Forms Of Intrahepatic Cholestasis Research Articles

Biopsie hépatique dans la prise en charge des cholestases de l’enfant

AbstractLiver biopsy remains the cornerstone of assessment for determining the diagnosis and prognosis during the management of a child with persistent cholestasis. Abdominal ultrasonography can be used to explore the intra- or extrahepatic origin of the cholestasis, which is the basis of the etiological hypothesis. While the diagnosis of biliary atresia, a diagnostic emergency, does not usually require any biopsy, diagnosis of most forms of intrahepatic cholestasis is facilitated by liver biopsy and by co-ordination of histopathological study with next-generation sequencing analysis.

ANKRD1 and SPP1 as diagnostic markers and correlated with immune infiltration in biliary atresia.

The diagnosis of biliary atresia (BA) remains a clinical challenge, reliable biomarkers that can easily distinguish BA and other forms of intrahepatic cholestasis (IC) are urgently needed.Differentially expressed genes were identified by R software. The least absolute shrinkage and selection operator regression and support vector machine algorithms were used to filter the diagnostic biomarkers of BA. The candidate biomarkers were further validated in another independent cohort of patients with BA and IC. Then CIBERSORT was used for estimating the fractions of immune cell types in BA. Gene set enrichment analyses were conducted and the correlation between diagnostic genes and immune cells was analyzed.A total of 419 differentially expressed genes in BA were detected and 2 genes (secreted phosphoprotein 1 [SPP1] and ankyrin repeat domain [ANKRD1]) among them were selected as diagnostic biomarkers. The SPP1 yielded an area under the curve (AUC) value of 0.798 (95% confidence interval [CI]: 0.742–0.854) to distinguish patients with BA from those with IC, and ANKRD1 exhibited AUC values of 0.686 (95% CI: 0.616–0.754) in discriminating BA patients and those with IC. Further integrating them into one variable resulted in a higher AUC of 0.830 (95% CI: 0.777–0.879). The regulatory T cells, M2 macrophages cells, CD4 memory T cells, and dendritic cells may be involved in the BA process. The ANKRD1 and SPP1 was negatively correlated with regulatory T cells.In conclusion, the ANKRD1 and SPP1 could potentially provide extra guidance in discriminating BA and IC. The immune cell infiltration of BA gives us new insight to explore its pathogenesis.

Molecular Modelling and Evaluation of Hidden Information in ABCB11 Gene Mutations.

Background:Cholestatic disorders are divided in the extra and intra-hepatic that created due to the severe liver diseases. ABCB11 encodes the bile salt export pump and this gene is mutated in several forms of intrahepatic cholestasis. So far, some molecular features of this gene was studies. Objective: Using a developed web server, we identified high number of rare codons in this gene, and four cases were related to BSEP-deficient patients which can be used for drug design. Material and Methods:By in-silico modelling of ABCB11, some of rare codons in different locations of ATP8b1 gene were identified and evaluated. Using several web servers a number of mutations that converted non-rare codons to rare codon in these patients were identified. Results: Some of these rare Codons were located at special positions by mutation of which, the new side chains do not seem suitable for protein structure and function. Furthermore, this mutation changed the protein folding rate that may have a critical role in proper folding. Thus, primary change of these codons contributes to BSEP deficiency. Conclusion:This work is a comprehensive analysis of rare codons of ABCB11 and assessment of a number of these rare codon in protein levels. Rare codons evaluation can enhance our understanding of ABCB11 structural protein of ABCB11, and help us to develop mutation-specific therapies in design of new drugs.

Intrahepatic Cholestasis Complicating Superior Mesenteric Artery Syndrome

Superior mesenteric artery (SMA) syndrome is a rare but potentially life-threatening entity of proximal intestinal obstruction, and characterized by extrinsic compression loss of fatty tissue of the aortomesenteric aperture as a result of a variety of debilitating conditions. Various gastrointestinal presentations of SMA syndrome have been documented. We herein describe a rare complication of SMA syndrome, in form of intrahepatic cholestasis. SMA syndrome seemingly appears under-diagnosed and the condition is more common in debilitating patients. A high awareness for timely recognition of SMA syndrome is important for proper management. Keywords: Hepatobiliary scan; Intrahepatic cholestasis; Superior mesenteric artery syndrome; Upper gastrointestinal obstruction

Genetic variants in adult liver diseases

In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development.

New approaches for cholestasis in hemoglobinopathies.

TO THE EDITOR: With approximately 7% of the worldwide population being carriers, hemoglobinopathies are the most common monogenic diseases [1]. The cumulative gene frequency of hemoglobinopathies in India is 4.2% [2]. Although liver involvement in the forms of intrahepatic cholestasis, hepatic crisis and cholelithiasis are common findings in patients with sickle cell disease [3], cholestasis is not a well-studied condition in non-transfusion dependent hemoglobinopathies. Herein, we report two cases of hemoglobin variants that presented with recurrent cholestasis and were managed with new therapeutic interventions.

