scholarly journals New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Eva Sticova ◽  
Milan Jirsa ◽  
Joanna Pawłowska
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Bile Secretion ◽  
Drug Induced ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
End Stage

Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)—with onset in early infancy and progression to end-stage liver disease—to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles ofATP8B1,ABCB11,ABCB4,TJP2,andNR1H4have been described. In addition to familial intrahepatic cholestasis, partial defects inATP8B1,ABCB11,andABCB4predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.

scholarly journals Combination of Novel c.3484G> T/p.Glu162Ter Variant in ABCB11 and c.208G> A/p.Asp70Asn Variant in ATP8B1 Are Associated with Severe Symptoms in Progressive Family Intrahepatic Cholestasis

2020 ◽  
Vol 09 (04) ◽  
pp. 285-288
Author(s):  
Mervan Bekdas ◽  
Guray Can ◽  
Recep Eroz ◽  
Selma Erdogan Duzcu
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Bile Secretion ◽  
Peripheral Blood Sample ◽  
Portal Fibrosis ◽  
Traditional Treatment ◽  
Pathogenic Variants ◽  
Chronic Cholestasis ◽  
Whole Exome

AbstractProgressive family intrahepatic cholestasis (PFIC) is an autosomal recessive disease that causes chronic cholestasis. It is associated with pathogenic variants in genes that encode proteins involved in bile secretion to canaliculus from hepatocytes. In this study, we present a 16-year-old boy who presented with severe pruritus and cholestatic jaundice. All possible infectious etiologies were negative. A liver biopsy was consistent with intrahepatic cholestasis and portal fibrosis. DNA was isolated from a peripheral blood sample, and whole exome sequencing was performed. A novel c.3484G > T/p.Glu162Ter variant in the ABCB11 gene and a c.208G> A/p.Asp70Asn variant in the ATP8B1 gene were detected. Despite traditional treatment, the patient's recurrent severe symptoms did not improve. The patient was referred for a liver transplantation. This novel c.3484G > T/p.Glu162Ter variant is associated with a severe and recurrent presentation, and the two compound variants could explain the severity of PFIC.

scholarly journals Liver Transplantation in Progressive Familial Intrahepatic Cholestasis With Normal Gamma-Glutamyl Transferase: Evaluation of Post-Transplant Steatosis and Steatohepatitis

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Mohammad Hossein Anbardar ◽  
Seyed Mohsen Dehghani ◽  
Maryam Poostkar ◽  
Seyed Ali Malek-Hosseini
Keyword(s):  
Liver Transplantation ◽  
Growth Retardation ◽  
Intrahepatic Cholestasis ◽  
Clinical Manifestations ◽  
Gamma Glutamyl Transferase ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Post Transplant ◽  
End Stage Liver Disease ◽  
Glutamyl Transferase ◽  
End Stage

Background: Progressive familial intrahepatic cholestasis is a disease presenting with severe cholestasis and progressing to the end-stage liver disease later. Liver transplantation is a treatment modality available for progressive familial intrahepatic cholestasis, especially in patients with end-stage liver disease or those who are unsuitable for or have failed biliary diversion. Objectives: To evaluate clinical and pathological characteristics of progressive familial intrahepatic cholestasis patients who had undergone liver transplantation and to determine post-transplant steatosis and steatohepatitis. Methods: We evaluated 111 progressive familial intrahepatic cholestasis patients with normal gamma-glutamyl transferase that performed liver transplantation in Shiraz Transplant Center in Iran between March 2000 and March 2017. Results: The most common clinical manifestations were jaundice and pruritus. Growth retardation and diarrhea were detected in 76.6% and 42.5% of the patients. After transplantation, growth retardation was seen in 31.5% of the patients, and diarrhea in 36.9% of them. Besides, 29.1% of the patients died post-transplant. Post-transplant liver biopsies were taken from 50 patients, and 15 (30%) patients had steatosis or steatohepatitis, five of whom (10%) had macro-vesicular steatosis alone, and 10 (20%) had steatohepatitis. Only one patient showed moderate bridging fibrosis (stage III), and none of them showed severe fibrosis. Conclusions: Liver transplantation is the final treatment option for these patients, and it can relieve most clinical manifestations. However, post-transplant mortality rate was relatively high in our center. Diarrhea, growth retardation, and steatosis are unique post-transplant complications in these patients. The rate of post-transplant steatosis and steatohepatitis in patients with liver biopsy in our study was 30%, with a significant difference from previous studies.

