A study of some hepatic immunological markers, iron load and virus genotype in chronic hepatitis C.

BACKGROUND/AIMS: Host factors that may influence progression of hepatitis C infection to chronic hepatitis include T-cell responses and iron accumulation. We evaluated the hepatic expression of immunological markers relevant for a cytotoxic response in relation to viral and HFE genotype. METHODS: Frozen liver biopsies were obtained at diagnosis from 28 HFE genotyped patients. Sections stained for CD8, MHC-I, beta(2)m, HFE and CD68 were analyzed blind by morphometry. Response to therapy was available in 12 cases. RESULTS: A negative correlation was found between the number of CD8(+) cells and fibrosis. CD8(+) cells localized as clusters in portal tracts and sinusoids and were seen interacting with MHC-I positive lining cells. MHC-I and beta(2)m were expressed mainly in the endothelial and Kupffer cells. HFE was expressed in most, but not all, round and dendritic CD68(+) cells. Patients with virus genotype 3a had higher hepatic MHC-I and HFE expression, and a better-sustained response to IFN therapy than other patients. CONCLUSIONS: In chronic hepatitis C virus infection MHC-I expression in the liver seems to relate to viral-genotype. In addition, the expression of MHC-I molecules by Kupffer cells places them as probable important players in the host response to HCV.We thank Dr Graça Porto for critical review of the manuscript. This study was supported by the EU QLG1-CT-1999-00665 project, the Calouste Gulbenkian Foundation/FCT Project on Hemochromatosis (Portugal) and the INNOVA Foundation/APBRF (USA)

Self-reported abdominal symptoms in relation to health status in adult patients with familial adenomatous polyposis

BACKGROUND: Patients with familial adenomatous polyposis who undergo surgery to prevent colorectal cancer experience various abdominal symptoms that may affect their physical and mental health. OBJECTIVE: This study was designed to investigate self-reported presence, frequency, and troublesomeness of abdominal symptoms in such patients in relation to sex, type of surgery, and physical and mental health. DESIGN: A cohort study with a descriptive and comparative cross-sectional design. SETTING AND PARTICIPANTS: All adult patients in the Swedish Polyposis Registry (Karolinska University Hospital, Stockholm, Sweden) who were diagnosed with familial adenomatous polyposis, had undergone prophylactic colorectal surgery, and were aged 18 to 75 years were invited to return a mailed questionnaire. MAIN OUTCOME MEASURES: Self-reported presence, frequency, and troublesomeness of 21 abdominal symptoms were assessed with the Abdominal Symptom Questionnaire. Physical health and mental health were evaluated with the Medical Outcomes Study Short Form 36 Health Survey. RESULTS: Of 275 eligible patients, 209 (76%) responded. Of respondents, 91% reported having had at least 1 symptom during the last 3 months. All 21 symptoms investigated were reported. A higher number of symptoms was reported by women than by men: mean, 7.55 (SD, 4.89) vs 5.14 (4.49); P < .01. No significant difference was found between women and men in overall troublesomeness of symptoms: 3.15 (1.30) vs 3.09 (1.27); P = .763. Self-reported number of symptoms was an independent predictor of physical and mental health, with a high number of symptoms related to poor physical and mental health. LIMITATIONS: The Abdominal Symptom Questionnaire has not been previously used in patients with FAP, and measurement of physical and mental health with the Short Form 36 Health Survey may not capture all aspects of health status in patients with familial adenomatous polyposis. CONCLUSION: Patients with familial adenomatous polyposis suffer from a wide variety of abdominal symptoms after colorectal surgery. Identification of patients with a high number of abdominal symptoms is especially important because the number of abdominal symptoms affects patients’ physical and mental health

A Dynamic Aspartate-to-Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.Peer reviewe

Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.Italian Ministry of University/FIRB/MERIT RBNE08NKH7_00

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10−5) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10−5, ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutatio

Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype

Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation

Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli.

BACKGROUND: Although most Caucasian patients with hereditary haemochromatosis (HH) show the same mutation in the HFE gene, the phenotypic expression of the disease varies greatly. We have previously shown that patients with HH who have high iron stores have low numbers of circulating CD8+ T lymphocytes. PATIENTS AND METHODS: Liver and peripheral blood were studied in 37 C282Y homozygous HH patients; nine normal livers and 11 livers from patients with cirrhosis due to hepatitis C virus or alcoholic liver disease were also investigated. Eleven jejunal biopsies from HH patients and 17 normal biopsies were studied. The numbers of CD8+ cells were determined in peripheral blood by fluorescence-activated cell sorting analysis, and in the liver or small intestine by immunohistochemistry. RESULTS: In HH patients the number of CD8+ T lymphocytes in peripheral blood correlated significantly with the number of CD8+ cells in the liver lobuli but not with that in the small intestine. Body iron stores correlated negatively with the number of CD8+ T lymphocytes in peripheral blood and in the liver, but not with the number in the small intestine. HH patients with cirrhosis had the lowest CD8+ cell count in liver sections, in contrast with other forms of cirrhosis. CONCLUSION: The results indicate that HH patients with the HFE C282Y mutation and low numbers of CD8+ cells in the liver lobuli have higher iron stores and are more prone to develop liver cirrhosis.This study was supported by the Swedish Medical Research Council (n. 9127), the Bengt Ihres Foundation, Ruth and Richard Julins Foundation and the Karolinska Institute. Elsa Cardoso is a recipient of a PRAXIS XXI Grant BD/5095/95