BACKGROUND AND AIM: Gene defects contribute to the aetiology of intrahepatic cholestasis. We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis. PATIENTS AND METHODS: Both paediatric (n = 33) and adult (n = 18) patients with cholestatic liver disease of unknown aetiology were eligible. WES was used for reassessment of 34 patients (23 children) without diagnostic genotypes in ABCB11, ATP8B1, ABCB4 or JAG1 demonstrable by previous Sanger sequencing, and for primary assessment of additional 17 patients (10 children). Nasopharyngeal swab mRNA was analysed to address variant pathogenicity in two families. RESULTS: WES revealed biallelic variation in 3 ciliopathy genes (PKHD1, TMEM67 and IFT172) in 4 clinically unrelated index subjects (3 children and 1 adult), heterozygosity for a known variant in PPOX in one adult index subject, and homozygosity for an unreported splice-site variation in F11R in one child. Whereas phenotypes of the index patients with mutated PKHD1, TMEM67, and PPOX corresponded with those elsewhere reported, how F11R variation underlies liver disease remains unclear. Two unrelated patients harboured different novel biallelic variants in IFT172, a gene implicated in short-rib thoracic dysplasia 10 and Bardet-Biedl syndrome 20. One patient, a homozygote for IFT172 rs780205001 c.167A>C p.(Lys56Thr) born to first cousins, had liver disease, interpreted on biopsy aged 4y as glycogen storage disease, followed by adult-onset nephronophthisis at 25y. The other, a compound heterozygote for novel frameshift variant IFT172 NM_015662.3 c.2070del p.(Met690Ilefs*11) and 2 syntenic missense variants IFT172 rs776310391 c.157T>A p.(Phe53Ile) and rs746462745 c.164C>G p.(Thr55Ser), had a severe 8mo cholestatic episode in early infancy, with persisting hyperbilirubinemia and fibrosis on imaging studies at 17y. No patient had skeletal malformations. CONCLUSION: Our findings suggest association of IFT172 variants with non-syndromic cholestatic liver disease.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• cholestáza * genetika   MeSH
• cytoskeletální proteiny genetika   MeSH
• flavoproteiny genetika   MeSH
• genotyp MeSH
• intrahepatální cholestáza * genetika   diagnóza   MeSH
• lidé MeSH
• mitochondriální proteiny genetika   MeSH
• mutace MeSH
• protoporfyrinogenoxidasa genetika   MeSH
• sekvenování exomu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

ATP-binding cassette (ABC) subfamily B member 4 (ABCB4), also known as multidrug resistance protein 3 (MDR3), encoded by ABCB4, is involved in biliary phospholipid secretion, protecting hepatobiliary system from deleterious detergent and lithogenic properties of the bile. ABCB4 mutations altering canalicular ABCB4 protein function and expression may have variable clinical presentation and predispose to several human liver diseases. Well-established phenotypes of ABCB4 deficit are: progressive familial intrahepatic cholestasis type 3, gallbladder disease 1 (syn. low phospholipid associated cholelithiasis syndrome), high ɣ-glutamyl transferase intrahepatic cholestasis of pregnancy, chronic cholangiopathy, and adult biliary fibrosis/cirrhosis. Moreover, ABCB4 aberrations may be involved in some cases of drug induced cholestasis, transient neonatal cholestasis, and parenteral nutrition-associated liver disease. Recently, genome-wide association studies have documented occurrence of malignant tumours, predominantly hepatobiliary malignancies, in patients with ABCB4/MDR3 deficit. The patient's age at the time of the first presentation of cholestatic disease, as well as the severity of liver disorder and response to treatment are related to the ABCB4 allelic status. Mutational analysis of ABCB4 in patients and their families should be considered in all individuals with cholestasis of unknown aetiology, regardless of age and/or time of onset of the first symptoms.

