Jm Schattenberg

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study

Aims/hypothesisRecent European guidelines for non-alcoholic fatty liver disease (NAFLD) call for reference values for HOMA-IR. In this study, we aimed to determine: (1) the upper limit of normal HOMA-IR in two population-based cohorts; (2) the HOMA-IR corresponding to NAFLD; (3) the effect of sex and PNPLA3 genotype at rs738409 on HOMA-IR; and (4) inter-laboratory variations in HOMA-IR.MethodsWe identified healthy individuals in two population-based cohorts (FINRISK 2007 [nxa0=xa05024] and the Programme for Prevention of Type 2 Diabetes in Finland [FIN-D2D; nxa0=xa02849]) to define the upper 95th percentile of HOMA-IR. Non-obese individuals with normal fasting glucose levels, no excessive alcohol use, no known diseases and no use of any drugs were considered healthy. The optimal HOMA-IR cut-off for NAFLD (liver fat ≥5.56%, based on the Dallas Heart Study) was determined in 368 non-diabetic individuals (35% with NAFLD), whose liver fat was measured using proton magnetic resonance spectroscopy (1H-MRS). Samples from ten individuals were simultaneously analysed for HOMA-IR in seven European laboratories.ResultsThe upper 95th percentiles of HOMA-IR were 1.9 and 2.0 in healthy individuals in the FINRISK (nxa0=xa01167) and FIN-D2D (nxa0=xa0459) cohorts. Sex or PNPLA3 genotype did not influence these values. The optimal HOMA-IR cut-off for NAFLD was 1.9 (sensitivity 87%, specificity 79%). A HOMA-IR of 2.0 corresponded to normal liver fat (<5.56% on 1H-MRS) in linear regression analysis. The 2.0 HOMA-IR measured in Helsinki corresponded to 1.3, 1.6, 1.8, 1.8, 2.0 and 2.1 in six other laboratories. The inter-laboratory CV% of HOMA-IR was 25% due to inter-assay variation in insulin (25%) rather than glucose (5%) measurements.Conclusions/interpretationThe upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat. Standardisation of insulin assays would be the first step towards definition of normal values for HOMA-IR.

Inclusion of targeted therapies in the standard of care for metastatic colorectal cancer patients in a German cancer center: the more the better?!

AbstractPurposenSignificant prolongation of overall survival (OS) has been reached in metastatic colorectal cancer (mCRC) treatment within the last 5–10xa0years. Our study was conducted in order to evaluate and compare OS of different standard of care treatment options in a university-based outpatient clinic.MethodsOne hundred and three mCRC patients were identified by retrospective analysis and treated according to available guidelines. OS was analyzed according to the different combinations of first- and second-line treatments.ResultsmCRC patients revealed an mOS of 34.4xa0months. Patients receiving anti-vascular endothelial growth factor (VEGF) blockade in at least one treatment line showed a significantly longer survival time (pxa0=xa00.0056) versus patients without any bevacizumab. No OS differences were detected comparing the different first- and second-line chemotherapy (CTX) strategies in the unselected population. However, wild-type (wt) Kras patients treated with anti-epidermal growth factor receptor (EGFR) therapy plus CTX in first-line therapy showed significantly longer OS compared to those receiving only additional VEGF inhibition or no targeted therapy (pxa0=xa00.0056; mOS 46.8 vs. 20.4xa0months, respectively). wt Kras patients profited in trend (pxa0=xa00.076) from CTX combinations of first-line anti-EGFR followed by second-line anti-VEGF compared to first-line anti-VEGF followed by second-line anti-EGFR (mOS 46.8 vs. 19.2xa0months, respectively).ConclusionsOur results indicate successful allocation of the current mCRC treatment according to the Kras status. Differences in OS of wt Kras patients indicated the further need for randomized trials to define the potential benefit of sequential therapy with EGFR inhibition in first-line therapy followed by VEGFR inhibition vice versa.

Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients

Minimal hepatic encephalopathy (HE) and HE grade 1 (HE1) according to the West Haven criteria have recently been grouped as one entity named—covert HE‐ (CHE). Data regarding the impact of CHE on health‐related quality of life (HRQoL) and sleep quality are controversial.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Design We analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. Results The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.