Ductular Cholestasis, an Unusual Form of Intrahepatic Cholestasis, Associated With Cardiogenic Shock and Ventricular Assist Device

Ventricular assist devices have been shown to be effective in advanced heart failure selected patients. They often have borderline end-organ function, what facilitates organ dysfunction. Liver failure is difficult to manage and leads to increased morbidity and mortality. We report a case of ductular cholestasis, an unusual cholestatic hepatic failure with untractable coagulopathy, developed during the use of a magnetic levitation centrifugal pump, implanted as a bridge to heart transplantation, in a patient with cardiogenic shock (as an end-stage disease of idiopathic dilated cardiomyopathy). We discussed the pathophysiology of this entity and the possible related factors, including the assist device. Preemptive interventions have been advocated as the primary way of treatment. Preoperative optimization of heart function and avoidance of visceral hypoperfusion and sepsis may play a major role.

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing

The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. This work is a comprehensive analysis of 80% of ABCB11 missense mutations and single-nucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency.

Cholestatic Diseases of Pregnancy

Cholestatic diseases of pregnancy (CDP) are also referred to as intrahepatic cholestasis of pregnancy, recurrent cholestatic jaundice of pregnancy, icterus gravidarum and cholestatic hepatosis. It is a form of intrahepatic cholestasis characterized by pruritus and mild jaundice that usually occurs in the third trimester of pregnancy, though occurrence in earlier gestations is encountered occasionally. It is the second most common cause of jaundice occurring in pregnancy, ranking next to viral hepatitis1. IFEMED Journal Vol. 14 (1) 2008: pp. 23-25

Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis

Inherited dysfunction of the bile salt export pump BSEP (ABCB11) causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively. We functionally characterized novel ABCB11 mutations encountered in two patients with a PFIC2 and a BRIC2 phenotype, respectively. BSEP expression was determined in liver biopsies by immunohistochemistry. ABCB11 mutations were functionally characterized by taurocholate transport in SF9 cells transfected with human ABCB11. The PFIC2 patient was compound heterozygous for a splicing mutation in intron 4 ((+3)A > C) combined with an early stop codon at position 930 (R930X), while the BRIC2 patient was compound heterozygous for two nonsynonymous mutations in exon 9 (E297G) and exon 12 (R432T), respectively. Hepatic BSEP expression was absent in PFIC2 and preserved in BRIC2. In BRIC2, taurocholate transport was decreased to 13% and 20% of reference levels for R432T and E297G, respectively. The intron 4 (+3)A > C, R930X and R432T represent previously undescribed mutations of the ABCB11 gene that confer a PFIC2 and a BRIC2 phenotype, respectively. By combining functional in-vitro characterization with immunohistochemical detection of variant BSEP we provide direct evidence for the role of ABCB11 mutations in the pathogenesis of different forms of intrahepatic cholestasis.

Intrahepatic cholestasis: Summary of an American Association for the Study of Liver Diseases single-topic conference

Intrahepatic cholestasis: Summary of an American Association for the Study of Liver Diseases single-topic conference

Cellular Mechanisms of Intrahepatic Cholestasis

Most forms of intrahepatic cholestasis are caused by a failure of hepatocytes to secrete osmotically active bile constituents into the minute channels of bile canaliculi. This overall vectorial bile secretory process is dependent upon a variety of polarised active transport functions at the basolateral (sinusoidal and lateral) and canalicular plasma membrane domains, as well as upon the coordinated vectorial movement of intracellular vesicles. Although considerable progress has been made in recent years in the identification, characterisation and exact localisation of a number of polarised hepatocellular transport systems, the primary mechanisms and targets leading to defective bile secretion and cholestasis are still not completely understood. For example, not all reported experimental data are compatible with the concept that estrogen-induced cholestasis represents a predominant sinusoidal disease process. In addition, the pathophysiological significance of disturbed transcytotic pathways and/or disrupted intracellular calcium homeostasis are not yet clear. For many forms of cholestasis, it remains uncertain as to whether leaky tight junctions represent a primary cause rather than a secondary phenomenon of the cholestatic state. However, the ongoing progress in the understanding of the normal mechanisms involved in the establishment, maintenance and regulation of ion homeostasis and polar transport functions in hepatocytes will, undoubtedly, improve our knowledge of the pathogenesis of intrahepatic cholestasis and, it is hoped, lead to better therapeutic strategies in the near future.

Intrahepatic “cholestasis facies”: Is it specific for Alagille syndrome?

In 1975 Alagille described in the English literature a syndromatic form of intrahepatic biliary hypoplasia associated with characteristic facial features (prominent forehead, deep-set eyes, mild hypertelorism, straight nose, and small pointed chin). To test the specificity of the facies for Alagille syndrome, close-up facial photographs of 15 children and young adults with various forms of intrahepatic cholestasis (including seven with Alagille syndrome) were examined by 13 pediatric hepatologists from the United States and Canada and by Dr. Alagille and eight of his co-workers from France, without knowledge of the individual diagnoses. Each examiner was asked to identify the patients with facies characteristic for Alagille syndrome. Fifty-one percent of the U.S./Canadian group's matchings and 49% of the French group's matchings of facies to underlying liver disease (presence or absence of Alagille syndrome) were incorrect. The sensitivity of the facies for diagnosing Alagille syndrome was 54% and 32%, the specificity 44% and 68%, and the predictive value 46% and 47% based on the U.S./Canadian and French groups, respectively. "Cholestasis facies" does not appear specific for Alagille syndrome; rather, it seems to be a general feature of congenital intrahepatic cholestatic liver disease.