Elisabeth P.C. Plompen

Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study

Given that little is known about the prevalence of, and factors associated with, liver fibrosis in the general population, we aimed to investigate this in a large, well‐characterized cohort by means of transient elastography (TE). This study was part of the Rotterdam Study, a population‐based study among individuals ≥45 years. All participants underwent abdominal ultrasound and TE. Liver stiffness measurement (LSM) ≥8.0 kilopascals (kPa) was used as a cutoff suggesting clinically relevant fibrosis. Of 3,041 participants (age, 66.0 ± 7.6 years) with reliable LSM, 169 (5.6%) participants had LSM ≥8.0 kPa. Age (odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.72‐3.36; P < 0.001), alanine aminotransferase (ALT; OR, 1.24; 95% CI: 1.12‐1.38; P < 0.001), smoking (OR, 1.77; 95% CI: 1.16‐2.70; P = 0.008), spleen size (OR, 1.23; 95% CI: 1.09‐1.40; P = 0.001), hepatitis B surface antigen, or anti–hepatitis C virus positivity (OR, 5.38; 95% CI: 1.60‐18.0; P = 0.006), and combined presence of diabetes mellitus (DM) and steatosis (OR, 5.20; 95% CI: 3.01‐8.98; P < 0.001 for combined presence) were associated with LSM ≥8.0 kPa in multivariable analyses. The adjusted predicted probability of LSM ≥8.0 kPa increased per age decade, with probabilities ranging from 1.4% (0.9‐3.6) in participants ages 50‐60 years to 9.9% (6.8‐14.5) in participants >80 years. Participants with both DM and steatosis had the highest probabilities of LSM ≥8.0 kPa (overall probability: 17.2% [12.5‐23.4]; this probability did not increase with age [P = 0.8]). Conclusion: In this large population‐based study of older adults, LSM ≥8.0 kPa, suggestive of clinically relevant fibrosis, was present in 5.6% and was strongly associated with steatosis and DM. In the context of an aging population and an increased prevalence of DM and obesity, this study illustrates that liver fibrosis may become a more prominent public health issue in the near future. (Hepatology 2016;63:138–147)

Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis.

We studied the role of the recently identified CALR mutations in 141 patients with Budd-Chiari Syndrome (BCS) or portal vein thrombosis (PVT) in a large multinational cohort. A CALR mutation was present in one of the 141 patients (0.7%). This patient was previously diagnosed with primary

Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population: The Rotterdam Study.

BACKGROUND & AIMS The coagulation system is known to be involved in fibrogenesis in patients with liver disease. We investigated whether common genetic prothrombotic risk factors are associated with an increased risk of fibrosis in the general population. METHODS This investigation was part of the Rotterdam Study, an ongoing, population-based cohort study. Liver stiffness (LS) was measured using transient elastography (Fibroscan) and associated with single nucleotide polymorphisms determining blood group type and presence of the Factor V Leiden (FVL) mutation or prothrombin G20210A gene variant. RESULTS Reliable LS measurements and genetic data were obtained from 1055 Caucasian participants. LS ⩾8.0 kPa, suggestive of clinically relevant fibrosis, was observed in 101 subjects (9.6%). Presence of FVL or prothrombin G20210A was independently associated with an increased risk of LS ⩾8.0 kPa (OR 2.09, 95%CI 1.07-4.07, p=0.03). Combination of blood group type non-O and the FVL mutation or prothrombin G20210A variant resulted in an even higher risk of LS ⩾8.0 kPa (OR 3.36, 95%CI 1.50-7.56, p=0.003). Presence of the FVL mutation or prothrombin G20210A variant in participants with blood group non-O was associated with a predicted probability of 14.3% (7.7-23.8) of LS ⩾8.0 kPa. CONCLUSIONS Participants carrying the FVL mutation or prothrombin G20210A variant have an increased risk of clinically relevant liver fibrosis, which is even higher in blood group type non-O carriers. The fact that genetic prothrombotic risk factors are associated with an increased risk of liver fibrosis suggests that coagulation plays an important role in fibrogenesis in the general population.

ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection

Background/Objective Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV. Patients and Methods This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed. Results In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04–0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64–1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024). Conclusion Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently.

Interferon gamma receptor 2 gene variants are associated with liver fibrosis in the general population: the Rotterdam Study

Dear Editor, Increasing evidence suggests that genetic factors play a role in the multifactorial aetiology of liver fibrosis. In their recent paper, Zhao et al 1 support this by describing the role of the Jnk1 gene in liver fibrogenesis. Previously, the role of other inflammatory-related genes in the development of liver fibrosis has been described in patients with chronic liver diseases. In patients with chronic hepatitis C, Nalpas et al 2 demonstrated a strong association between single nucleotide polymorphisms (SNP) in the interferon gamma receptor 2 ( IFNGR2 ) gene and progression of liver fibrosis. The role of interferon gamma in liver fibrogenesis has been reported before, but the precise mechanism of this effect has not yet been fully elucidated.3 ,4 Currently, it is not known whether the genetic variants in the IFNGR2 gene also influence liver fibrogenesis in individuals without liver disease. Therefore, we aimed to study the association between the IFNGR2 SNPs and liver fibrosis in the general population. For this purpose, we assessed the extent of liver fibrosis non-invasively by measuring liver stiffness (LS) using transient elastography (TE) (Fibroscan, Echosens) in 1059 participants of the Rotterdam study. Genotyping in these, almost exclusively Caucasian (99.6%) participants was performed with the Infinium II HumanHap 550K Genotyping Bead-Chip V.3 (Illumina, San Diego, California, USA). The Rotterdam Study is a large, ongoing, prospective population-based cohort study in subjects aged ≥55 years in …

