Davor Štimac

Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease.

Introduction: Interferon γ is a potent proinflammatory cytokine implicated in the inflammation of Crohn’s disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe CD. Methods: A total of 133 patients with Crohn’s disease activity index (CDAI) scores between 250 and 450, inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or more), and remission (CDAI ⩽150). Results: There was no statistically significant difference in the primary end point of the study (clinical response) between the fontolizumab and placebo groups after a single dose at day 28. However, patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo: 32% (9/28) versus 69% (22/32, p = 0.02) and 67% (21/31, p = 0.03) for the placebo, and 4 and 10 mg/kg fontolizumab groups, respectively. Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit. Two grade 3 adverse events were reported and were considered to be related to CD. One death (during sleep) and one serious adverse event (an elective hospitalisation) occurred, both considered unrelated. Conclusion: Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.

NK cells link obesity-induced adipose stress to inflammation and insulin resistance

An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell–activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.

Peginterferon alpha‐2a is associated with higher sustained virological response than peginterferon alfa‐2b in chronic hepatitis C: Systematic review of randomized trials

A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin represents the standard of care for the treatment of chronic hepatitis C according to current guidelines. It is not established which of the two licensed products (peginterferon alpha‐2a or peginterferon alfa‐2b) is most effective. We performed a systematic review of head‐to‐head randomized trials to assess the benefits and harms of the two treatments. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. Using standardized forms, two reviewers independently extracted data from each eligible trial report. We statistically combined data using a random effects meta‐analysis according to the intention‐to‐treat principle. We identified 12 randomized clinical trials, including 5,008 patients, that compared peginterferon alpha‐2a plus ribavirin versus peginterferon alfa‐2b plus ribavirin. Overall, peginterferon alpha‐2a significantly increased the number of patients who achieved a sustained virological response (SVR) versus peginterferon alfa‐2b (47% versus 41%; risk ratio 1.11, 95% confidence interval 1.04–1.19; P = 0.004 [eight trials]). Subgroup analyses of risk of bias, viral genotype, and treatment history yielded similar results. The meta‐analysis of adverse events leading to treatment discontinuation included 11 trials and revealed no significant differences between the two peginterferons. Conclusion: Current evidence suggests that peginterferon alpha‐2a is associated with higher SVR than peginterferon alfa‐2b. However, the paucity of evidence on adverse events curbs the decision to definitively recommend one peginterferon over the other, because any potential benefit must outweigh the risk of harm. (HEPATOLOGY 2010.)

World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Review Team, Douglas R. LaBrecque, MD, FACP (chair, USA), Zaigham Abbas, MD, MBBS, FCPS, FRCP, FRCPI, FACP, FACG, AGAF (Pakistan), Frank Anania, MD, FACP, AGAF (USA), Peter Ferenci, MD (Austria), Aamir G. Khan, MD (Pakistan), Khean-Lee Goh, MBBS, FRCP (Glasgow, London), MD, FACG, FASGE (Malaysia), Saeed S. Hamid, MD (Pakistan), Vasily Isakov, MD, PhD, AGAF (Russia), Maribel Lizarzabal, MD, PhD (Venezuela), Manuel M. Peñaranda, MD (Colombia), Juan F.R. Ramos, MD (Mexico), Shiv Sarin, MD, DM (India), Davor Stimac, MD (Croatia), Alan B.R. Thomson, MD (Canada), Muhammed Umar, MD, MBBS, MCPS, FCPS (PAK), FACG (USA), FRCP (L), FRCP (G), ASGE-M (USA), AGAF (USA) (Pakistan), Justus Krabshuis, (France), and Anton LeMair, MD (Netherlands)

Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disorder in Western countries, with a prevalence of 20–30%. NAFLD comprises ‘silent liver disease’, in which simple steatosis is the only histological finding and which is benign in course, and nonalcoholic steatohepatitis, which is characterized by hepatocellular injury and inflammation with or without fibrosis. NAFLD is clinically important, because even benign fatty liver can progress to steatohepatitis in many patients, which can lead to liver cirrhosis and its complications and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome; it is closely related to other clinical features of metabolic syndrome, and thus to cardiovascular morbidity. There are several different noninvasive techniques for formal diagnosis and follow-up, but liver biopsy remains the gold standard. The most important therapeutic strategies include lifestyle changes, including changes in dietary habits aimed at weight loss and blood pressure regulation, with a consequent decrease in insulin resistance. For some patients with NAFLD/nonalcoholic steatohepatitis, pharmacological treatment is the best option, although further studies are needed to confirm its efficacy and tolerability.

