Benign Recurrent Intrahepatic Cholestasis Type Research Articles

Clinicopathologic Features, Genetics, Treatment, and Long-Term Outcomes in Japanese Children and Young Adults with Benign Recurrent Intrahepatic Cholestasis: A Multicenter Study.

Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory.

A 19-year-old Patient with Recurrent Pruritus and Jaundice

Аim: to highlight the importance of broad differential diagnosis and possibility of conversion of benign recurrent intrahepatic cholestasis type 2 into more aggressive clinical phenotype.Key points. A 19-year-old female patient was admitted to the Clinic with skin pruritus, jaundice, dark urine, clay-colored stool, and general fatigue. Past medical history was significant for recurrent aforementioned symptoms since 3 years old, that relapsed every 1–2 years and were usually ameliorated with conservative therapy. During recent years, frequency of relapses and recovery period increased, at the same time effectiveness of medical therapy decreased. Blood chemistry results revealed an elevation of total bilirubin (up to 634 μmol/L), direct bilirubin (up to 354 μmol/L), bile acids (up to 510 μmol/L) and normal gamma glutamyl transferase level. Workup was negative for viral hepatitis, autoimmune liver diseases, obstructive choledochal lesions, storage diseases, although mutation in gene ABCB11 was found. Benign recurrent intrahepatic cholestasis type 2 was diagnosed. Following conservative therapy and plasmapheresis, jaundice and skin pruritus significantly diminished, levels of bilirubin and bile acids normalized. Regular follow up, liver biopsy and measures for relapse prevention given clinical features of aggressive phenotype were recommended.Conclusion. Identification of etiology of cholestatic liver diseases requires broad differential diagnosis. Clinical course of patients with benign recurrent intrahepatic cholestasis may transform into aggressive phenotype, reminiscent of progressive familial intrahepatic cholestasis.

Improvement of cholestatic episodes in patients with benign recurrent intrahepatic cholestasis (BRIC) treated with rifampicin. A long-term follow-up

Objective Patients with benign recurrent intrahepatic cholestasis (BRIC) suffer from recurrent episodes of cholestatic jaundice. Treatment options remain limited and are mainly symptomatic. In case reports rifampicin, plasmapheresis, and nasobiliary drainage have been reported to be effective. In this case series, we present long-term experience indicating disease-modifying effects of non-invasive treatment with rifampicin for recurrent cholestasis in BRIC type 1 (BRIC1). Materials and methods We included all adult BRIC1 patients diagnosed and followed up at a single centre in Bergen, Norway. Data regarding clinical and biochemical features during BRIC attacks with and without rifampicin treatment were retrieved from medical journals and a data registry. Results Five males with BRIC1 were included. Median age at diagnosis was 22 years (range 15–41). Together they had suffered from 65 cholestatic attacks (including four documented abortive attacks). Twenty-eight attacks were treated with rifampicin alone over the last 12 years; all cases showed symptomatic relief and reduction in the levels of bilirubin and alkaline phosphatase in blood. The attacks treated with rifampicin seemed to have shorter duration and were less likely to result in complications or hospitalization compared to attacks prior to the introduction of rifampicin. No side effects attributable to rifampicin were noted. Conclusions Episodic treatment of recurrent BRIC1 attacks with rifampicin seems to ameliorate severity and shorten the duration of attacks. Timely diagnosis and effective treatment are of major importance in BRIC, not only to decrease complications but also improving patients’ quality of life.

S2678 Benign Recurrent Intrahepatic Cholestasis Type 2 Presenting With Worse Outcome During Pregnancy

S2678 Benign Recurrent Intrahepatic Cholestasis Type 2 Presenting With Worse Outcome During Pregnancy

ПРОГРЕССИРУЮЩИЙ СЕМЕЙНЫЙ ВНУТРИПЕЧЁНОЧНЫЙ ХОЛЕСТАЗ: ДИАГНОСТИКА, ЛЕЧЕНИЕ (КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ)

Jaundice is a manifestation of many diseases both benign and malignant. Genetic progress allowed to distinguish the group of unknown earlier rare cholestatic jaundices, which are resulted from gene mutations. There are no described algorithms of their diagnosis or treatment. In this article case report of the patient with benign recurrent intrahepatic cholestasis type 1 is presented. There is also literature analysis of this theme.