GI ischemia in patients with portal vein thrombosis: A prospective cohort study

BACKGROUND AND AIMS GI ischemia is a concerning adverse event of portal vein thrombosis (PVT). Minimally invasive techniques, such as visible light spectroscopy (VLS), have greatly improved the ability to diagnose GI ischemia. The aim of this study was to assess the clinical presentation and characteristics of GI ischemia in patients with PVT. METHODS Patients with noncirrhotic, nonmalignant PVT were included in this prospective cohort study. Clinical symptoms of GI ischemia were assessed by a structured questionnaire, VLS, and radiologic evaluation of the mesenteric vasculature. VLS measurements were compared with those in patients with cirrhosis and with a reference population. RESULTS We included 15 patients with chronic PVT and 1 patient with acute PVT (median age 46.1 years [interquartile range [IQR], 30.9-53.7]; 44% male). Decreased mucosal oxygenation in at least 1 location of the GI tract was found in 12 patients (75%). Compared with the reference population (median 60.0 [IQR, 56.2-61.7]), VLS measurements were mostly decreased in the descending duodenum in patients with PVT (median 55.5 [IQR, 52.3-58.8]; P = .02) and patients with cirrhosis (median 52.0 [IQR, 46.5-54.0], P = .003). Symptoms typical for GI ischemia, such as postprandial pain and exercise-induced pain, were reported in 10 patients (63%) with PVT. In patients with extension of thrombosis into the superior mesenteric vein and splenic vein and/or presence of hypercoagulability, decreased VLS measurements were observed compared with historical control subjects. CONCLUSIONS In patients with chronic PVT, GI ischemia is frequent. VLS enables objective and quantitative determination of GI mucosal ischemia. Onset of abdominal symptoms such as postprandial pain should prompt the physician to re-evaluate extent, cause, and treatment of PVT.

Prediction of long-term clinical outcome in a diverse chronic hepatitis b population: role of the PAGE-B score

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment‐naïve CHB patients at one tertiary care centre were scored by a single hepato‐pathologist. Laboratory values at liver biopsy were used to calculate the PAGE‐B, REACH‐B, GAG‐HCC, CU‐HCC and FIB‐4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow‐up of 10.1 (IQR 5.7‐15.9) years. The PAGE‐B score predicted any clinical event (C‐statistic.86, 95% CI: 0.80‐0.92), HCC development (C‐statistic .91) and reduced transplant‐free survival (C‐statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C‐statistics (95% CI) of the REACH‐B, GAG‐HCC, CU‐HCC and FIB‐4 scores for any event were .70 (0.59‐0.81), .82 (0.75‐0.89), .73 (0.63‐0.84) and.79 (0.69‐0.89), respectively. The PAGE‐B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C‐statistic .87, 95% CI: 0.82‐0.93). The PAGE‐B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow‐up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

P0983 : Association between macro-nutrient intake and presence of nonalcoholic fatty liver disease in the Rotterdam study: a population-based study

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is associated with coronary artery calcification and increased prevalence of cardiovascular disease in many cross-sectional studies. However, whether NAFLD per se affect the progression of coronary artery calcification still remains to be elucidated. The aim of this study was to investigate the prospective association between NAFLD and the incidence and progression of coronary artery calcification (CAC) in a longitudinal cohort study. Methods: Among 1732 subjects who underwent serial CAC score evaluation, we evaluated 847 subjects with NAFLD and 885 subjects without NAFLD. Only those without viral hepatitis, significant alcohol consumption and known coronary artery disease were enrolled. NAFLD was diagnosed by ultrasonography in subjects without significant alcohol consumption. CAC score was evaluated by the Agatston method with multi-detector computed tomography. Results: The baseline CAC score was higher in those with NAFLD, and greater number of these subjects showed progression (48.8% vs. 38.4%, p < 0.001 in subjects with vs. without NAFLD). NAFLD was prospectively associated with progression of CAC score (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.26–1.85, p < 0.001). Noticeably, the impact of NAFLD significantly varied with the severity of baseline coronary atherosclerosis. In those without calcification at baseline, NAFLD significantly affected progression of atherosclerosis (adjusted OR 1.54, 95%CI 1.05–2.27, p =0.028), after adjustment for age, hypertension diabetes mellitus, dyslipidemia, smoking, gender and body mass index. Analysis according to the severity of NAFLD showed that NAFLD in its more severe form promotes progression of CAC (adjusted OR 1.77, 95%CI 1.08–2.88, p =0.022). However, in subjects with baseline CAC, NAFLD did not affect progression of CAC (p =0.482). Conclusions: NAFLD plays a role in early stage of coronary atherosclerosis, and it also seems that greater degree of NAFLD affects the progression independent of traditional risk factors. Thus NAFLD does not solely show a simple association, but also plays a role in the development and progression of coronary artery disease.