Cholestatic Episodes Research Articles

Benign Recurrent Intrahepatic Cholestasis: Where Are We Now?

Benign recurrent intrahepatic cholestasis (BRIC) stands as a rare genetic contributor to cholestasis, aligning itself within the spectrum of inherited intrahepatic cholestasis syndromes, such as progressive familial intrahepatic cholestasis (PFIC) and intrahepatic cholestasis of pregnancy. Manifesting in infancy or early adulthood, BRIC is marked by recurrent episodes of jaundice accompanied by intense pruritus, enduring from weeks to years across the lifespan. Normal gamma-glutamyl transferase (GGT) levels are a characteristic laboratory finding. Initially considered unlikely to progress to chronic liver disease or cirrhosis, some reports suggest BRIC may evolve into a continuous and progressive form of cholestasis. Moreover, these recurrent cholestatic episodes significantly impact quality of life, and certain mutations elevate the risk of hepatobiliary malignancy. Between episodes, histological findings of centrilobular cholestasis and abnormal laboratory parameters revert to normal, potentially obviating the need for liver biopsy. This review focuses on the genetic aspects of BRIC, its pathophysiology, clinical presentation, and prognosis. Additionally, it outlines triggering factors and available treatment options.

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.

Identification of low gamma-glutamyl transferase familial intrahepatic cholestasis - benign recurrent intrahepatic cholestasis in a 22-year-old woman: A case report and literature review

Introduction: Benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic disorder characterized by recurrent episodes of cholestatic jaundice that may last days to months. It can start at any age, but often in a first decade of life. The syndrome does not lead to progressive liver dysfunction and cirrhosis. Between cholestatic episodes patients have no symptoms and laboratory levels are within the norms. The exact mechanism of cholestasis in BRIC and many other cholestatic conditions is poorly understood. Syndrome the first time was described in 1959r., in 2004 was proposed the following diagnostic criteria. The report presents a 22-year-old woman with the diagnosis of jaundice with an accompanying severe pruritus (first episode of BRIC).
 The aim: This article describes clinical presentation, laboratory abnormalities, and proposed etiologic factors responsible for BRIC. We intend to report this case due to rarity of this disease in Poland.
 Clinical case: Described as a clinical case course features of the BRIC. Knowledge of this entity is important issue as an early recognition that might prevent performance of expensive diagnostic algorithm. The laboratory tests and the whole clinical picture had conclusive results. Moreover, despite negative genetic test, the authors were sure that it is BRIC.
 Conclusion: BRIC is a disease not leading to progressive liver dysfunction and cirrhosis. It should be remembered the characteristic symptoms of BRIC, a very low level of GGT accompanied by jaundice and itching. It has a great diagnostic importance (by shortening the procedure algorithm), allowing for a quick diagnosis.

Mutations in Myosin 5B in Children With Early-onset Cholestasis.

Mutations in Myosin 5B (MYO5B) are known to be associated with microvillous inclusion disease (MVID) a genetic cause of neonatal intractable diarrhoea. More recently, they have been reported in children with cholestasis but without typical gastrointestinal symptoms of MVID. We describe our series of children with cholestasis and mutations in MYO5B. Clinical, laboratory, and histological data were collected from patients with cholestasis and pathogenic mutations in MYO5B, found by next generation sequencing (NGS) but with minimal gastrointestinal disease. Six patients (3 boys) were identified. Median age at presentation was 19 months (range, 3-92). Presenting features were jaundice, pale stools, pruritus, and failure to thrive. Patients 5 and 6 had intractable diarrhoea until the age of 3 and 7 years, respectively, but currently are on full enteral diet with no intestinal symptoms. Median values for serum total bilirubin were 55 μmol/L (2-500), alanine aminotransferase 73I IU/L (32-114), γ-glutamyltransferase 7 IU/L (7-10), and serum bile acids 134 μmol/L (18-274). Three patients underwent 1 or more types of biliary diversion for symptom control. Median follow-up was 5 years (2-22). At most recent follow-up, they all reported pruritus while on antipruritics. Patient 1 had a liver transplant. We identified 6 patients, with mutations in MYO5B, early-onset cholestasis and pruritus, with variable response to biliary diversion without typical MVID.