The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies.

The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of pregnancy (ICP). Over the past few years, several small molecular weight compounds have been identified, which hold the potential to treat these genetic diseases (chaperones and potentiators). As the treatment response is mutation-specific, genetic analysis of the patients and their families is required. Furthermore, some of the mutations are refractory to therapy, with the only remaining treatment option being liver transplantation. In this review, we will focus on the molecular structure of ABCB11, reported mutations involved in cholestasis and current treatment options for inherited BSEP deficiencies.

Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages.

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte‐derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin‐10 (IL‐10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c‐related surface markers cluster of differentiation (CD)14 and CD163 were 2.3‐fold and 2.1‐fold lower (95% confidence interval, 2.0‐2.5 for CD14 and 1.7‐2.4 for CD163), respectively, in patients with IL‐10‐treated HMDMs from PFIC1 compared with BRIC1. Conclusion: CD14 and CD163 expression levels in IL‐10‐treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency.

1295 A Unique BRIC Case With Response to Glucocorticoids

INTRODUCTION: Benign Recurrent Intrahepatic Cholestasis (BRIC) represents a rare class of autosomal recessive chronic cholestasis disorders usually presenting with intense pruritus and jaundice. BRIC type 2 (BRIC 2) results from a defect in the ABCB11 gene, which encodes the ATP dependent bile salt export pump (BSEP). 1 Here we report a unique case of a 27-year-old heterozygous female presenting with BRIC 2 and a response to steroids that may have implications for future treatment. CASE DESCRIPTION/METHODS: A 27-year-old female presented with 4 weeks of progressive jaundice, pruritus, and weakness. A prior episode one year earlier was notable for similar symptoms that resolved with supportive measures and a liver biopsy that showed nonspecific cholestasis with features suggesting extrahepatic duct obstruction. Presenting labs were notable for AST 63, ALT 74, total bilirubin (TB) 9.1, direct bilirubin (DB) 6.7, GGT 22, and alkaline phosphatase 227. Hepatitis serology, α-1 antitrypsin, hemochromatosis, and autoimmune workup were negative. Abdominal ultrasound and CT were unremarkable. MRCP revealed mild liver enlargement (19 cm), but no biliary stricture or dilatation. Liver biopsy showed extensive canalicular cholestasis with associated mild hepatocyte pericentral and perisinusoidal fibrosis. Her symptoms and labs continued to worsen, with TB peaking at 14.2 and DB at 11.5. On day 18, she was started on methylprednisolone 40 mg IV daily and achieved modest symptomatic improvement. On day 21, TB had downtrended to 8.1, and she was discharged home with a five-day course of prednisone. Genetic testing revealed heterozygosity for ABCB11. DISCUSSION: This report demonstrates a fairly typical presentation of BRIC, but in an older patient than typically seen. Though BRIC classically presents with its first episode prior to second decade of life, it can present in patients of any age.1 Our patient's heterozygosity for CFTR, NPHP4, and A1ATD (SERPINA1) may explain the severe nature of her disease expression, as heterozygosity in each of these genes has been associated with cholestasis. Her steroid response suggests a potentially novel treatment for BRIC and highlights the need for further consideration of steroid therapy in BSEP-related diseases.

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients.

Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

Can genetic testing guide the therapy of cholestatic pruritus? A case of benign recurrent intrahepatic cholestasis type 2 with severe nasobiliary drainage-refractory itch.