scholarly journals Lyme Neuroborreliosis: Mechanisms of B. burgdorferi Infection of the Nervous System

2021 ◽  
Vol 11 (6) ◽  
pp. 789
Author(s):  
Lenzie Ford ◽  
Danielle M. Tufts
Keyword(s):  
United States ◽  
Nervous System ◽  
Antibiotic Treatment ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
The United States ◽  
Sensu Stricto ◽  
Lyme Neuroborreliosis

Lyme borreliosis is the most prevalent tick-borne disease in the United States, infecting ~476,000 people annually. Borrelia spp. spirochetal bacteria are the causative agents of Lyme disease in humans and are transmitted by Ixodes spp ticks. Clinical manifestations vary depending on which Borrelia genospecies infects the patient and may be a consequence of distinct organotropism between species. In the US, B. burgdorferi sensu stricto is the most commonly reported genospecies and infection can manifest as mild to severe symptoms. Different genotypes of B. burgdorferi sensu stricto may be responsible for causing varying degrees of clinical manifestations. While the majority of Lyme borreliae-infected patients fully recover with antibiotic treatment, approximately 15% of infected individuals experience long-term neurological and psychological symptoms that are unresponsive to antibiotics. Currently, long-term antibiotic treatment remains the only FDA-approved option for those suffering from these chronic effects. Here, we discuss the current knowledge pertaining to B. burgdorferi sensu stricto infection in the central nervous system (CNS), termed Lyme neuroborreliosis (LNB), within North America and specifically the United States. We explore the molecular mechanisms of spirochete entry into the brain and the role B. burgdorferi sensu stricto genotypes play in CNS infectivity. Understanding infectivity can provide therapeutic targets for LNB treatment and offer public health understanding of the B. burgdorferi sensu stricto genotypes that cause long-lasting symptoms.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

PEDIATRICS ◽  
1973 ◽  
Vol 51 (6) ◽  
pp. 998-1007
Author(s):  
Mark Ballow ◽  
Carmi Margolis ◽  
Bernard Schachtel ◽  
Y. Edward Hsia
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Elevated Serum ◽  
Intermediate Form ◽  
Elevated Alkaline Phosphatase ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
Conjugated Hyperbilirubinemia ◽  
Genetically Determined ◽  
Fat Soluble Vitamins ◽  
Autosomal Recessive Pattern

Two brothers with an early onset of fluctuating jaundice, pruritus, malabsorption, and rickets are reported. Biochemical features included conjugated hyperbilirubinemia, elevated alkaline phosphatase, normal cholesterol, slightly elevated transaminase, elevated serum bile salts, and hypoglycemia. There was also evidence of rickets and deficiency of the fat soluble vitamins. Histological appearance of the liver showed bile stasis and paucity of the interlobular bile ducts. The familial incidence, clinical course, biochemical findings, and liver histology in our cases and in similar reported cases, are distinctive of an intermediate form of familial progressive intrahepatic cholestasis, milder than congenital intrahepatic biliary atresia, but more severe than benign recurrent intrahepatic cholestasis. A defect in the hepatic excretory mechanism is postulated for this group of intrahepatic cholestatic disorders which appear to be genetically determined with an autosomal recessive pattern of inheritance. Both brothers had symptomatic and chemical improvement with phenobarbital therapy.

scholarly journals An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Chun-Bing Chen ◽  
Riichiro Abe ◽  
Ren-You Pan ◽  
Chuang-Wei Wang ◽  
Shuen-Iu Hung ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Drug Hypersensitivity ◽  
Clinical Manifestations ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Cell Receptor ◽  
Stevens Johnson Syndrome ◽  
Diagnostic Tools ◽  
Drug Induced ◽  
Skin Reactions

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function

2015 ◽  
Vol 33 (3) ◽  
pp. 314-318 ◽  
Author(s):  
Jyoti Naik ◽  
Dirk R. de Waart ◽  
Karina Utsunomiya ◽  
Suzanne Duijst ◽  
Kam Ho Mok ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Membrane Transporters ◽  
Cholestatic Liver Disease ◽  
Canalicular Membrane ◽  
Transport Vesicles ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
Conjugated Hyperbilirubinemia ◽  
Deficient Mice

