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Nonalcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence of 25% in the general population. Given the epidemic increase, regulatory agencies have defined an unmet medical need and implemented initiatives to expedite the development of drugs for NASH treatment.Literature search in Medline and worldwide web was accessed latest in 23.01.2021. In recent years new drugs acting on various pathophysiological processes in NASH have entered clinical development. These drugs combine beneficial metabolic effects with anti-inflammatory and anti-fibrotic effects to treat NASH. Current drug classes being investigated for NASH treatment are agonists of nuclear receptors such as FXR agonists (including FGF19), PPAR agonists, chemokine receptor inhibitors, thyroid hormone receptor-ß agonists and analogues of enterohepatic hormones including GLP-1 and FGF21 or SGLT2 inhibitors.Obeticholic acid is the only drug with significant benefit in the phase 3 interim results and remains the candidate for first conditional approval as a NASH therapeutic. However, monotherapy with these drugs leads to a histological resolution of NASH in less than one-third of patients in recent trials. Therefore, the future of NASH therapy will putatively be a combination therapy of two different drug classes with complementary effects.

Background Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients. Methods The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores. Results At the time of study inclusion 12.3% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3%) in contrast to HCV patients +S (26%). This effect was mainly observed in GT-3 patients (34.4% vs. 20.6%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4–24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m2) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT. Conclusion Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.

Doctor, Do You Know Red Yeast Rice?

Nonalcoholic fatty liver disease (NAFLD) is increasing globally with an estimated prevalence of approximately 25 %. Nonalcoholic steatohepatitis as the progressive disease entity often leads to fibrosis and end-stage disease. The magnitude of NAFLD patients are not diagnosed and have no access to further clinical assessment. Diagnostic pathways for individual risk evaluation fitting with available resources are of utmost importance in real-world clinical practice. Retrospective analysis of 1346 anonymized outpatient datasets at Würzburg University Hospital, Germany. Transient elastography (TE) with controlled attenuation parameter and laboratory-based risk scores (NFS, FIB-4) were the main diagnostic workup tools for risk stratification. After preselection based on questionnaire information NAFLD still accounts for one-fifth of patients in the liver outpatient service. More than 80 % of NAFLD patients receive their first-time diagnosis in our unit. Laboratory-based risk scores and TE are valuable tools for second-step risk assessment as shown in our clinical data analysis. Moreover, 65 % of NAFLD patients use inpatient services for at least 1 day. The policy to perform liver biopsy in high-risk patients above the recommended threshold of 9.6 kPa if any clinical doubt exists regarding the diagnosis of cirrhosis leads to a histological down staging in almost 80 %. Questionnaire-based referral from primary care followed by broadly available fast-track TE and eventually liver biopsy for selected patients is the standard practice in our unit. This approach represents a feasible model to handle the large gap between availability and clinical need for TE facilities.EINFüHRUNG UND ZIELSETZUNG: Die nichtalkoholische Fettlebererkrankung (NAFLD) nimmt weltweit zu und erreicht mittlerweile eine Prävalenz von etwa 25 %. Die nichtalkoholische Steatohepatitis (NASH) als fortschreitende Erkrankungsentität führt oft zur Fibrose bis hin zur Zirrhose. Die Mehrheit der NAFLD-Patienten wird weder diagnostiziert, noch haben sie Zugang zu weiteren medizinischen Maßnahmen. Diagnostische Algorithmen zur individuellen Risikoabschätzung, die mit den verfügbaren Ressourcen vereinbar sind, werden im klinischen Ambulanzalltag dringlich benötigt. Es wurde eine retrospektive Analyse von 1346 anonymisierten Ambulanzdatensätzen am Universitätsklinikum Würzburg durchgeführt. Die transiente Elastografie (TE) mit Controlled Attenuation Parameter (CAP) und laborbasierten Risikoscores (NFS, FIB-4) wurde als primäres Diagnoseverfahren zur Risikostratifizierung eingesetzt. Nach Präselektion basierend auf einem Zuweisungsfragebogen umfasst die NAFLD ein Fünftel der Patienten in der Leberambulanz. Über 80 % der NAFLD-Patienten erhalten die erstmalige Diagnose in unserer Abteilung. Laborbasierte Risikoscores und eine breit verfügbare TE sind dabei hilfreiche Methoden der weiterführenden Risikoabschätzung. 65 % der NAFLD-Patienten werden im Verlauf für mindestens einen Tag hospitalisiert. Die Strategie, eine Leberbiopsie bei Hochrisikopatienten über dem Grenzwert von 9,6 kPa durchzuführen, wenn klinisch Zweifel an der Diagnose einer Zirrhose bestehen, führt bei nahezu 80 % zur histologischen Herabstufung des Fibrosegrades. Die auf einem Zuweisungsfragebogen basierende Vorstellung von Patienten aus der Primärversorgung zur breit und rasch verfügbaren TE ist das Standardvorgehen in unserer Abteilung. Für selektionierte Patienten folgt im Einzelfall eine direkt veranlasste Leberbiopsie. Diese Vorgehensweise hat sich als hilfreich erwiesen, um die Lücke zwischen Bedarf und Verfügbarkeit an weiterführender NAFLD-Diagnostik inklusive ambulanter TE zu schließen.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) and fibrosis play critical roles for the prognosis of patients with nonalcoholic fatty liver disease (NAFLD). Identification of patients at risk of NASH and fibrosis is therefore critical for disease management. NAFLD Fibrosis Score (NFS) and transient elastography (TE) have been suggested to exclude advanced fibrosis. However, there is increasing evidence that also patients with NASH and early fibrosis are at risk of disease progression and complications, emphasizing the need for improved noninvasive risk stratification in NAFLD. METHODS: Because hepatocyte apoptosis plays an early role in NASH pathogenesis, we evaluated whether the apoptosis biomarker M30 might identify NAFLD patients who are at risk of NASH and fibrosis despite low NFS or TE values. Serum M30 levels were assessed by enzyme-linked immunosorbent assay in combination with NFS and/or TE in an exploration (n = 103) and validation (n = 100) cohort of patients with biopsy-proven NAFLD. RESULTS: Most patients with low NFS (cutoff value < −1.455) revealed increased M30 levels (>200 U/L) in the exploration (62%) and validation (67%) cohort, and more than 70% of them had NASH, mostly with histological fibrosis. Vice versa, most patients with NFS < −1.455 but nonelevated M30 levels showed no NASH. NASH was also detected in most patients with indeterminate NFS (−1.455 to 0.676) but elevated M30 levels, from which ∼90% showed fibrosis. Similar results were obtained when using TE instead of NFS. DISCUSSION: The combination of the M30 biomarker with NFS or TE enables a more reliable identification of patients with an increased risk of progressed NAFLD and improves patient stratification.