Benign recurrent intrahepatic cholestasis (BRIC) is a peculiar familial disease caused by mutations of the genes encoding hepatocanalicular flippase for phosphatidylserine (ATP8B1; BRIC type 1) or the bile salt export pump (ABCB11; BRIC type 2). Here, we report on a patient with nasobiliary drainage‐refractory BRIC type 2 who improved under plasma separation and anion absorption therapy. We also suggest that nasobiliary drainage might be an ineffective approach in carriers of severe loss‐of‐function mutations of the bile salt export pump ABCB11. (Hepatology Communications 2018;2:152–154)

THU-431 - Successful Treatment with 4-Phenylbutyrate with Rifampicine Refractory Benign Recurrent Intrahepatic Cholestasis Type 1: First Report of 2 Cases

THU-431 - Successful Treatment with 4-Phenylbutyrate with Rifampicine Refractory Benign Recurrent Intrahepatic Cholestasis Type 1: First Report of 2 Cases

Successful treatment with 4-phenylbutyrate in a patient with benign recurrent intrahepatic cholestasis type 2 refractory to biliary drainage and bilirubin absorption.

Benign recurrent intrahepatic cholestasis type 2 (BRIC2) is caused by mutations in ABCB11, a gene encoding the bile salt export pump (BSEP) that mediates biliary bile salt secretion, and presents with repeated intermittent cholestasis with refractory itching. Currently, no effective medical therapy has been established. We previously provided experimental and clinical evidence suggesting the therapeutic potential of 4-phenylbutyrate (4PB) for the cholestatic attacks of BRIC2. After examining the potential therapeutic use of 4PB treatment by in vitro studies, a patient with BRIC2 was treated p.o. with 4PB at gradually increasing doses (200, 350, and 500mg/kg per day) for 4months. Biochemical, histological and clinical data were collected. The patient was diagnosed with BRIC2 because he had non-synonymous mutations (c.1211A>G [p.D404G] and 1331T>C [p.V444A]) in ABCB11, reduced hepatocanalicular expression of BSEP and low biliary bile salt concentrations. In vitro analysis showed that 4PB treatment partially restored the decreased expression of BSEP caused by p.D404G mutation. During the first 2months of 4PB therapy at 200 and 350mg/kg per day, the patient had no relief from his symptoms. No beneficial effect was observed after additional treatment with bilirubin absorption and endoscopic nasobiliary drainage. However, after starting treatment at a dose of 500mg/kg per day, the patient's liver function tests and intractable itching were markedly improved. No apparent side-effects were observed during or after 4PB therapy. The symptoms relapsed within 1.5months after cessation of 4PB therapy. 4PB therapy would have a therapeutic effect on the cholestatic attacks of BRIC2.

The lipid flippase heterodimer ATP8B1–CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells

Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea.Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation.Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased.The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.