The Combination of Nilotinib + Pegylated IFN Alpha 2a Provides Somewhat Higher Cumulative Incidence Rates of MR4.5 at M36 Versus Nilotinib Alone in Newly Diagnosed CP CML Patients. Updated Results of the Petals Phase III National Study.

The Combination of Nilotinib + Pegylated IFN Alpha 2a Provides Somewhat Higher Cumulative Incidence Rates of MR4.5 at M36 Versus Nilotinib Alone in Newly Diagnosed CP CML Patients. Updated Results of the Petals Phase III National Study.

Nilotinib Versus Nilotinib Combined to Pegylated-Interferon Alfa 2a in First-Line Chronic Phase Chronic Myelogenous Leukemia Patients. Interim Analysis of a Phase III Trial

Nilotinib Versus Nilotinib Combined to Pegylated-Interferon Alfa 2a in First-Line Chronic Phase Chronic Myelogenous Leukemia Patients. Interim Analysis of a Phase III Trial

Clinical Variability After Partial External Biliary Diversion in Familial Intrahepatic Cholestasis 1 Deficiency.

Familial intrahepatic cholestasis 1 (FIC1) deficiency is caused by a mutation in the ATP8B1 gene. Partial external biliary diversion (PEBD) is pursued to improve pruritus and arrest disease progression. Our aim is to describe clinical variability after PEBD in FIC1 disease. We performed a single-center, retrospective review of genetically confirmed FIC1 deficient patients who received PEBD. Clinical outcomes after PEBD were cholestasis, pruritus, fat-soluble vitamin supplementation, growth, and markers of disease progression that included splenomegaly and aspartate aminotransferase-to-platelet ratio index. Eight patients with FIC1 disease and PEBD were included. Mean follow-up was 32 months (range 15-65 months). After PEBD, total bilirubin was <2 mg/dL in all patients at 8 months after surgery, but 7 of 8 subsequently experienced a total of 15 recurrent cholestatic events. Subjective assessments of pruritus demonstrated improvement, but itching exacerbation occurred during cholestatic episodes. High-dose fat-soluble vitamin supplementation persisted, with increases needed during cholestatic episodes. Weight z scores improved (-3.4 to -1.65, P < 0.01). Splenomegaly did not worsen or develop and 1 patient developed an aminotransferase-to-platelet ratio index score of >0.7 suggesting development of fibrosis 24 months after PEBD. Clinical variability is evident among genetically defined FIC1 deficient patients after PEBD, even among those with identical mutations. Recurrent, self-limited episodes of cholestasis and pruritus are reminiscent of the benign recurrent intrahepatic cholestasis phenotype. Despite diversion of bile from the intestinal lumen, weight gain improved while fat-soluble vitamin requirements persisted. Significant progression of liver disease was not evident during follow-up.

Pegylated Interferon-α 2a in Combination to Nilotinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Provides High Rates of MR4.5. Preliminary Results of a Phase II Study.

Pegylated Interferon-α 2a in Combination to Nilotinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Provides High Rates of MR4.5. Preliminary Results of a Phase II Study.

