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
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• cytoskeletální proteiny MeSH
• flavoproteiny MeSH
• IFT172 protein, human MeSH Prohlížeč
• mitochondriální proteiny MeSH
• PPOX protein, human MeSH Prohlížeč
• protoporfyrinogenoxidasa MeSH

Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4×NBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients.

• Klíčová slova
• MRN complex, genetic predisposition, germline mutation, hepatocellular carcinoma, liver cirrhosis, liver transplantation, panel sequencing,
• Publikační typ
• časopisecké články MeSH

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361-0.7719 and OR 0.1522; 95% CI 0.02941-0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

• Klíčová slova
• S allele, SERPINA1 gene, Z allele, alpha-1-antitrypsin, cirrhosis, hepatocellular carcinoma,
• MeSH
• alely MeSH
• alfa-1-antitrypsin krev   genetika   MeSH
• frekvence genu MeSH
• genotyp MeSH
• hepatocelulární karcinom komplikace   genetika   MeSH
• index tělesné hmotnosti MeSH
• jaterní cirhóza komplikace   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• multivariační analýza MeSH
• nádory jater komplikace   genetika   MeSH
• rizikové faktory MeSH
• sexuální faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-1-antitrypsin MeSH
• SERPINA1 protein, human MeSH Prohlížeč

Liver stiffness is a reliable non-invasive predictor of Hepatic Venous Pressure Gradient (HVPG) above 10 mm Hg. However, it failed to predict higher thresholds of HVPG. Our aim was to investigate whether liver stiffness and selected previously published non-invasive blood biomarkers could predict higher HVPG thresholds in liver transplant candidates without ongoing alcohol use. One hundred and nine liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG measurement, liver stiffness measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France) and assessment of blood HVPG biomarkers (osteopontin, VCAM-1, IL-6, TNF-α, IL-1ra/IL-1F3 and ELF score). The correlation between liver stiffness and HVPG was linear up to 30 mm Hg of HVPG (r = 0.765, p < 0.0001). The regression lines had similar slopes for HVPG values below and above 16 mm Hg (p > 0.05) and the correlation in patients with HVPG <16 mm Hg (r = 0.456, p = 0.01) was similar to patients with HVPG ≥ 16 mm Hg (r = 0.499, p < 0.0001). The correlation was similar in the subgroup patients with alcoholic (r = 0.718, p < 0.0001), NASH (r = 0.740, p = 0.008), cryptogenic (r = 0.648, p = 0,0377), cholestatic and autoimmune (r = 0.706, p < 0.0001) and viral cirrhosis (r = 0.756, p < 0.0001). Liver stiffness distinguished patients with HVPG above 16, and 20 mm Hg with AUROCs 0.90243, and 0.86824, sensitivity 0.7656, and 0.7027, and specificity 0.9333, and 0.8750. All studied blood biomarkers correlated better with liver stiffness than with HVPG and their AUROCs did not exceed 0.8 at both HVPG thresholds. Therefore, a composite predictor superior to liver stiffness could not be established. We conclude that liver stiffness is a clinically reliable predictor of higher HVPG thresholds in non-drinking subjects with advanced liver cirrhosis.

• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• elastografie metody   MeSH
• fibróza patologie   MeSH
• jaterní cirhóza patologie   MeSH
• játra patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• portální hypertenze patologie   MeSH
• portální tlak fyziologie   MeSH
• prospektivní studie MeSH
• pružnost fyziologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• venae hepaticae patologie   MeSH
• venózní tlak fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• biologické markery MeSH

BACKGROUND: The rs58542926 polymorphism in transmembrane 6 superfamily member 2 (TM6SF2) is a genetic factor predisposing to nonalcoholic fatty liver disease. We aimed to explore the effect of recipient and donor TM6SF2 rs58542926 genotypes on liver graft fat content after liver transplantation. METHODS: Steatosis was evaluated in liver biopsies from 268 adult recipients. The influence of recipient and donor TM6SF2 genotypes, patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 genotypes, and nongenetic factors on the steatosis grade assessed 6-30 months after transplantation was analyzed by ordinal logistic regression. RESULTS: The presence of the TM6SF2 c.499A allele in the donor (P = 0.014), PNPLA3 c.444G allele in the donor (P < 0.001), posttransplant body mass index (P < 0.001), and serum triglycerides (P = 0.047) independently predicted increased liver fat content on multivariable analysis, whereas noncirrhotic liver disease, as an indication for liver transplantation, was associated with lower risk of steatosis (P = 0.003). The effects of the donor TM6SF2 A and PNPLA3 G alleles were additive, with an odds ratio of 4.90 (95% confidence interval, 2.01-13.00; P < 0.001), when both minor alleles were present compared with an odds ratio of 2.22 (95% confidence interval, 1.42-3.61; P = 0.002) when only one of these alleles was present. CONCLUSIONS: The donor TM6SF2 c.499A allele is an independent risk factor of liver graft steatosis after liver transplantation that is additive to the effects of donor PNPLA3 c.444G allele.