• MeSH
• alely MeSH
• biliární cirhóza genetika   MeSH
• cholagoga a choleretika terapeutické užití   MeSH
• cholelitiáza genetika   MeSH
• cholestáza genetika   MeSH
• intrahepatální cholestáza genetika   MeSH
• komplikace těhotenství genetika   MeSH
• kyselina ursodeoxycholová terapeutické užití   MeSH
• lékové postižení jater genetika   MeSH
• lidé MeSH
• nemoci jater etiologie   genetika   MeSH
• nemoci žlučníku genetika   MeSH
• nemoci žlučových cest genetika   MeSH
• P-glykoproteiny nedostatek   genetika   metabolismus   MeSH
• parenterální výživa škodlivé účinky   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• cholestáza * etiologie   genetika   klasifikace   MeSH
• Criglerův-Najjarův syndrom etiologie   genetika   klasifikace   MeSH
• familiární hyperbilirubinemie diagnóza   etiologie   genetika   MeSH
• genetické nemoci vrozené * diagnóza   etiologie   genetika   MeSH
• Gilbertova nemoc diagnóza   etiologie   genetika   MeSH
• hyperbilirubinemie * etiologie   genetika   klasifikace   MeSH
• intrahepatální cholestáza etiologie   genetika   klasifikace   MeSH
• komplikace těhotenství diagnóza   etiologie   genetika   MeSH
• lidé MeSH
• žloutenka chronická idiopatická diagnóza   etiologie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

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 of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose 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.

• MeSH
• ABC transportér, podrodina B, člen 11 genetika   MeSH
• adenosintrifosfatasy genetika   MeSH
• intrahepatální cholestáza genetika   metabolismus   MeSH
• komplikace těhotenství genetika   MeSH
• lidé MeSH
• P-glykoproteiny nedostatek   genetika   MeSH
• proteiny přenášející anionty metabolismus   MeSH
• receptory cytoplazmatické a nukleární genetika   metabolismus   MeSH
• žlučové kyseliny a soli biosyntéza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Intrahepatic cholestasis of pregnancy (ICP) is a frequent liver disorder, mostly occurring in the third trimester. ICP is not harmful to the mothers but threatens the fetus. The authors evaluated steroid alterations in maternal and mixed umbilical blood to elucidate their role in the ICP development. Ten women with ICP were included in the study. Steroids in the maternal blood were measured by Gas Chromatography-Mass Spectrometry (GC-MS) (n=58) and RIA (n=5) at the diagnosis of ICP, labor, day 5 postpartum, week 3 postpartum and week 6 postpartum. The results were evaluated by ANOVA consisting of the subject factor, between subject factors ICP, gestational age at the diagnosis of ICP and gestational age at labor, within-subject factor Stage and ICP × Stage interaction. The 17 controls were firstly examined in the week 36 of gestation. ICP patients showed reduced CYP17A1 activity in the C17,20 lyase step thus shifting the balance between the toxic conjugated pregnanediols and harmless sulfated 5alpha/beta-reduced-17-oxo C19 steroids. Hence, more toxic metabolites originating in maternal liver from the placental pregnanes may penetrate backward to the fetal circulation. As these alterations persist in puerperium, the circulating steroids could be potentially used for predicting the predisposition to ICP even before next pregnancy.

• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• genetická predispozice k nemoci genetika   MeSH
• intrahepatální cholestáza krev   diagnóza   genetika   MeSH
• jaterní testy trendy   MeSH
• komplikace těhotenství krev   diagnóza   genetika   MeSH
• lidé MeSH
• placentární oběh fyziologie   MeSH
• steroidy krev   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• deficit alfa1-antitrypsinu * diagnóza   genetika   MeSH
• hemochromatóza * diagnóza   genetika   MeSH
• hepatolentikulární degenerace * diagnóza   etiologie   terapie   MeSH
• intrahepatální cholestáza * diagnóza   genetika   terapie   MeSH
• jaterní porfyrie * diagnóza   genetika   MeSH
• lidé MeSH
• nemoci jater * genetika   MeSH
• vrozené poruchy metabolismu * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• deficit alfa1-antitrypsinu diagnóza   genetika   MeSH
• familiární hyperbilirubinemie diagnóza   genetika   MeSH
• hemochromatóza diagnóza   genetika   MeSH
• hepatolentikulární degenerace diagnóza   etiologie   terapie   MeSH
• intrahepatální cholestáza diagnóza   genetika   terapie   MeSH
• jaterní porfyrie diagnóza   genetika   MeSH
• lidé MeSH
• nemoci jater * genetika   MeSH
• vrozené poruchy metabolismu * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Intrahepatic cholestasis of pregnancy (ICP) is a disorder of liver function, commonly occurring in the third trimester but sometimes also as soon as the end of the second trimester of pregnancy. Symptoms of this disorder include pruritus, plus abnormal values of bile acids and hepatic transaminases. After birth, symptoms disappear and liver function returns to normal. Though ICP is relatively non-complicated and often symptomatically mild from the point-of-view of the mother, it presents a serious risk to the fetus, making this disease the subject of great interest. The etiology and pathogenesis of ICP is multifactorial and as yet not fully elucidated. Hormonal factors likely play a significant role, along with genetic as well as exogenous factors. Here we summarize the knowledge of changes in steroid hormones and their role in the development of intrahepatic cholestasis of pregnancy. In addition, we consider the role of exogenous factors as possible triggers of steroid hormone changes, the relationship between metabolic steroids and bile acids, as well as the combination of these factors in the development of ICP in predisposed pregnant women.

• MeSH
• intrahepatální cholestáza krev   etiologie   genetika   MeSH
• komplikace těhotenství krev   etiologie   genetika   MeSH
• lidé MeSH
• pohlavní steroidní hormony fyziologie   MeSH
• těhotenství MeSH
• žlučové kyseliny a soli krev   genetika   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Progresivní familiární intrahepatální cholestáza 2. typu je autozomálně recesivně dědičná cholestáza podmíněná defektem ATP dependentní pumpy žlučových kyselin BSEP. V práci jsou uvedeny kazuistiky a souborná data šesti dětí s tímto onemocněním diagnostikovaných v ČR v letech 2005–2015, vč. výsledků jejich molekulárně genetických analýz, kterými bylo nalezeno sedm nových mutací v genu ABCB11.

Summary: Progressive familial intrahepatic cholestasis type 2 is an autosomal recessive cholestatic liver disease caused by a deficiency in canalicular ATP-dependent bile salt export pump BSEP. We present case reports and collected data of six Czech patients suffering from this disease, diagnosed between 2005 and 2015, in whom seven new mutations in ABCB11 were revealed by molecular analysis. Key words: progressive familial intrahepatic cholestasis type 2 - BSEP – ursodeoxycholic acid – pruritus – liver transplantation The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers. Submitted: 20. 11. 2015 Accepted: 27. 11. 2015

• Klíčová slova
• BSEP, ABCB1,
• MeSH
• ABC transportéry analýza   genetika   metabolismus   MeSH
• dítě MeSH
• hepatocelulární karcinom diagnóza   komplikace   MeSH
• imunohistochemie MeSH
• intrahepatální cholestáza * diagnóza   genetika   terapie   MeSH
• kojenec MeSH
• kyselina ursodeoxycholová terapeutické užití   MeSH
• lidé MeSH
• membránové glykoproteiny analýza   MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• pruritus etiologie   farmakoterapie   MeSH
• transplantace jater MeSH
• transportní proteiny analýza   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• Klíčová slova
• hepatobiliární transport, transportní receptorové mechanismy,
• MeSH
• biliární cirhóza diagnóza   farmakoterapie   genetika   MeSH
• bilirubin fyziologie   MeSH
• cholestáza * klasifikace   MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• dospělí MeSH
• intrahepatální cholestáza genetika   vrozené   MeSH
• kojenec MeSH
• kyselina ursodeoxycholová terapeutické užití   MeSH
• lidé MeSH
• metabolické nemoci kostí etiologie   farmakoterapie   MeSH
• nemoci jater MeSH
• novorozenec MeSH
• pruritus etiologie   farmakoterapie   MeSH
• sklerozující cholangitida diagnóza   genetika   terapie   MeSH
• těhotenství MeSH
• žlučové kyseliny a soli fyziologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH