M. Reichert

Large‐scale computational models of liver metabolism: How far from the clinics?

Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases. This knowledge can be obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modeling can reveal hidden principles of the system by classification of individual components, analyzing their interactions and simulating the effects that are difficult to investigate experimentally. Herein, we review the state‐of‐the‐art computational models that describe liver dynamics from metabolic, gene regulatory, and signal transduction perspectives. We focus especially on large‐scale liver models described either by genome scale metabolic networks or an object‐oriented approach. We also discuss the benefits and limitations of each modeling approach and their value for clinical applications in diagnosis, therapy, and prevention of liver diseases as well as precision medicine in hepatology. (Hepatology 2017;66:1323‐1334).

The genetic epidemiology of diverticulosis and diverticular disease: Emerging evidence

Diverticular disease (DD) is one of the most prevalent gastrointestinal disorders. The pathogenesis of diverticulosis and DD is controversially discussed. Current studies call the traditional concept of a fibre-deficient diet causing the development of diverticula into question. Data from two recent twin studies have provided conclusive evidence for a strong genetic component to diverticulosis. Although genomewide association studies have provided new insights into the polygenic architecture of human diseases, genomic research in diverticulosis and DD has just been started. This is an astonishing fact given the high morbidity and mortality of the disease, as well as the substantial economic burden on health care systems. For this review, we provide an update of the molecular pathobiology and summarise recent evidence supporting the hypothesis that distinct, yet unidentified genetic variants contribute to the development of diverticulosis and DD.

The INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) : study protocol for a randomized controlled trial

BackgroundPatients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP.Methods/DesignThe INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014.DiscussionPreventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms.Trial registrationsGerman Clinical Trials Register DRKS00005616. Registered 22 January 2014.EU Clinical Trials Register EudraCT 2013-001626-26. Registered 26 January 2015.

Experimental infection of juvenile domestic and Canada geese with two different clades of H5N1 high pathogenicity avian influenza virus.

Eighteen-day-old domestic geese (Anser anser f. domestica) and 3-week-old Canada geese (Branta canadensis) were experimentally infected with 10(6) EID50/bird of H5N1 high pathogenicity avian influenza (HPAI) virus isolates belonging to clades 1 and 2.2. Clinical signs were observed in all of the groups and included listlessness, inappetence, marked incoordination, torticollis, paralysis and lethargy. Mortality reached 100% (Canada geese) and 40-50% (domestic geese). During necropsy, congestion and hemorrhagic lesions were most often observed. Histopathological lesions were located in multiple organs and included inflammatory and hemorrhagic changes and, in later stages, occurrences of necrosis. All of the tested organ samples collected between 3 and 8 days PI were found positive in rRT-PCR, but the highest concentration of RNA was found in the brain. The observed delayed onset of mortality and prolonged duration of the disease in young domestic geese may be related to numerous host and virus factors.

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.

Recurrent Gastrointestinal Bleeding due to Multiple Pyogenic Granulomas in the Stomach

A 65-year-old man presented 7 years after being treated by a local physician for left-sided ulcerative colitis (UC). A colonoscopy suggested that the UC was nearly in remission, but, unexpectedly, a rectal biopsy revealed lymphoma. The patient was referred to our hospital. Colonoscopy revealed edematous and fine granular mucosa with tiny erosions extending from the sigmoid colon to the rectum (a). Abdominal computed tomography revealed wall thickening at multiple sites in the jejunum; one site showed mass formation. Enteroscopy showed fine, granular, edematous mucosa extending from the duodenum into the jejunum. There were ulcerated areas, and at one site a mass occupied half the lumen (b). Biopsy specimens from the small and large intestines revealed that the epithelium of the crypts and the stromal tissue were infiltrated by abnormal lymphocytes that were positive for CD3 CD7, CD8, and CD56 and negative for CD4, CD20, TIA1, and granzyme B (c). The findings led to a diagnosis of enteropathy-associated T-cell lymphoma in immunostaining. After diagnosis, symptoms of intestinal obstruction developed and laparoscopic partial resection of the jejunum was performed. During the fifth course of chemotherapy, the patient developed septicemia and disseminated intravascular coagulopathy, which led to his death 7 months after presentation. (Informed consent was obtained from the patient’s family to publish these images.)

NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients

Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn’s disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.

Secondary sclerosing cholangitis rapidly leading to liver cirrhosis: a possible post-ICU treatment sequel

Learning points for clinicians Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) should be suspected in patients who present with cholestasis after treatment on intensive care unit, regardless of the duration of the intensive care therapy. Increased awareness of this condition is necessary, because it may rapidly lead to liver cirrhosis. ERCP, ursodeoxycholic acid and transplantation represent currently available therapeutic options. A 64-year-old man was admitted to our department with increasing jaundice (bilirubin 9.1 mg/dl, gamma-GT 1492 U/l, AP 1745 U/L). He had a negative history of viral and non-viral liver diseases (including primary sclerosing cholangitis) and displayed no signs of inflammatory bowel disease in colonoscopy. Twenty-five days prior to …