Posttranslational regulation of the bile salt export pump

Bile plays an essential role in the nutrient uptake of the human body. It consists mostly of amphipathic bile salts, phospholipids and cholesterol in mixed micelles. The bile solubilizes lipophilic nutrients, such as lipids and fat-soluble vitamins, and facilitates their uptake. The formation of bile depends on the activity of various ATP-binding cassette (ABC) transporters localized in the apical membrane of hepatocytes. The main components of bile, phosphatidylcholine, cholesterol and bile salts, are transported by multidrug resistance protein 3 (MDR3, ABCB4), ABCG5/G8 and the bile salt export pump (BSEP, ABCB11), respectively. BSEP, as the transporter of the main solute in bile, is considered to be the primary driving force of bile formation. BSEP belongs to the family of ABC transporters, which constitute one of the largest protein families. They are primary active transporters with a common functional unit: two nucleotide–binding domains and two transmembrane domains. The nucleotide–binding domains fuel the transport by hydrolyzing ATP, while the transmembrane domains provide the translocation pathway over the membrane and are thought to be responsible for substrate recognition. Eukaryotic ABC transporters are usually encoded by one gene as in the case of BSEP (full-size transporters) or by two genes coding for one nucleotide-binding domain and one transmembrane domain each. In the latter case the transporter is called a half-size transporter and the two polypeptides homo- or heterodimerize to form a functional unit. An example for such a half-size transporter is ABCG5/G8. Mutations in ABC transporters can lead to severe diseases. For example an impairment of targeting or activity in BSEP leads to the accumulation of bile salts in the hepatocytes. Bile salts, in addition to their detergent function, can furthermore act as signaling molecules and thereby cause different forms of cholestasis, such as progressive familial intrahepatic cholestasis type 2 (PFIC2) or benign recurrent intrahepatic cholestasis type 2 (BRIC2). An additional influence that can affect the development of diseases is the post-translational regulation of ABC transporter functionality. The regulation can occur directly in the form of chemical modifications or can be mediated for example by protein-protein interactions. For several ABC transporters of the apical hepatocyte membrane an influence of protein-protein interactions on targeting, turnover or activity could be shown. MRP2 for example interacts with NHERF-1, a scaffold protein that is responsible for linking its interacting partners to the cytoskeleton. It has furthermore been reported that the interaction of MRP2 with NHERF-1 influences the apical membrane expression of MRP2. For example, NHERF-1 knock–out mice show reduced abundance of MRP2 in the membrane [1]. For BSEP two interaction partners are known to date. One of them is the AP2 adaptor related protein complex, which is involved in internalization of BSEP [2]. To study ABC transporters in their isolated form a heterologous overexpression system is required to obtain sufficient amounts of protein. Initially, toxicity of the BSEP cDNA for Escherichia coli was an obstacle. Therefore a Saccharomyces cerevisiae based cloning technique has been developed, which is independent of E. coli[3]. Subsequently, with the optimized cloning procedure an overexpression of BSEP could be established in the methylotrophic yeast Pichia pastoris. With the help of a GFP-fusion protein BSEP could be traced to the P. pastoris plasma membrane. Additionally, sucrose density centrifugation experiments confirmed the correct localization of BSEP. A subsequent detergent screen led to the identification of detergents suitable for BSEP solubilization. The transporter appears to be in a detergent-resistant environment as only the lipid–like, zwitter–ionic detergents of the Fos–choline and Cyclofos series, comparatively “harsh” detergents, could efficiently extract BSEP. Finally, a purification protocol was established to obtain BSEP in a detergent-solubilized form. With a dual–affinity tag tandem affinity purification could be employed to obtain the ABC transporter with approximately 75% purity [4]. In summary, the optimized cloning strategy for BSEP cDNA in S. cerevisiae as well as the efficient expression and purification protocols enable us to investigate the interaction of BSEP with other proteins in vitro.

Hepatotoxicity from anabolic androgenic steroids marketed as dietary supplements: contribution from ATP8B1/ABCB11 mutations?

Though possession of androgenic anabolic steroids (AAS) is illegal, non-prescription use of AAS persists. We describe two Caucasian males (aged 25 and 45 years) with cholestatic hepatitis following ingestion of the dietary supplement Mass-Drol ('Celtic Dragon') containing the AAS 2α-17α-dimethyl-etiocholan-3-one,17β-ol. Despite substantial hyperbilirubinaemia peak gamma-glutamyl transferase (GGT) remained normal. Besides 'bland' intralobular cholestasis, liver biopsy in both found deficiency of canalicular expression of ectoenzymes as seen in ATP8B1 disease. In the older patient, bile salt export pump marking (encoded by ABCB11) was focally diminished. We hypothesized that AAS had either induced inhibition of normal ATP8B1/ABCB11 expression or triggered initial episodes of benign recurrent intrahepatic cholestasis (BRIC) type 1/or 2. On sequencing, ATP8B1 was normal in both patients although the younger was heterozygous for the c.2093G>A mutation in ABCB11, a polymorphism previously encountered in drug-induced liver injury. AAS marketed as dietary supplements continue to cause hepatotoxicity in the UK; underlying mechanisms may include unmasking of genetic cholestatic syndromes.

PWE-148 Hepatotoxicity From Anabolic Androgenic Steroids Marketed as Dietary Supplements: Contribution from Atp8B1/Abcb11 Mutations?

IntroductionIn the United Kingdom (UK) it is illegal to produce, supply, or possess androgenic anabolic steroids (AAS) with intent. Despite this, non-prescription use of AAS, often marketed as dietary supplements,...

Biosynthesis and trafficking of the bile salt export pump, BSEP: Therapeutic implications of BSEP mutations

The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter.

