Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secretion of bile acids is the major driving force for bile flow in mammals. The recently described adenosine triphosphate (ATP)-dependent bile acid transporter, bile salt export pump (BSEP), formerly called sister of p-glycoprotein, is responsible for active transport of bile acids across the hepatocyte canalicular membrane into bile. It is now recognized that mutations in the gene encoding this protein (ABCB11) are responsible for a subgroup of infants and children with progressive familial cholestasis (PFIC-2), a cholestatic disorder causing extreme pruritus, growth failure, and progression to cirrhosis in the first decade of life. Understanding the structure and function of BSEP has improved our understanding of the mechanisms underlying bile secretion. Determining genotype/phenotype relationships in patients with mutations in this gene are currently ongoing.
 ...
PMID:BSEP: function and role in progressive familial intrahepatic cholestasis. 1174 42

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the occurrence of pruritus mostly in the third trimenon. Diagnosis is based on the presence of pruritus and elevated levels of serum bile acids in the absence of pruritic skin diseases. There is strong evidence of a genetic predisposition for ICP. Numerous studies have investigated the association of known cholestasis genes such as ABCB4 (also designated MDR3), ABCB11 ( BSEP) and ATP8B1 ( FIC1) with ICP. The results of these studies implicate a heterogeneous etiology of this syndrome. ICP increases the risk of preterm delivery and fetal loss. Furthermore, intense pruritus may necessitate premature induction of labor with its known higher frequency of complications for mother and child. Therefore, ICP pregnancies should be managed as high-risk pregnancies. Pharmaceuticals to alleviate pruritus or improve cholestasis like antihistamines, phenobarbital, anion exchange resins, dexamethasone or S-adenosylmethionine are not widely accepted because of questionable efficacy or side effects. Recent randomized studies have shown beneficial effects of ursodeoxycholic acid (UDCA) on laboratory data and pruritus in patients with ICP. Improved knowledge about the diagnostic classification of different types and pathophysiological mechanisms of ICP may allow for a more targeted treatment of this disease in future.
 ...
PMID:Diagnosis and therapy of intrahepatic cholestasis of pregnancy. 1524 12

Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP). Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis can be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of hepatocellular carcinoma, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy or specific targeted pharmacotherapy may represent alternative treatments in the future.
 ...
PMID:Progressive familial intrahepatic cholestasis. 1913 30

Bile formation at the canalicular membrane is a delicate process. This is illustrated by inherited liver diseases due to mutations in ATP8B1, ABCB11, ABCB4, ABCC2 and ABCG5/8, all encoding hepatocanalicular transporters. Effective treatment of these canalicular transport defects is a clinical and scientific challenge that is still ongoing. Current evidence indicates that ursodeoxycholic acid (UDCA) can be effective in selected patients with PFIC3 (ABCB4 deficiency), while rifampicin reduces pruritus in patients with PFIC1 (ATP8B1 deficiency) and PFIC2 (ABCB11 deficiency), and might abort cholestatic episodes in BRIC (mild ATP8B1 or ABCB11 deficiency). Cholestyramine is essential in the treatment of sitosterolemia (ABCG5/8 deficiency). Most patients with PFIC1 and PFIC2 will benefit from partial biliary drainage. Nevertheless liver transplantation is needed in a substantial proportion of these patients, as it is in PFIC3 patients. New developments in the treatment of canalicular transport defects by using nuclear receptors as a target, enhancing the expression of the mutated transporter protein by employing chaperones, or by mutation specific therapy show substantial promise. This review will focus on the therapy that is currently available as well as on those developments that are likely to influence clinical practice in the near future.
 ...
PMID:Liver disease associated with canalicular transport defects: current and future therapies. 2003 95

Progressive familial intrahepatic cholestasis is a syndrome of severe cholestasis progressing to biliary cirrhosis and liver failure that develops in childhood. This report describes two siblings with PFIC-2 who underwent living-related liver transplantation from their genetically proven heterozygous parents. Both patients had normal gamma-glutamyl transpeptidase levels, but showed severe pruritus with sleep disturbance, cholestasis, jaundice and growth failure. Genetic testing of each patient revealed two missense mutations of the bile salt export pump, S901R and C1083Y, which have not previously been associated with PFIC-2. Usual medical treatment failed to improve their clinical symptoms, and the two siblings underwent living-related liver transplantation from their heterozygous parents. The transplants improved their clinical symptoms significantly, and the patients have since shown age-appropriate growth. Electron microscopic findings of the explanted liver of the younger sister revealed dense and amorphous bile, which is characteristic of PFIC-2. In the cases presented here, living-related liver transplantation from a heterozygous donor was associated with better quality of life and improvement of growth, and thus appears to be a feasible option for PFIC-2 patients. Mutation analysis is a useful tool to help decide the course of treatment of PFIC.
 ...
PMID:Living-related liver transplantation for siblings with progressive familial intrahepatic cholestasis 2, with novel genetic findings. 2121 77

Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future.
 ...
PMID:Progressive familial intrahepatic cholestasis. 2314 90

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.
...
PMID:Progressive familial intrahepatic cholestasis. 2575 32

Familial intrahepatic cholestasis (FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phenotypes range from benign recurrent intrahepatic cholestasis (BRIC), associated with recurrent cholestatic attacks, to progressive FIC (PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency (PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency (PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.
 ...
PMID:Current and future therapies for inherited cholestatic liver diseases. 2822 21

Recurrent bile salt export pump (rBSEP) disease has been reported in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients following liver transplantation (LT) and is often refractory to standard anti-cellular rejection immunosuppressants. The mechanism of rBSEP disease is proposed to be a form of type II hypersensitivity reaction with de novo anti-BSEP antibodies blocking the function of allograft BSEP. Utilization of C4d has not been evaluated in rBSEP. We describe a girl with 3 episodes of rBSEP with severe pruritus at 8.9, 10.3, and 11.0 years post-LT, respectively. Patient's serum reacted with normal liver canaliculi by indirect immunofluorescence (IF), whereas patient's liver showed canalicular immunoglobulin G deposition. The histologic features of all 3 liver biopsies recapitulate PFIC2 with cholestatic giant cell hepatitis. Canalicular BSEP expression was not detected in areas of feathery degeneration by immunohistochemistry, but was retained in morphologically normal liver. By direct IF, C4d showed diffuse sinusoidal staining in the third biopsy. Patient responded well to rituximab with or without intravenous immunoglobulin with subsiding symptoms and normalization of serum bile acid levels. In conclusion, rBSEP disease should be considered in the differential diagnosis when evaluating for rejection in a PFIC2 patient post-LT presenting with pruritus. A portion of liver core may be snap frozen in OCT medium for possible direct IF for C4d, that can serve as a surrogate marker for complement activation and antibody-mediated graft dysfunction.
 ...
PMID:Post-transplant Recurrent Bile Salt Export Pump Disease: A Form of Antibody-mediated Graft Dysfunction and Utilization of C4d. 2894 5

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515-528).
 ...
PMID:Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. 2976 Nov 68


1 2 Next >>