Montserrat Fraga

Clinical phenotype and outcome of hepatitis E virus–associated neuralgic amyotrophy

Objective: To determine the clinical phenotype and outcome in hepatitis E virus–associated neuralgic amyotrophy (HEV-NA). Methods: Cases of NA were identified in 11 centers from 7 European countries, with retrospective analysis of demographics, clinical/laboratory findings, and treatment and outcome. Cases of HEV-NA were compared with NA cases without evidence of HEV infection. Results: Fifty-seven cases of HEV-NA and 61 NA cases without HEV were studied. Fifty-six of 57 HEV-NA cases were anti-HEV IgM positive; 53/57 were IgG positive. In 38 cases, HEV RNA was recovered from the serum and in 1 from the CSF (all genotype 3). Fifty-one of 57 HEV-NA cases were anicteric; median alanine aminotransferase 259 IU/L (range 12–2,961 IU/L); in 6 cases, liver function tests were normal. HEV-NA cases were more likely to have bilateral involvement (80.0% vs 8.6%, p < 0.001), damage outside the brachial plexus (58.5% vs 10.5%, p < 0.01), including phrenic nerve and lumbosacral plexus injury (25.0% vs 3.5%, p = 0.01, and 26.4% vs 7.0%, p = 0.001), reduced reflexes (p = 0.03), sensory symptoms (p = 0.04) with more extensive damage to the brachial plexus. There was no difference in outcome between the 2 groups at 12 months. Conclusions: Patients with HEV-NA are usually anicteric and have a distinct clinical phenotype, with predominately bilateral asymmetrical involvement of, and more extensive damage to, the brachial plexus. Involvement outside the brachial plexus is more common in HEV-NA. The relationship between HEV and NA is likely to be causal, but is easily overlooked. Patients presenting with NA should be tested for HEV, irrespective of liver function test results. Prospective treatment/outcome studies of HEV-NA are warranted.

Primary sclerosing cholangitis in the Swiss Inflammatory Bowel Disease Cohort Study: prevalence, risk factors, and long-term follow-up.

Background and aim Primary sclerosing cholangitis (PSC) represents the most common hepatobiliary extraintestinal manifestation of inflammatory bowel disease (IBD). We aimed to assess the prevalence of PSC in the Swiss Inflammatory Bowel Disease Cohort Study, to identify associated risk factors, and to describe the long-term evolution. Patients and methods Data of patients enrolled into the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. Logistic regression modeling was performed to identify risk factors for PSC. Results Among 2744 patients [1188 ulcerative colitis (UC); 1556 Crohn’s disease (CD)], 57 had PSC (48 UC-PSC, nine CD-PSC). The prevalence of PSC was higher in UC compared with CD (4.04 vs. 0.58%, P<0.001). We identified the following significant independent risk factors for PSC in patients with UC: male sex [odds ratio (OR) 2.771, P=0.022], pancolitis (OR 2.855, P=0.011), nonsmoker at diagnosis (OR 9.253, P=0.030), and a history of appendicectomy (OR 4.114, P=0.019). During a median follow-up time of 74.8 months, four (7.0%) of PSC patients developed cholangiocarcinoma, six (10.5%) underwent liver transplantation, and five (8.8%) died. Survival of IBD-PSC patients was significantly worse compared with IBD patients without PSC (P=0.001). UC-PSC patients developed significantly more frequently colorectal cancer compared with UC patients without PSC (2/48 vs. 9/1440, P=0.017). Conclusion Approximately 4% of UC patients and 0.6% of CD patients had PSC. Male sex, pancolitis, nonsmoker status, and a history of appendicectomy were significantly associated with PSC. PSC is associated with considerable morbidity and mortality in the long term.

Visualization of hepatitis E virus RNA and proteins in the human liver

BACKGROUND & AIMS Although hepatitis E constitutes a substantial disease burden worldwide, surprisingly little is known about the localization of hepatitis E virus (HEV) in the human liver. We therefore aimed to visualize HEV RNA and proteins in situ. METHODS A panel of 12 different antibodies against HEV open reading frame (ORF) 1-3 proteins was evaluated for immunohistochemistry (IHC) and two probes for in situ hybridization (ISH) in formalin-fixed, paraffin-embedded (FFPE) HuH7 cells transfected with HEV ORF1-3 expression vectors. IHC (and partly ISH) were then applied to Hep293TT cells replicating infectious HEV and liver specimens from patients with hepatitis E (n=20) and controls (n=134). RESULTS Whereas ORF1-3 proteins were all detectable in transfected, HEV protein-expressing cells, only ORF2 and 3 proteins were traceable in cells replicating infectious HEV. Only the ORF2-encoded capsid protein was also unequivocally detectable in liver specimens from patients with hepatitis E. IHC for ORF2 protein revealed a patchy expression in individual or grouped hepatocytes, generally stronger in chronic compared to acute hepatitis. Besides cytoplasmic and canalicular, ORF2 protein also displayed a hitherto unknown nuclear localization. Positivity for ORF2 protein in defined areas correlated with HEV RNA detection by ISH. IHC was specific and comparably sensitive as PCR for HEV RNA. CONCLUSIONS ORF2 protein can be reliably visualized in the liver of patients with hepatitis E, allowing for sensitive and specific detection of HEV in FFPE samples. Its variable subcellular distribution in individual hepatocytes of the same liver suggests a redistribution of ORF2 protein during infection and interaction with nuclear components. LAY SUMMARY The open reading frame (ORF) 2 protein can be used to visualize the hepatitis E virus (HEV) in the human liver. This enabled us to discover a hitherto unknown localization of the HEV ORF2 protein in the nucleus of hepatocytes and to develop a test for rapid histopathologic diagnosis of hepatitis E, the most common cause of acute hepatitis worldwide.

