
• 6 Stathers G, Reed C SH, Hirst E. Idiopathic recurrent cholestasis.  Gastroenterology. 1967;  52(3) 536-543
  PubMedSearch in Google Scholar
• 7 Tygstrup N. Intermittent possibly familial intrahepatic cholestatic jaundice.  Lancet. 1960;  1(7135) 1171-1172
  PubMedSearch in Google Scholar
• 8 Schapiro R H, Isselbacher K J. Benign recurrent intrahepatic cholestasis.  N Engl J Med. 1963;  268 708-711
  CrossrefPubMedSearch in Google Scholar
• 9 De Koning T J, Sandkuijl L A, De Schryver J EAR, Hennekam E A, Beemer F A, Houwen R H. Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis.  Am J Med Genet. 1995;  57(3) 479-482
  CrossrefPubMedSearch in Google Scholar
• 10 Paulusma C C, Oude Elferink R PJ, Jansen P LM. Progressive familial intrahepatic cholestasis type 1.  Semin Liver Dis. 2010;  30(2) 115-122
  PubMedSearch in Google Scholar
• 11 van Mil S W, van der Woerd W L, van der Brugge G et al.. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.  Gastroenterology. 2004;  127(2) 379-384
  CrossrefPubMedSearch in Google Scholar
• 12 Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.  Semin Liver Dis. 2010;  30(2) 132-144
  PubMedSearch in Google Scholar
• 13 de Pagter A GF, van Berge Henegouwen G P, ten Bokkel Huinink J A, Brandt K H. Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?.  Gastroenterology. 1976;  71(2) 202-207
  PubMedSearch in Google Scholar
• 14 Lesser P B. Benign familial recurrent intrahepatic cholestasis.  Am J Dig Dis. 1973;  18(4) 259-264
  CrossrefPubMedSearch in Google Scholar
• 15 Tang X, Halleck M S, Schlegel R A, Williamson P. A subfamily of P-type ATPases with aminophospholipid transporting activity.  Science. 1996;  272(5267) 1495-1497
  CrossrefPubMedSearch in Google Scholar
• 16 Biempica L, Gutstein S, Arias I M. Morphological and biochemical studies of benign recurrent cholestasis.  Gastroenterology. 1967;  52(3) 521-535
  PubMedSearch in Google Scholar
• 17 Endo T, Uchida K, Amuro Y, Higashino K, Yamamura Y. Bile acid metabolism in benign recurrent intrahepatic cholestasis. Comparative studies on the icteric and anicteric phases of a single case.  Gastroenterology. 1979;  76(5 Pt 1) 1002-1006
  PubMedSearch in Google Scholar
• 18 Spiegel E L, Schubert W, Perrin E, Schiff L. Benign recurrent intrahepatic cholestasis, with response to cholestyramine.  Am J Med. 1965;  39(4) 682-688
  CrossrefPubMedSearch in Google Scholar
• 19 van Berge Henegouwen G P, Brandt K-H, de Pagter A GF. Is an acute disturbance in hepatic transport of bile-acids the primary cause of cholestasis in benign recurrent intrahepatic cholestasis?.  Lancet. 1974;  1(7869) 1249-1251
  PubMedSearch in Google Scholar
• 20 Freedman M R, Holzbach R T, Ferguson D R. Pruritus in cholestasis: no direct causative role for bile acid retention.  Am J Med. 1981;  70(5) 1011-1016
  CrossrefPubMedSearch in Google Scholar
• 21 Ghent C N, Bloomer J R, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and topruritus.  Gastroenterology. 1977;  73(5) 1125-1130
  PubMedSearch in Google Scholar
• 22 Bijleveld C MA, Vonk R J, Kuipers F et al.. Benign recurrent intrahepatic cholestasis: altered bile acid metabolism.  Gastroenterology. 1989;  97(2) 427-432
  PubMedSearch in Google Scholar
• 23 Tygstrup N, Jensen B. Intermittent intrahepatic cholestasis of unknown etiology in five young males from the Faroe Islands.  Acta Med Scand. 1969;  185(6) 523-530
  CrossrefPubMedSearch in Google Scholar
• 24 Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis.  Orphanet J Rare Dis. 2009;  4 1-12
  CrossrefPubMedSearch in Google Scholar
• 25 Strautnieks S S, Byrne J A, Pawlikowska L et al.. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.  Gastroenterology. 2008;  134(4) 1203-1214
  CrossrefPubMedSearch in Google Scholar
• 26 Paulusma C C, Groen A, Kunne C et al.. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.  Hepatology. 2006;  44(1) 195-204
  CrossrefPubMedSearch in Google Scholar
• 27 Carlton V EH, Knisely A S, Freimer N B. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.  Hum Mol Genet. 1995;  4(6) 1049-1053
  CrossrefPubMedSearch in Google Scholar
• 28 Oude Elferink R PJ, van Berge Henegouwen G P. Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis.  J Hepatol. 1998;  29(2) 317-320
  CrossrefPubMedSearch in Google Scholar
• 29 Shiffman M L, Heuman D H. Pathophysiology and pharmacology of cholestasis. In: McCallum RW, Friedman G, Jacobson ED Gastrointestinal Pharmacology and Therapeutics. New York; Raven Press 1996: 401-416
  Search in Google Scholar
• 30 Summerskill W HJ. The syndrome of benign recurrent cholestasis.  Am J Med. 1965;  38 298-305
  CrossrefPubMedSearch in Google Scholar
• 31 Williams R, Cartter M A, Sherlock S, Scheuer P J, Hill K R. Idiopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases.  Q J Med. 1964;  33 387-399
  PubMedSearch in Google Scholar
• 32 Stapelbroek J M, van Erpecum K J, Klomp L WJ et al.. Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis.  Hepatology. 2006;  43(1) 51-53
  CrossrefPubMedSearch in Google Scholar

Lawrence U LiuM.D. 

Division of Liver Diseases, The Mount Sinai Medical Center

One Gustave L. Levy Place, Box 1104, New York, NY 10029

Email: Lawrence.Liu@mountsinai.org