Background & aims Current non-invasive scores for the assessment of severity of non-alcoholic fatty liver disease (NAFLD) and identification of patients with non-alcoholic steatohepatitis (NASH) have insufficient performance to be included in clinical routine. In the current study, we developed a novel machine learning approach to overcome the caveats of existing approaches. Methods Non-invasive parameters were selected by an ensemble feature selection (EFS) from a retrospectively collected training cohort of 164 obese individuals (age: 43.5±10.3y; BMI: 54.1 ±10.1kg/m ² ) to develop a model able to predict the histological assessed NAFLD activity score (NAS). The model was evaluated in an independent validation cohort (122 patients, age: 45.2±11.75y, BMI: 50.8±8.61kg/m ² ). Results EFS identified age, γGT, HbA1c, adiponectin, and M30 as being highly associated with NAFLD. The model reached a Spearman correlation coefficient with the NAS of 0.46 in the training cohort and was able to differentiate between NAFL (NAS4) and NASH (NAS>4) with an AUC of 0.73. In the independent validation cohort, an AUC of 0.7 was achieved for this separation. We further analyzed the potential of the new model for disease monitoring in an obese cohort of 38 patients under lifestyle intervention for one year. While all patients lost weight under intervention, increasing scores were observed in 15 patients. Increasing scores were associated with significantly lower absolute weight loss, lower reduction of waist circumference and basal metabolic rate. Conclusions A newly developed model (http://CHek.heiderlab.de) can predict presence or absence of NASH with reasonable performance. The new score could be used to detect NASH and monitor disease progression or therapy response to weight loss interventions. CA extern