Hepatitis E Virus as a Cause of Acute Hepatitis Acquired in Switzerland

Autochthonous hepatitis E is increasingly recognized as zoonotic infection in western countries. Serological assays have varying sensitivity and specificity.

Heterotopic Gastric Mucosa in a Duplication Cyst of the Common Hepatic Duct Mimicking Cholangiocarcinoma

Heterotopic gastric mucosa in biliary tract is a congenital anomaly that can prove significant clinical dilemmas. Here we report the case of a 28-year-old female patient presenting with jaundice, pruritus, and altered liver tests, with predominant cholestasis. Liver biopsy revealed histological changes suggesting large bile duct obstruction with advanced fibrosis. At imaging, common hepatic duct stricture due to an intraluminal enhancing mass was observed. Endoscopic retrograde cholangiopancreatography and upper echoendoscopy revealed a firm mass of the common hepatic duct with a complete obstruction, suspicious for cholangiocarcinoma. Fine-needle aspiration biopsy performed under echoendoscopic guidance revealed fundic type gastric mucosa. Despite histological result, radiological suspicion of malignancy together with advanced fibrosis prompted a segmental resection of biliary tract. At macroscopic examination, the common hepatic duct presented a focal pseudocystic appearance with a firm zone of subtotal stenosis. Histology revealed a duplication cyst lined by heterotopic fundic gastric mucosa. Heterotopic gastric mucosa of the biliary tract should be suspected in young patients without know risk factors for hepatobiliary malignancies. Imaging and careful histological examination are mandatory for optimal management. Liver fibrosis, secondary to chronic biliary obstruction may be a significant late complication.

Frequency and type of drug-related side effects necessitating treatment discontinuation in the Swiss Inflammatory Bowel Disease Cohort.

Background and aim Systematic analyses of inflammatory bowel disease (IBD) drug-related side effects necessitating treatment cessation in large cohorts of patients with IBD are scarce. We aimed to assess the frequency and type of drug-related side effects requiring drug cessation in patients included in the Swiss IBD Cohort. Patients and methods A retrospective review was performed of data from the Swiss IBD Cohort physician questionnaires documenting a treatment cessation for the following drug categories: aminosalicylates, topical and systemic steroids, thiopurines, methotrexate, tumor necrosis factor-antagonists, and calcineurin inhibitors (tacrolimus, cyclosporine). Results A total of 3192 patients were analyzed, of whom 1792 (56.1%) had Crohn’s disease, 1322 (41.4%) had ulcerative colitis, and 78 (2.5%) had IBD unclassified. Of 3138 patients treated with IBD drugs, 2129 (67.8%) presented with one or several drug-related side effects necessitating drug cessation. We found a significant positive correlation between the number of concomitantly administered IBD drugs and the occurrence of side effects requiring drug cessation (P<0.001). Logistic regression modeling identified Crohn’s disease diagnosis [odds ratio (OR)=1.361, P=0.017], presence of extraintestinal manifestations (OR=2.262, P<0.001), IBD-related surgery (OR=1.419, P=0.006), and the increasing number of concomitantly used IBD drugs [OR=2.007 (P<0.001) for two concomitantly used IBD drugs; OR=3.225 (P<0.001) for at least three concomitantly used IBD drugs] to be associated significantly with the occurrence of IBD drug-related adverse events that necessitated treatment cessation. Conclusion Physicians should keep in mind that the number of concomitantly administered IBD drugs is the main risk factor for drug-related adverse events necessitating treatment cessation.

Akute und chronische Hepatitis E

Zusammenfassung. Das Hepatitis E Virus (HEV) ist eine der haufigsten Ursachen der akuten Hepatitis weltweit. Es wird bei uns als Zoonose hauptsachlich durch den Konsum von rohem oder unzureichend erhitztem Schweinefleisch oder Wild ubertragen. Die autochthone Hepatitis E verlauft meist asymptomatisch oder mild, schwere Verlaufe werden aber bei Patienten mit vorbestehenden chronischen Lebererkrankungen beobachtet. Neurologische Komplikationen, insbesondere die neuralgische Amyotrophie, sind Teil des klinischen Spektrums. Bei immunsupprimierten Patienten kann es zu einem chronischen Verlauf mit Ubergang in eine Leberzirrhose kommen. In diesem Beitrag werden der aktuelle Stand und neue Entwicklungen in der Virologie, Epidemiologie, Diagnostik, Klinik, Therapie und Pravention der Hepatitis E zusammenfassend dargestellt.