Evolving Changes in Aetiology of Gallstones in Children

To the Editor: Bogue et al (1) describe their large series on gallstones in multiethnic children. They have highlighted novel information on aetiology, namely frequent history of prematurity, short gut, haematological malignancies, cardiac surgery, and use of diuretics (1). However, by not reporting information about the presence of low/normal or elevated serum γ-glutamyl transpeptidase, they have missed the opportunity to investigate the role of emerging conditions such as familial intrahepatic cholestasis-1 disease, bile salt export pump, and MDR-3 deficiency, belonging to progressive familial intrahepatic cholestasis (PFIC) syndrome, often associated with propensity for gallstone formation (2). Of note, the authors have observed that some of their patients had a history of exposure to cephalosporins, occasionally implicated as a trigger for cholestatic episodes of the PFIC syndrome (2). Our recent pilot analysis demonstrated that of the 19 infants with cholesterol gallstones 1 had heterozygous MDR-3 mutation (A934T), whereas 7 had single nucleotide polymorphisms, resulting in amino acid substitutions in 2 (3). Ursodeoxycholic acid–induced choleresis is a widely used approach to ameliorate various forms of paediatric cholestasis, including the PFIC syndrome. It remains unclear whether in the cases of 29% of the children from their series who have “spontaneously cleared the gallstones” any medication such as ursodeoxycholic or phenobarbitone had been used. Modern management of gallstone disease, although simple, must be multidisciplinary. This should include the assumption that most of the underlying conditions will not be cured by the surgery. Because those belonging to the PFIC syndrome could cause chronic liver disease with its lifelong complications (4,5), they need to be recognised and these patients monitored post-cholecystectomy.

Follow‐up in Children With Progressive Familial Intrahepatic Cholestasis After Partial External Biliary Diversion

The aim of this study was to examine whether reversion of histological fibrosis followed partial external biliary diversion (PEBD) in patients with progressive familial intrahepatic cholestasis (PFIC); whether the duration of cholestatic episodes after PEBD influenced the evolution of fibrosis; and whether genotyping was helpful in predicting outcome of PEBD. Children with PFIC who underwent PEBD were investigated with genetic, biochemical, and anthropometric standard methods. Serial liver specimens were assessed histologically without knowledge of genotype and outcome. Findings were evaluated in the contexts of the total duration of cholestasis and the clinical outcome after PEBD. From a total of 18 children with PFIC, 13 underwent PEBD, and 12 of these (among them 10 with identified ABCB11 mutations) were amenable for clinical and histological follow-up. When compared with baseline at PEBD, statistically significant reductions were found in histological cholestasis 1 and 3 years after PEBD, and in fibrosis 5 and >10 years after PEBD. The relative duration of cholestatic episodes after PEBD was positively correlated with the severity of fibrosis. Children homozygous for the missense mutation c.890A>G in ABCB11 responded well to PEBD. Biliary diversion should be regarded as the first choice of surgical treatment in noncirrhotic patients with severe ABCB11 disease and may also be efficacious in other forms of PFIC.

Progressive Familial Intrahepatic Cholestasis Type 1

Progressive familial intrahepatic cholestasis type 1 is a rare genetic liver disease that presents in the first year of life. Bile salts are elevated and these patients are often jaundiced. Despite the cholestasis, serum gamma-glutamyltransferase activity is normal or reduced. Pruritus is a major symptom in these patients. Partial external biliary diversion is helpful in several patients as it reduces the pruritus and postpones or even avoids liver transplantation. The disease is caused by mutations in the gene ATP8B1 that preclude the normal expression of ATP8B1. ATP8B1 is a protein that acts as a lipid flippase, transporting phosphatidylserine from the exoplasmic to the cytoplasmic leaflet of the canalicular membrane of hepatocytes. The authors have shown that the canalicular membrane of ATP8B1-deficient hepatocytes is less stable as evidenced by enhanced extraction of membrane constituents by bile salts. Recent evidence suggests membrane instability in ATP8B1-deficient hair cells of the ear, providing an explanation for hearing loss in ATP8B1 deficiency. Although the exact etiology of cholestasis is incompletely understood, it is hypothesized that ATP8B1 deficiency results in enhanced cholesterol extraction from the canalicular membrane, which impairs the function of the bile salt export pump (BSEP), resulting in cholestasis. Mutations in ATP8B1 also cause benign recurrent intrahepatic cholestasis, a milder variant of the disease characterized by episodes of cholestasis. The onset and resolution of the cholestatic episodes in these patients is still not well understood.

Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes?

Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed. Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations. The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p=0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of alpha-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges. The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and alpha-tocopherol levels within reference ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended.

