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American Journal of Clinical Dermatology Mar 2022Pruritus in pregnancy is a common and burdensome symptom that may be a first sign of a pregnancy-specific pruritic disease (atopic eruption of pregnancy, polymorphic... (Review)
Review
Pruritus in pregnancy is a common and burdensome symptom that may be a first sign of a pregnancy-specific pruritic disease (atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis, and intrahepatic cholestasis in pregnancy) or a dermatosis coinciding with pregnancy by chance. Despite its high prevalence, pruritus is often underrated by physicians, and data regarding the safety profiles of drugs for pruritus are very limited. In this review, we illustrate the epidemiology, possible pathophysiology, clinical characteristics, and diagnostic workup of various pregnancy-related diseases and discuss antipruritic treatments. The prevalence of pruritus in pregnancy demonstrates the importance of symptom recognition and the need for an holistic approach, taking into account both the potential benefits for the patient and the potential risks to the fetus.
Topics: Cholestasis, Intrahepatic; Exanthema; Female; Humans; Pemphigoid Gestationis; Pregnancy; Pregnancy Complications; Pruritus
PubMed: 35191007
DOI: 10.1007/s40257-021-00668-7 -
Canadian Journal of Gastroenterology &... 2021Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids,... (Review)
Review
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids, causing several adverse outcomes for fetuses, including an increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth. Genetic, hormonal, immunological, and environmental factors contribute to the pathogenesis of ICP, and the estrogen-bile acid axis is thought to play a dominant role. The advances in the past 10 years uncover more details of this axis. Moreover, dysregulation of extracellular matrix and oxygen supply, organelle dysfunction, and epigenetic changes are also found to cause ICP, illuminating more potential drug targets for interfering with. Here, we summarize the molecular pathogenesis of ICP with an emphasis on the advancement in the past 10 years, aiming to give an updated full view of this field.
Topics: Cholestasis, Intrahepatic; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications; Premature Birth; Stillbirth
PubMed: 34195157
DOI: 10.1155/2021/6679322 -
CMAJ : Canadian Medical Association... Dec 2022
Topics: Pregnancy; Female; Humans; Cholestasis, Intrahepatic; Pregnancy Complications
PubMed: 36511865
DOI: 10.1503/cmaj.220334 -
Journal of Biomedical Science Oct 2018Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated... (Review)
Review
BACKGROUND
Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.
MAIN BODY
The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.
SHORT CONCLUSION
Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.
Topics: Cholestasis, Intrahepatic; Humans; Jaundice, Obstructive
PubMed: 30367658
DOI: 10.1186/s12929-018-0475-8 -
World Journal of Gastroenterology Dec 2020Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for... (Review)
Review
Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for the complex process of bile formation and secretion, and/or caused by defects in the secretory machinery of cholangiocytes. Several mutations and pathways that lead to cholestasis have been described. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes. PFIC 1, also known as Byler's disease, is caused by mutations of the gene, which encodes the familial intrahepatic cholestasis 1 protein. PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump (BSEP) expression variations in the gene. Mutations of the gene result in lower expression of the multidrug resistance class 3 glycoprotein, leading to the third type of PFIC. Newer variations of this disease have been described. Loss of function of the tight junction protein 2 protein results in PFIC 4, while mutations of the gene, which encodes farnesoid X receptor, an important transcription factor for bile formation, cause PFIC 5. A recently described type of PFIC is associated with a mutation in the gene, important for the trafficking of BSEP and hepatocyte membrane polarization. In this review, we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.
Topics: ATP-Binding Cassette Transporters; Cholestasis; Cholestasis, Intrahepatic; Humans; Mutation
PubMed: 33384548
DOI: 10.3748/wjg.v26.i47.7470 -
Lancet (London, England) Mar 2019
Topics: Biomarkers; Cholestasis, Intrahepatic; Female; Humans; Parturition; Pregnancy; Pregnancy Complications
PubMed: 30773279
DOI: 10.1016/S0140-6736(18)32323-7 -
Clinics and Research in Hepatology and... Feb 2019Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is...
BACKGROUND AND AIMS
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is the first systematic review of the epidemiology, natural history and burden of PFIC.
METHODS
MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life (HRQoL) of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.
RESULTS
Of 1269 records screened, 20 were eligible (epidemiology, 17; humanistic burden, 5; both, 2). Incidence of intrahepatic cholestasis, including but not limited to PFIC, was 1/18 000 live births in one study that did not use genetic testing. In two studies of infants and children (2-18 years) with cholestasis, 12-13% had genetically diagnosed PFIC. Of the three main PFIC subtypes, PFIC2 was the most common (21-91% of patients). Common symptoms (e.g. pruritus, jaundice, hepatomegaly, splenomegaly) generally appeared at about 3 months of age and tended to emerge earliest in patients with PFIC2. Patients reported that pruritus was often severe and led to dermal damage and reduced HRQoL. Disease progression led to complications including liver failure and hepatocellular carcinoma, with 20-83% of patients requiring liver transplantation. Mortality was 0-87% across 10 studies (treatment varied among studies), with a median age at death of ~4 years in one study.
CONCLUSIONS
Patients with PFIC face debilitating symptoms and poor prognosis. Further research is needed to inform patient management and clinical trial design. Published data on the epidemiology and socioeconomic burden of PFIC is limited.
Topics: Cholestasis, Intrahepatic; Humans
PubMed: 30236549
DOI: 10.1016/j.clinre.2018.07.010 -
Orphanet Journal of Rare Diseases Jun 2021Progressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of... (Review)
Review
BACKGROUND
Progressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance.
METHODS
Databases including MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.
RESULTS
Three systematic reviews and twenty-two studies were eligible for inclusion for the epidemiology of PFIC including a total of 2603 patients. Study periods ranged from 3 to 33 years. Local population prevalence of PFIC was reported in three studies, ranging from 9.0 to 12.0% of children admitted with cholestasis, acute liver failure, or splenomegaly. The most detailed data come from the NAPPED study where native liver survival of >15 years is predicted in PFIC2 patients with a serum bile acid concentration below 102 µmol/L following bile diversion surgery. Burden of disease was mainly reported through health-related quality of life (HRQL), rates of surgery and survival. Rates of biliary diversion and liver transplant varied widely depending on study period, sample size and PFIC type, with many patients have multiple surgeries and progressing to liver transplant. This renders data unsuitable for comparison.
CONCLUSION
Using robust and transparent methods, this systematic review summarises our current knowledge of PFIC. The epidemiological overview is highly mixed and dependent on presentation and PFIC subtype. Only two studies reported HRQL and mortality results were variable across different subtypes. Lack of data and extensive heterogeneity severely limit understanding across this disease area, particularly variation around and within subtypes.
Topics: Activities of Daily Living; Child; Cholestasis; Cholestasis, Intrahepatic; Humans; Quality of Life
PubMed: 34082807
DOI: 10.1186/s13023-021-01884-4 -
Hepatology Communications Dec 2023Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the...
Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.
Topics: Humans; Alagille Syndrome; Quality of Life; Cholestasis; Pruritus
PubMed: 38055640
DOI: 10.1097/HC9.0000000000000314 -
Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis.International Journal of Molecular... Mar 2023Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more... (Review)
Review
Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (); 2. the multidrug resistance protein-2 (MRP2, ) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.
Topics: Adult; Humans; Cholestasis; Hepatocytes; Bile; Bile Acids and Salts; Cholestasis, Intrahepatic
PubMed: 36982896
DOI: 10.3390/ijms24065823