Prevalence of non-alcoholic fatty liver disease is rising in the Western world and reaches up to 90% in patients undergoing bariatric surgery. Fibroscan(®) as a non-invasive tool for liver stiffness measurement (LSM) has several limitations in morbidly obese patients. Only few data exist about the technical feasibility and accuracy of LSM in these patients. We aimed to analyse the feasibility of LSM by Fibroscan(®) in bariatric patients.In morbidly obese patients, LSM was performed using XL probe. Measurements were termed reliable if 10 successful measurements with a success rate ≥60% and an interquartile range/median (IQR/M)0.3 were obtained, unreliable if 10 successful measurements were obtained but the IQR/M was0.3, and they were termed failed if they were neither reliable nor unreliable.A total of 149 patients were included (87 with liver biopsies); mean BMI was 51.6 ± 8.5 kg/m(2). In 41% LSM using XL-probe was reliable, in 22% unreliable and in 37% failed. Failed LSM was significantly more frequent in patients with higher BMI compared to reliable and unreliable measurements (p 0.05). In patients with failed measurement, sonographic paramedian and intercostal distances were significantly higher compared to reliable measurements. All three patients with F4 fibrosis could successfully be differentiated by LSM from patients without fibrosis.LSM with XL probe is feasible in almost two-thirds of morbidly obese patients with a BMI ≥50 kg/m(2). Reliable prediction of advanced fibrosis appears to be possible even if formal criteria of successful measurements are not met.

Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4+ effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4+CD45RA+CD25++) and higher frequencies of IFN-γ+ and/or IL-4+ cells were detected among CD4+ T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17+ cells among intrahepatic CD4+ T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17+ cells among intrahepatic CD4+ T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.

The gut-derived hormone fibroblast growth factor 15/19 (FGF15/19) is an emerging versatile regulator of various metabolic pathways. As such, FGF15/19 has been implicated in homeostatic control of bile acid, carbohydrate and lipid metabolism in multiple target organs including the liver, adipose tissue and brain. In line with this, growing evidence suggests that dysregulation of FGF15/19 contributes to a number of metabolic and bile acid-associated disorders such as fatty liver disease, Type 2 diabetes and different gastrointestinal dysfunctions. In this review we summarize the current knowledge on the organ-specific functions of FGF15/19 and address their underlying molecular mechanisms. Moreover, recent advances in the characterization of factors that control the release of the hormone in the gut will be discussed and linked to the current view of how alterations of FGF15/19 signaling may contribute to disease development. Finally, the suitability of FGF15/19 as a potential therapeutic target will be critically reviewed.

Non-alcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence about 25% in the general population [1]. Given a substantial liver-related and ...

Background Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed. DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades, ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic anemia (IHA) has especially been reported to cause severe complications and fatal outcomes. Case presentation A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks. Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune hemolytic (DIIHA) anemia to ceftriaxone could be confirmed. Conclusions The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for this complication must be raised among treating physicians.

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.

Non-alcoholic fatty liver (NAFL) disease is defined by an accumulation of liver fat exceeding 5% of its weight in the absence of significant alcoholic intake. In 5-20%, there is a progression from NAFL to non-alcoholic steatohepatitis (NASH). Until now, it is not well understood why only some patients develop NASH, and currently, no drugs are licensed for this indication. Different T-cell populations such as T-regulatory, Th1 and Th17 cells play a central role in the immunopathogenesis of fatty liver disease and open the option of future interleukin (IL)-17-based therapeutics. The inflammatory process underlying NASH is furthermore characterized by elevated expression of pro-inflammatory cytokines such as TNFα and IL-1β. Anakinra, a recombinant version of IL-1Ra shows promising metabolic effects with improved hyperglycemia and beta-cell secretory function in a double-blind placebo controlled randomized trial in type 2 diabetic patients but such studies are still in their preliminary stages for NASH. Several studies point out that bile acid farnesoid X receptor (FXR)-mediated signals (such as the enterohepatic hormone fibroblast growth factor 15/19) are involved in the regulation of triglyceride and glucose metabolism. Recent clinical trials have revealed a beneficial impact of the FXR agonist obeticholic acid on body weight, insulin sensitivity and liver histology in patients with NASH. Further potential novel therapeutic targets in NASH are currently in phase II clinical development.