• MeSH
• alely MeSH
• alografty patologie   MeSH
• biopsie MeSH
• dárci tkání statistika a číselné údaje   MeSH
• dospělí MeSH
• genotypizační techniky statistika a číselné údaje   MeSH
• játra patologie   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipasa genetika   MeSH
• membránové proteiny genetika   MeSH
• mladý dospělý MeSH
• následné studie MeSH
• nealkoholová steatóza jater diagnóza   epidemiologie   genetika   patologie   MeSH
• pooperační komplikace diagnóza   epidemiologie   genetika   patologie   MeSH
• prevalence MeSH
• příjemce transplantátu statistika a číselné údaje   MeSH
• rizikové faktory MeSH
• stupeň závažnosti nemoci MeSH
• transplantace jater škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adiponutrin, human MeSH Prohlížeč
• lipasa MeSH
• membránové proteiny MeSH
• TM6SF2 protein, human MeSH Prohlížeč

INTRODUCTION: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare autosomal recessive cholestatic liver disorder caused by genetic deficiency of ATP-binding cassette subfamily B member 4 (ABCB4), a hepatocanalicular floppase translocating phospholipids from the inner to the outer leaflet of the canalicular membrane lipid bilayer. PFIC3 is characterised by production of hydrophilic bile with lithogenic properties which is harmful to the hepatobiliary epithelia. Chronic cholestasis in some patients may be accompanied by excessive accumulation of copper in the liver and by increased urinary copper excretion, the findings mimicking Wilson disease (WD). METHODS AND RESULTS: We report an 11 y/o male patient with growth retardation, mild craniofacial dysmorphic features and chronic liver disease, initially diagnosed and treated as WD. Whereas genetic testing for WD was negative, further molecular and histopathological analysis revealed two novel mutations (c.833+1G>T and c.1798T>A) in ABCB4 and complete absence of the ABCB4/MDR3 protein in the liver, determining PFIC3 as the correct diagnosis. CONCLUSION: PFIC3 and WD display pleomorphic and sometimes overlapping clinical and laboratory features, which may pose a differential diagnostic problem. Since the patient management in WD and PFIC3 differs significantly, an early and accurate diagnosis is crucial for optimising of therapeutic approach and prevention of possible complications.

• Klíčová slova
• ABCB4, ATP7B, Wilson disease, copper metabolism, progressive familial intrahepatic cholestasis type 3,
• MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• hepatolentikulární degenerace diagnóza   MeSH
• intrahepatální cholestáza diagnóza   MeSH
• lidé MeSH
• P-glykoproteiny nedostatek   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• P-glykoproteiny MeSH

BACKGROUND: PNPLA3 rs738409 minor allele c.444G represents a risk factor for liver steatosis and fibrosis progression also in chronic hepatitis C (HCV). We investigated its impact on the timing of liver transplantation (LT) in patients with genotype 1b HCV cirrhosis. METHODS: We genotyped and evaluated 172 LT candidates with liver cirrhosis owing to chronic HCV infection, genotype 1b. One hundred patients needed LT for chronic liver failure (CLF) and 72 for a small hepatocellular carcinoma (HCC) in the cirrhotic liver without CLF. Population controls (n = 647) were selected from the Czech cross-sectional study MONICA. RESULTS: The CLF patients were younger (53.5 ± 7.2 vs. 59.6 ± 6.6, P < 0.001) with more advanced liver disease than HCC patients (Child-Pugh's score 9.1 ± 1.8 vs. 7.1 ± 1.9, P < 0.001, MELD 14.1 ± 3.9 vs. 11.1 ± 3.7, P < 0.001). PNPLA3 G allele increased the risk of LT for CLF in both allelic and recessive models (CG + GG vs. CC: OR, 1.90; 95% CI, 1.017-3.472, P = 0.045 and GG vs. CC + CG: OR, 2.94; 95% CI, 1.032-7.513, P = 0.042). Multivariate analysis identified younger age (P < 0.001) and the G allele (P < 0.05) as risk factors for CLF. The genotype frequencies between the CLF group and MONICA study significantly differed in both, allelic and recessive model (P = 0.004, OR 1.87, 95% CI 1.222-2.875; P < 0.001, OR 3.33, 95% CI 1.824-6.084, respectively). The OR values almost doubled in the recessive model compared with the allelic model suggesting the additive effect of allele G. In contrast, genotype frequencies in the HCC group were similar to the MONICA study in both models. Pretransplant viral load was significantly lower in GG than in CC + CG genotypes (median, IQR; 162,500 (61,550-319,000) IU/ml vs. 570,000 (172,000-1,595,000) IU/ml, P < 0.0009). CONCLUSIONS: Our results suggest that PNPLA3 rs738409 G allele carriage may be associated with a faster progression of HCV cirrhosis to chronic liver failure.