The bile salt export pump (BSEP) in health and disease

The bile salt export pump (BSEP) is the major transporter for the secretion of bile acids from hepatocytes into bile in humans. Mutations of BSEP are associated with cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 2 (PFIC-2), benign recurrent intrahepatic cholestasis type 2 (BRIC-2) and genetic polymorphisms are linked to intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). Detailed analysis of these diseases has considerably increased our knowledge about physiology and pathophysiology of bile secretion in humans. This review focuses on expression, localization, and function, short- and long-term regulation of BSEP as well as diseases association and treatment options for BSEP-associated diseases.

Familial cholestasis: Progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy

Progressive familial intrahepatic cholestasis (PFIC) type 1, 2 and 3 are due to mutations in ATP8B1, ABCB11 and ABCB4, respectively. Each of these genes encodes a hepatocanalicular transporter, which is essential for the proper formation of bile. Mutations in ABCB4 can result in progressive cholestatic disease, while mutations in ATP8B1 and ABCB11 can result both in episodic cholestasis, referred to as benign recurrent intrahepatic cholestasis (BRIC) type 1 and 2, as well as in progressive cholestatic disease. This suggests a clinical continuum and these diseases are therefore preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. Similarly PFIC type 3 is designated as ABCB4 deficiency. Heterozygous mutations in each of these transporters can also be associated with intrahepatic cholestasis of pregnancy. This review summarizes the pathophysiology, clinical features and current as well as future therapeutic options for progressive familial- and benign recurrent intrahepatic cholestasis as well as intrahepatic cholestasis of pregnancy.

Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: A new tool in a near future?

COMMENTARY ON: Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. van der Velden LM, Stapelbroek JM, Krieger E, van den Berghe PVE, Berger R, Verhulst PM, Holthuis JCM, Houwen RHJ, Klomp LWJ, van de Graaf SFJ. Hepatology 2010;51:286-296. Copyright 2010. Abstract reprinted with permission of John Wiley and Sons, Inc. www.ncbi.nlm.nih.gov/pubmed/19918981 Abstract: Deficiency in P-type ATP8B1 is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It presents either as a progressive (pro- gressive familial intrahepatic cholestasis type 1 (PFIC1)) or intermit- tent (benign recurrent intrahepatic cholestasis type 1 (BRIC1)) disease. ATP8B1 deficiency is caused by autosomal recessive mutations in the gene encoding ATP8B1, a putative aminophospho- lipid-translocating P-type adenosine triphosphatase. The exact path- ogenesis of the disease is elusive, and no effective pharmacological therapy is currently available. Here, the molecular consequences of six distinct ATP8B1 missense mutations (p.L127P, p.G308V, p.D454G, p.D554N, p.I661T, and p.G1040R) and one nonsense muta- tion (p.R1164X) associated with PFIC1 and/or BRIC1 were systemat- ically characterized. Except for the p.L127P mutation, all mutations resulted in markedly reduced ATP8B1 protein expression, whereas messenger RNA expression was unaffected. Five out of seven mutations resulted in (partial) retention of ATP8B1 in the endoplasmic reticulum. Reduced protein expression was partially restored by culturing the cells at 30 C and by treatment with proteasomal inhibitors, which indicates protein misfolding and subsequent proteosomal degrada- tion. Protein misfolding was corroborated by predicting the conse- quences of most mutations onto a homology model of ATP8B1. Treatment with 4-phenylbutyrate, a clinically approved pharmacolog- ical chaperone, partially restored defects in expression and localization of ATP8B1 substitutions G308V, D454G, D554N, and in particular I661T, which is the most frequently identified mutation in BRIC1. Conclusion: A surprisingly large proportion of ATP8B1 mutations resulted in aberrant folding and decreased expression at the plasma membrane. These effects were partially restored by treatment with 4-phenylbutyrate. We propose that treatment with pharmacological chaperones may represent an effective therapeutic strategy to ameliorate the recurrent attacks of cholestasis in patients with inter- mittent (BRIC1) disease.