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
Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the worlds major causes of chronic liver disease. Care of patients infected with HBV and HCV and/or over the last 20 years has significantly improved thanks to the better understanding of the pathophysiology of disease, improvement of diagnostic, therapeutic and preventive options. The goal of treatment of chronic hepatitis B is to extend the length of life and improve its quality through the barriers of the progression of chronic hepatitis to cirrhosis, decompensation cirrhosis and hepatocellular carcinoma (HCC). Chronic HBV infection can by currently treated either with tenofovir or entecavir orally (absolute majority of cases), and that in the long-term (years), or even for life-long therapy, or with pegylated interferon α-2a, which is given by injection once a week for 48 weeks (limited possibility of use). The primary goal of chronic hepatitis C treatment is to cure the infection, by achieving a sustained virological response defined as undetectable virus nucleic acid (HCV RNA) in peripheral blood 12 or 24 weeks after the end of therapy. At present, IFN-free regimens become the standard of chronic HCV therapy with the efficiency of 95-100 % and with minimum of side effects and contraindications.Key words: chronic hepatitis B - chronic hepatitis C - IFN-free therapy.
- MeSH
- antivirové látky terapeutické užití MeSH
- chronická hepatitida B komplikace farmakoterapie MeSH
- chronická hepatitida C komplikace farmakoterapie MeSH
- hepatocelulární karcinom prevence a kontrola virologie MeSH
- jaterní cirhóza prevence a kontrola virologie MeSH
- lidé MeSH
- nádory jater prevence a kontrola virologie MeSH
- prevalence MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky MeSH
Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in ovo with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci: HRAS, EGFR, MET, and RON Insertionally mutated genes correlated with tumor type: HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs, and EGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of EGFR and RON, also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated EGFR and RON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII and sfRON).IMPORTANCE These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.
- Klíčová slova
- avian retroviruses, insertional mutagenesis, retroviral oncogenesis,
- MeSH
- cholangiokarcinom genetika virologie MeSH
- geny erbB-1 * MeSH
- hemangiosarkom genetika virologie MeSH
- hepatocelulární karcinom genetika virologie MeSH
- integrace viru MeSH
- inzerční mutageneze * MeSH
- karcinogeneze * MeSH
- kur domácí genetika MeSH
- lidé MeSH
- nádory jater genetika virologie MeSH
- onkogeny MeSH
- protoonkogenní proteiny c-met genetika MeSH
- proviry genetika fyziologie MeSH
- ptačí proteiny genetika MeSH
- tyrosinkinasové receptory genetika MeSH
- virus ptačí myeloblastózy genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- protoonkogenní proteiny c-met MeSH
- ptačí proteiny MeSH
- RON protein MeSH Prohlížeč
- tyrosinkinasové receptory MeSH
INTRODUCTION: The study introduces the first international, Czech and Slovak Domino Transplantation performed based on a tight cooperation between the Czech and Slovak transplant centres. MATERIAL AND METHODS: The donor of the cadaveric graft was a young Slovak man with Familial amyloidotic polyneuropathy. The livers of these patients are the predominant source of circulating transthyretin, and liver transplantation is the only treatment available for the disease. The graft was obtained from heart beating deceased donor with brain death. The domino graft was then transplanted to Czech sixty-three years old man with hepatocellular carcinoma and liver cirrhosis based on HCV. RESULTS: Both recipients had an uneventful immediate postoperative course with early graft function. The Czech patient faced early HCV recurrence in a graft which necessitated the reduction of immunosuppressives. CONCLUSION: The domino liver transplantation represents a suitable way for addressing graft shortage and reducing waiting list time. A well-organized cooperation between the two international centres is required to complete successful domino transplantation.
- MeSH
- dospělí MeSH
- familiární amyloidové neuropatie chirurgie MeSH
- hepatitida C komplikace MeSH
- hepatocelulární karcinom chirurgie virologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mozková smrt MeSH
- nádory jater chirurgie virologie MeSH
- transplantace jater * MeSH
- žijící dárci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
The etiological association between primary hepatocellular carcinoma (PHCC) and chronic viral hepatitis has been proved by now beyond doubt in the hepatitis B virus (HBV) and C virus (HCV). PHCC develops most frequently in cirrhotic livers, sometimes also in the absence of cirrhosis. Extensive epidemiological studies provided convincing evidence of this etiological relationship which is also supported by observations and animal experiments. An important factor in hepatocarcinogenesis due to the influence of HBV is integration of the viral genoma into the liver cell genoma. In the tumourous part of the liver integrated HBV sequences are more frequent than in the non-tumourous part. The integration can produce changes in the genome of the liver cell which may sometimes lead to malignant transformation. The mechanisms of this process are not quite clear so far. Their outcome--the development of carcinoma--can be summarized as the peak effect of factors leading to the disorganization of DNA with participation of chromosomal changes, the action of transactivation of HBs protein, transformation growth factors and the important influence of mutations of the suppressor gene p 53 on the 17th chromosome which is probably the target of HBV. HCV produces chronic live: disease developing into cirrhosis and PHCC, even more frequent than HBV; however its integration into the liver cell does not take place. The genetic variability of this gene is great. Its transformating action is probably implemented rather as a co-carcinogen on the background of cirrhosis of the liver which alone regardless of its cause is an increased risk for the development of PHCC. In clinical practice these findings imply the necessity of optimal prevention of chronic viral hepatic infection (vaccination, so far available for HBV, transfusions) and the necessity to assess the virological status in patients with chronic liver disease and early detection of small tumourous liver lesions where nowadays due to modern therapeutic approaches the prognosis has improved greatly.