• MeSH
• alely MeSH
• chronická hepatitida C genetika   virologie   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• hepatocelulární karcinom genetika   virologie   MeSH
• jaterní cirhóza genetika   virologie   MeSH
• játra virologie   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipasa genetika   MeSH
• membránové proteiny genetika   MeSH
• nádory jater genetika   virologie   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• selhání jater genetika   virologie   MeSH
• studie případů a kontrol MeSH
• transplantace jater metody   MeSH
• virová nálož metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adiponutrin, human MeSH Prohlížeč
• lipasa MeSH
• membránové proteiny MeSH

BACKGROUND: Cytomegalovirus (CMV) disease represents a serious complication in liver transplant (OLT) recipients. CMV prophylaxis reduces incidence of CMV disease in the early post-transplant period (on-prophylaxis disease, OPD) but may postpone its manifestation after the completion of prophylaxis. Post-prophylaxis disease (PPD) incidence after prophylaxis cessation may be modified by genetic factors. METHODS: We analyzed impact of IL28B rs1297986 variants on CMV disease incidence in 743 adult OLT recipients receiving universal prophylaxis. RESULTS: One hundred and forty-four (19.4%) patients had at least one CMV disease episode. One hundred and two of them (70.8%) had at least one OPD and 36 (25%) patients had PPD, six (4.2%) patients had both. The rate of IL28B T allele carriers was lower in PPD group (38.9%) in comparison with OPD group (66.7%, P = 0.005) and group without CMV disease (61.4%, P = 0.009). The impact of IL28B genotype on the risk of CMV OPD was significant neither in the allelic (TT + CT vs CC, P = 0.32) nor in the recessive model (TT vs CT + CC, P = 0.79). Contrarily, in the PPD group, T allele (TT + CT vs CC) had a protective effect, OR 0.4 (95% CI 0.2-0.8, P = 0.008). Further risk factors of PPD were age <55 years and valganciclovir prophylaxis, whereas the risk factors of OPD were age <55 years, cyclosporine A therapy and pre-transplant CMV serostatus (donor +/recipient -). CONCLUSIONS: IL28B rs12979860 T allele carriers had a lower risk of CMV PPD.

• Klíčová slova
• IL28B, cytomegalovirus, gene variants, immunosuppression, interferon lambda 4, liver transplantation,
• MeSH
• alely MeSH
• antivirové látky terapeutické užití   MeSH
• cytomegalovirové infekce genetika   prevence a kontrola   MeSH
• dárci tkání MeSH
• dospělí MeSH
• ganciklovir terapeutické užití   MeSH
• genotyp MeSH
• incidence MeSH
• interferony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• příjemce transplantátu MeSH
• senioři MeSH
• transplantace jater * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky MeSH
• ganciklovir MeSH
• interferon-lambda, human MeSH Prohlížeč
• interferony MeSH

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency. Analysis of X-inactivation ratios by DNA methylation-based assays showed remarkable intra-organ variation ranging from 46:54 to 82:18 (average 70:30, n = 37), in favor of the active X chromosome carrying the mutation c.583G>C (p.G195R), in the first patient and from 75:25 to 90:10 (average 82:18, n = 20) in favor of the active X chromosome carrying the splicing mutation c.663+1G>A in the second patient. The X-inactivation ratios in liver samples correlated highly with the proportions of OTC-positive hepatocytes calculated from high-resolution image analyses of the immunohistochemically detected OTC in frozen sections that was performed on total area > 5 cm2. X-inactivation ratios in blood in both female patients corresponded to the lower limit of the liver values. Our data indicate that the proportion of about 20-30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X-inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver.

• Klíčová slova
• Glutamine synthetase, Glycogen storage, Liver, Liver zonation, Ornithine transcarbamylase, X chromosome inactivation,
• MeSH
• biopsie MeSH
• genotyp MeSH
• glutaminsynthetasa genetika   metabolismus   MeSH
• heterozygot MeSH
• inaktivace chromozomu X * MeSH
• játra enzymologie   MeSH
• lidé MeSH
• lidské chromozomy X genetika   MeSH
• nemoc z nedostatku ornithinkarbamoyltransferázy genetika   MeSH
• ornithinkarbamoyltransferasa genetika   metabolismus   MeSH
• pohlavní dimorfismus MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glutaminsynthetasa MeSH
• ornithinkarbamoyltransferasa MeSH

AIM: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. METHODS: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. RESULTS: In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. CONCLUSION: These findings support the role of rare variants and nominate loci for follow-up studies.

• Klíčová slova
• CLCN1, atorvastatin, gene, myopathy, rosuvastatin, simvastatin, statin,
• MeSH
• celogenomová asociační studie MeSH
• chloridové kanály genetika   MeSH
• dospělí MeSH
• exom genetika   MeSH
• genetická variace MeSH
• genotyp MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci svalů chemicky indukované   epidemiologie   genetika   MeSH
• polypeptid C přenášející organické anionty genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• statiny škodlivé účinky   MeSH
• vzácné nemoci genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chloridové kanály MeSH
• CLC-1 channel MeSH Prohlížeč
• polypeptid C přenášející organické anionty MeSH
• SLCO1B1 protein, human MeSH Prohlížeč
• statiny MeSH