Rezidivierende Schwangerschaftscholestase und perlenschnurartige Choledocholithiasis bei einer Patientin mit Stoppcodon im ABCB4-Gen des hepatischen Phospholipidtransporters

We report the case of a 40-years-old female patient with recurrent cholestatic liver disease who presented twice with severe intrahepatic cholestasis of pregnancy and pronounced choledocholithiasis between pregnancies. Bile duct stones were removed endoscopically and a laparoscopic cholecystectomy was performed after the second pregnancy. Liver histology revealed intrahepatic cholestasis with portal inflammation and fibrosis, resembling progressive familial intrahepatic cholestasis (PFIC). Molecular genetic studies identified the heterozygous mutation c.957C > T in the ABCB4 gene encoding the hepatobiliary phospholipid transporter. This is the first report of this mutation that introduces a stop codon in an index patient with intrahepatic cholestasis of pregnancy and multiple bile duct stones. In addition, we detected the ABCB11 polymorphism V 444A, which is associated with a decreased expression of the bile salt export pump. Whereas homozygous carriers of the ABCB4 mutation develop PFIC type 3, the heterozygous ABC transporter mutations represent genetic risk factors for cholelithiasis and recurrent cholestatic hepatitis upon challenge with oral contraceptives or during pregnancy. Of note, the patient presented with normal serum gamma-glutamyltranspeptidase activities during pregnancy-associated cholestatic episodes but normal liver enzymes after delivery, whereas choledocholithiasis was associated with high gamma-glutamyl transpeptidase levels. It is unknown whether ursodeoxycholic acid prevents cholestasis or gallstones in patients with ABCB4 deficiency.

Prognosis, with evaluation of general biochemistry, of liver disease in lymphoedema cholestasis syndrome 1 (LCS1/Aagenaes syndrome)

Objective. To investigate the prognosis of liver disease in Aagenaes syndrome (lymphoedema cholestasis syndrome 1 (LCS1)), which is an autosomal recessive inherited syndrome consisting of neonatal cholestasis with intermittent cholestatic episodes in childhood into adulthood and development of lymphoedema. Forty Norwegian patients are known to have this condition, 25 of whom are alive. A clinical description of the liver disease is supplied with a case-control study. Material and methods. In this paper we review the course of the liver disease in the Norwegian cohort of patients and present results from a case-control study in the patients above 10 years of age. The case-control study was performed on 15 patients without clinical cholestasis (itching and sometimes jaundice) at the time of the study. An evaluation of 11 patients above 15 years of age without chronic biochemical cholestasis (increased alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and/or serum bile acids) was also carried out. For each patient one randomly identified control person was included (15 in one study, 11 in the other). Results. Cirrhosis with either transplantation or death in infancy or early childhood occurred in six patients; slowly developing cirrhosis occurred in three patients. Two patients may be in the process of developing cirrhosis. Significantly increased ALP and GGT levels were found in patients with normal liver biochemistry in the preceding years when compared with the case control group. Additionally, albumin was found to be lower in older patients. Conclusions. Compared with that for other types of hereditary neonatal cholestasis, patients with LCS1 have a relatively good prognosis. More than 50% can expect a normal life span.

Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of γ-glutamyl transpeptidase

Objective: Rifampicin is an effective drug against pruritus in intrahepatic cholestasis. However, there is no specific hepatic disease in which its use could cause undoubtedly biochemical improvement. The aim of this study was to describe patients with complete remission of cholestatic symptoms after rifampicin therapy. Methods: We reported three female patients with intrahepatic cholestasis with no evidence of viral, metabolic, or autoimmune liver diseases. Total bilirubin levels ranged from 13.2 to 27.2 mg/dl (before the first treatment with rifampicin), and in all of them γ-glutamyl transpeptidase values were within the normal range or slightly increased. Rifampicin therapy was administered orally, without any concomitant drug, with an effective dosage of 5–17 mg/kg/day. Results: In all patients, pruritus ceased completely and bilirubin returned to normal values. The symptoms recurred after rifampicin withdrawal on, at least, three occasions in each patient, and these symptoms were always eliminated after its reintroduction. The patients had a total of 16 cholestatic episodes during a follow-up of 8 yr, with a complete clinical recovery in all of them. Undergoing therapy with a suitable dosage of rifampicin, none of the patients had a cholestatic crisis even during a period for as long as 12 months. The diagnosis of two patients was consistent with benign recurrent intrahepatic cholestasis, and it was not well defined in the remaining. Conclusion: Rifampicin may induce clinical remission, and perhaps prevent clinical relapses of intrahepatic cholestasis with normal or slightly increased levels of γ-glutamyl transpeptidase.

Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of γ-glutamyl transpeptidase

Objective: Rifampicin is an effective drug against pruritus in intrahepatic cholestasis. However, there is no specific hepatic disease in which its use could cause undoubtedly biochemical improvement. The aim of this study was to describe patients with complete remission of cholestatic symptoms after rifampicin therapy. Methods: We reported three female patients with intrahepatic cholestasis with no evidence of viral, metabolic, or autoimmune liver diseases. Total bilirubin levels ranged from 13.2 to 27.2 mg/dl (before the first treatment with rifampicin), and in all of them γ-glutamyl transpeptidase values were within the normal range or slightly increased. Rifampicin therapy was administered orally, without any concomitant drug, with an effective dosage of 5–17 mg/kg/day. Results: In all patients, pruritus ceased completely and bilirubin returned to normal values. The symptoms recurred after rifampicin withdrawal on, at least, three occasions in each patient, and these symptoms were always eliminated after its reintroduction. The patients had a total of 16 cholestatic episodes during a follow-up of 8 yr, with a complete clinical recovery in all of them. Undergoing therapy with a suitable dosage of rifampicin, none of the patients had a cholestatic crisis even during a period for as long as 12 months. The diagnosis of two patients was consistent with benign recurrent intrahepatic cholestasis, and it was not well defined in the remaining. Conclusion: Rifampicin may induce clinical remission, and perhaps prevent clinical relapses of intrahepatic cholestasis with normal or slightly increased levels of γ-glutamyl transpeptidase.

Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: A study of bile acid metabolism

Ursodeoxycholic acid was administered to a patient with benign recurrent intrahepatic cholestasis to prevent cholestatic episodes. A detailed study of bile acid metabolism in this patient was carried out in the anicteric and icteric phases before and after ursodeoxycholic acid (750 mg/day) administration. Urinary, biliary and serum bile acids were measured by gas chromatography-mass spectrometry and by high-performance liquid chromatography techniques. During the anicteric phase the daily urinary excretion and serum concentrations of bile acids were within normal ranges, indicating normal hepatic uptake and secretion of bile acids during the cholestasis-free period. Only slight qualitative differences from normal individuals were observed; the relative proportions of deoxycholic acid in the bile and serum were higher, and 12-oxo-lithocholic acid was the predominant urinary bile acid. During the icteric phase a marked increase in the urinary excretion of primary bile acids and C-1, C-2, C-4 and C-6 hydroxylated metabolites was found. Serum bile acid concentrations increased before the rise in bilirubin, suggesting an acute disturbance in bile acid transport at the onset of the cholestatic attack. After ursodeoxycholic acid administration in the anicteric phase, bile became enriched with the exogenous bile acid, but little qualitative change was found in the other metabolites present in the urine, serum or bile during the anicteric or icteric phases. Prolonged administration of ursodeoxycholic acid failed to prevent recurrence of a cholestatic episode, suggesting that in benign recurrent intrahepatic cholestasis, oral ursodeoxycholic acid may be of little benefit in the treatment or prevention of cholestasis despite marked enrichment of the bile acid pool with this hydrophilic bile acid.

Plasmapheresis : An effective therapy for cholestatic episodes of benign recurrent intrahepatic cholestasis ?

Plasmapheresis : An effective therapy for cholestatic episodes of benign recurrent intrahepatic cholestasis ?