Objective.To analyze clinical manifestations, serum ferritin, and serum cytokine levels in patients with adult-onset Still’s disease (AOSD) or bacterial sepsis and to evaluate their potential use for differential diagnosis.Methods.Twenty-two consecutive patients with the first flare of AOSD and 6 patients with an established diagnosis of AOSD under immunosuppressive therapy were compared with 14 patients with bacterial sepsis. Clinical manifestations were scored in a Pouchot AOSD activity score including elevated serum ferritin levels to obtain a modified Pouchot score. Serum cytokine profiles were analyzed from each patient.Results.The scores of clinical manifestations using a modified Pouchot activity score were significantly higher in patients with active untreated AOSD (mean 5.60 ± 1.93) compared with patients with chronic AOSD (mean 1.16 ± 0.98; p < 0.001) and patients with sepsis (mean 2.38 ± 1.19; p < 0.001). A modified Pouchot score ≥ 4 shows a sensitivity of 92% and a specificity of 93% for active AOSD. Serum cytokine levels of interleukin 1ß (IL-1ß), IL-6, IL-8, IL-10, IL-12, IL-18, interferon-γ, tumor necrosis factor-α, and calprotectin were elevated in acute AOSD and sepsis. Significant differences were detected only in patients with sepsis who had higher levels of IL-6 and IL-8. The overlap of the 2 groups limits the use of cytokines for differential diagnosis in individual patients.Conclusion.A modified Pouchot AOSD activity score including elevated serum ferritin levels was more useful to confirm the diagnosis of AOSD compared to patients with sepsis. Elevated serum cytokines correlate with inflammation but are of limited use to differentiate between active AOSD and bacterial sepsis.

Non-alcoholic fatty liver disease is the most common chronic liver disease in Europe and in the USA with rising prevalence. Patients with a metabolic syndrome (diabetes mellitus, obesity, dyslipidemia) are patients at risk with the highest prevalence for NAFLD. Progression from a non-alcoholic fatty liver (NAFL) to a non-alcoholic steatohepatitis (NASH) occurs in 5-20% of patients with the potential to develop a liver fibrosis/cirrhosis. NASH patients and NAFLD patients with higher fibrosis should be identified because they are at risk of a higher mortality. A specific treatment for NASH is not available at the moment. Therefore, the treatment of risk factors and metabolic syndrome has high priority.

Objectives Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. Methods Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. Results The new finding of our study is the different profile of circulating miR-21 in NASH patients (p

Item does not contain fulltext Human iron homeostasis is regulated by intestinal iron transport, hepatic hepcidin release, and signals from pathways that consume or supply iron. The aim of this study was to characterize the adaptation of iron homeostasis under hypoxia in mountaineers at the levels of (1) hepatic hepcidin release, (2) intestinal iron transport, and (3) systemic inflammatory and erythropoietic responses. Twenty-five healthy mountaineers were studied. Blood samples and duodenal biopsies were taken at baseline of 446 m as well as on day 2 (MG2) and 4 (MG4) after rapid ascent to 4559 m. Divalent metal-ion transporter 1 (DMT-1), ferroportin 1 (FP-1) messenger RNA (mRNA), and protein expression were analyzed in biopsy specimens by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Serum hepcidin levels were analyzed by mass spectrometry. Serum iron, ferritin, transferrin, interleukin (IL)-6, and C-reactive protein (CRP) were quantified by standard techniques. Serum erythropoietin and growth differentiation factor 15 (GDF15) levels were measured by enzyme-linked immunosorbent assay (ELISA). Under hypoxia, erythropoietin peaked at MG2 (P < 0.001) paralleled by increased GDF15 on MG2 (P < 0.001). Serum iron and ferritin levels declined rapidly on MG2 and MG4 (P < 0.001). Duodenal DMT-1 and FP-1 mRNA expression increased up to 10-fold from baseline on MG2 and MG4 (P < 0.001). Plasma CRP increased on MG2 and MG4, while IL-6 only increased on MG2 (P < 0.001). Serum hepcidin levels decreased at high altitude on MG2 and MG4 (P < 0.001). Conclusion: This study in healthy volunteers showed that under hypoxemic conditions hepcidin is repressed and duodenal iron transport is rapidly up-regulated. These changes may increase dietary iron uptake and allow release of stored iron to ensure a sufficient iron supply for hypoxia-induced compensatory erythropoiesis. (Hepatology 2013; 58:2153-2162).

BACKGROUND & AIMS: In the last decade pegylated interferon-α (Peg-INF-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed to study genetic determinants of RBV kinetics, efficacy and treatment associated anemia. METHODS: We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726 and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101 and followed regarding treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients RBV serum levels were additionally measured during treatment. RESULTS: Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ⩾ 3 g/dl during treatment in genotype (relative risk (RR)=2.1, 95%CI 1.3-3.5) as well as in allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as in allelic analyses (RR=2.0, 95% CI 1.1-3.4). CONCLUSIONS: The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV induced anemia and treatment response may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.

BACKGROUND & AIMS: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy. METHODS: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis. RESULTS: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable. CONCLUSIONS: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.