P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe Cholestatic liver disease. Mutation of ATP8B1 cause progressive familial Intrahepatic Cholestasis type 1 (PFIC1)and benign recurrent intrahepatic cholestasis type 1 (BRIC 1). From our observations we hypothesized that ATP8B1 deficiency causes a phospholipids randomization at the canalicular membrane, which results in extraction of cholesterol due to increase sensitivity of the canalicular membrane. Deficiency of ATP11C causes conjugated hyperbilirubinemia. In our preliminary result we observed accumulation of unconjugated bile salts in Atp11c deficient mice probably because of regulation in the expression or function of OATP1B2. Similar to ATP8B1, ATP11C have regulation on membrane transporters.

scholarly journals Molecular Mechanisms for Biliary Phospholipid and Drug Efflux Mediated by ABCB4 and Bile Salts

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Shin-ya Morita ◽  
Tomohiro Terada
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Molecular Mechanisms ◽  
Mixed Micelles ◽  
Biliary Cirrhosis ◽  
Culture Studies ◽  
Physiological Relevance ◽  
Type 3 ◽  
Cholestasis Of Pregnancy

On the canalicular membranes of hepatocytes, several ABC transporters are responsible for the secretion of bile lipids. Among them, ABCB4, also called MDR3, is essential for the secretion of phospholipids from hepatocytes into bile. The biliary phospholipids are associated with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallization. Mutations in theABCB4gene result in progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, low-phospholipid-associated cholelithiasis, primary biliary cirrhosis, and cholangiocarcinoma.In vivoand cell culture studies have demonstrated that the secretion of biliary phospholipids depends on both ABCB4 expression and bile salts. In the presence of bile salts, ABCB4 located in nonraft membranes mediates the efflux of phospholipids, preferentially phosphatidylcholine. Despite high homology with ABCB1, ABCB4 expression cannot confer multidrug resistance. This review summarizes our current understanding of ABCB4 functions and physiological relevance, and discusses the molecular mechanism for the ABCB4-mediated efflux of phospholipids.

ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine

2019 ◽  
Vol 400 (10) ◽  
pp. 1245-1259 ◽  
Author(s):  
Martin Prescher ◽  
Tim Kroll ◽  
Lutz Schmitt
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Biliary Tree ◽  
Drug Induced ◽  
Bile Formation ◽  
Canalicular Membrane ◽  
Outer Leaflet ◽  
Separate Step ◽  
Type 3

Abstract Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30–40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.

Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis

1995 ◽  
Vol 57 (3) ◽  
pp. 479-482 ◽  
Author(s):  
Tom J. de Koning ◽  
Lodewijk A. Sandkuijl ◽  
Jan E. A. R. de Schryver ◽  
Eric A. M. Hennekam ◽  
Frits A. Beemer ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance ◽  
Benign Recurrent Intrahepatic Cholestasis

scholarly journals The flickering jaundice

2020 ◽  
Vol 8 (2) ◽  
pp. 757
Author(s):  
Cynthia Amrutha ◽  
Shipra Rai
Keyword(s):  
Case Report ◽  
Autosomal Recessive ◽  
Young Male ◽  
Autosomal Recessive Disorder ◽  
Diagnostic Procedures ◽  
Acute Onset ◽  
Cholestatic Jaundice ◽  
First Episode ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
End Stage

Benign Recurrent Intrahepatic Cholestasis (BRIC) is a rare autosomal recessive disorder characterized by intermittent episodes of jaundice and pruritus. It is also known as Summerskill-Walshe-Tygstrup syndrome. It is a benign disease with no progression to end stage liver disease.. The first episode of cholestatic jaundice occurs early in life and there are asymptomatic periods between attacks lasting weeks to years. This case report presents a young male who presented with severe pruritus and acute onset jaundice. He had his first episode of jaundice at the age of twelve and had several intermittent episodes since then. Diagnosis was made by the unique clinical presentation with exclusion of other causes of cholestatic jaundice. This case report highlights the importance of detecting such cases of rarity and preventing unnecessary invasive diagnostic procedures on such patients.

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