Incidence of inflammatory bowel disease in Primorsko-goranska County, Croatia, 2000-2004: A prospective population-based study.

Objective. It has been suggested that the incidence of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohns disease (CD), is higher in northern than in southern Europe. Recent epidemiological studies showed the loss of the previously described geographical north–south gradient. The aim of this study was to investigate the incidence of UC and CD in Primorsko-goranska County, Croatia. Material and methods. In the period 1 January 2000 to 31 December 2004 (5 years) all new patients diagnosed with IBD were prospectively identified according to a standard protocol for case ascertainment and definition. A total of 178 residents (81 F, 97 M) were newly diagnosed as having IBD during the study period. Of these, 70 had UC and 100 CD. Eight patients had indeterminate IBD. The data on patients were collected using a data form completed by gastroenterologists. Results. Annual age-standardized incidence rates were 4.3/105 (95% CI 2.6–6.0) for UC and 7.0/105 (95% CI 3.4–10.6) for CD. The highest incidence rate was observed in the age group 35–44 years for UC and the 25–34 years age group for CD. The incidence of IBD was higher in the urban than in the rural population, with the exception of on the islands. Conclusions. The incidence of IBD was higher than previously observed in Croatia. Our results suggest that CD incidence rates in the northern coastal part of Croatia are currently comparable with those reported in northern Europe.

Androgenic/anabolic steroid-induced toxic hepatitis

Athletes and bodybuilders often misuse androgenic/anabolic steroids. When used in therapeutic doses, these drugs produce clinical jaundice in just a small number of recipients. We present a 26-year-old male bodybuilder who self-administered high doses of androgenic/anabolic steroids that induced liver damage. One month before admission to the hospital, he used testosterone enanthate (500 mg intramuscularly, twice weekly), stanozolol (40 mg/d), and methylandrostenediol (30 mg/d by mouth, for 5 weeks). On admission, his bilirubin level was 470 micromol/L (direct, 360 micromol/L), his aspartate aminotransferase (AST) level was 5,870 IU/L, his alanine aminotransferase (ALT) level was 10,580 IU/L, his alkaline phosphatase (ALP) level was 152 IU/L, his gamma-glutamyl-transpeptidase level was 140 IU/L, his albumin level was 27.6 g/L, and his prothrombin time was 29%. During the patients prolonged hospitalization, multiple tests and liver biopsy were performed, showing only toxic hepatic lesions. The patient was provided with supportive medical treatment. Clinical signs and laboratory findings improved substantially 12 weeks after the patient discontinued androgenic/anabolic steroids. The reasons for presenting this case were the much higher values of AST and ALT levels than reported in other studies, although the values of bilirubin and ALP were similar to those found in the literature. To our knowledge, it is the first case of toxic hepatitis induced by androgenic/anabolic steroids with predominantly hepatocellular necrosis instead of intrahepatic cholestasis.

Sonographic measurement of absolute and relative renal length in adults

The aim of this study was to evaluate sonographically measured absolute and relative lengths of normal kidneys according to subject height, sex, and age.

Low serum albumin levels and liver metastasis are powerful prognostic markers for survival in patients with carcinomas of unknown primary site.

The authors investigated how lymphopenia and low serum albumin levels correlate with the prognosis of patients with carcinoma of unknown primary (CUP).

Non-alcoholic fatty liver disease and obesity : Biochemical, metabolic and clinical presentations

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m(2). However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m(2)) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.