Summary Background Hepatitis E virus ( HEV ) is a leading cause of acute icteric hepatitis and acute liver failure in the developing world. During the last decade, there has been increasing recognition of autochthonous (locally acquired) HEV infection in developed countries. Chronic HEV infection is now recognised, and in transplant recipients this may lead to cirrhosis and organ failure. Aim To detail current understanding of the molecular biology of HEV , diagnostic and therapeutic strategies and propose future directions for basic science and clinical research. Methods PubMed was searched for English language articles using the key words “hepatitis E”, “viral hepatitis”, “autochthonous infection”, “antiviral therapy”, “liver transplantation”, “acute”, “chronic”, “ HEV ”, “genotype”, “transmission” “food‐borne”, “transfusion”. Additional relevant publications were identified from article reference lists. Results There has been increasing recognition of autochthonous HEV infection in Western countries, mainly associated with genotype 3. Chronic HEV infection has been recognised since 2008, and in transplant recipients this may lead to cirrhosis and organ failure. Modes of transmission include food‐borne transmission, transfusion of blood products and solid organ transplantation. Ribavirin therapy is used to treat patients with chronic HEV infection, but new therapies are required as there have been reports of treatment failure with ribavirin. Conclusions Autochthonous HEV infection is a clinical issue with increasing burden. Future work should focus on increasing awareness of HEV infection in the developed world, emphasising the need for clinicians to have a low threshold for HEV testing, particularly in immunosuppressed patients. Patients at potential risk of chronic HEV infection must also be educated and given advice regarding prevention of infection.
The RNA virus, hepatitis E virus (HEV) is the most or second-most important cause of acute clinical hepatitis in adults throughout much of Asia, the Middle East, and Africa. In these regions it is an important cause of acute liver failure, especially in pregnant women who have a mortality rate of 20–30%. Until recently, hepatitis E was rarely identified in industrialized countries, but Hepatitis E now is reported increasingly throughout Western Europe, some Eastern European countries, and Japan. Most of these cases are caused by genotype 3, which is endemic in swine, and these cases are thought to be zoonotically acquired. However, transmission routes are not well understood. HEV that infect humans are divided into nonzoonotic (types 1, 2) and zoonotic (types 3, 4) genotypes. HEV cell culture is inefficient and limited, and thus far HEV has been cultured only in human cell lines. The HEV strain Kernow-C1 (genotype 3) isolated from a chronically infected patient was used to identify human, pig, and deer cell lines permissive for infection. Cross-species infections by genotypes 1 and 3 were studied with this set of cultures. Adaptation of the Kernow-C1 strain to growth in human hepatoma cells selected for a rare virus recombinant that contained an insertion of 174 ribonucleotides (58 amino acids) of a human ribosomal protein gene.
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.
Anti-thrombotics (antiplatelets and anticoagulants; ATs) have been identified as risk factors for upper gastrointestinal bleeding (UGIB). However few international studies have evaluated their effect on patient outcome. We aimed to assess the effects of AT use on outcome in patients with high-risk UGIB requiring endoscopic therapy.
Methods
Patients presenting with UGIB who required endoscopic therapy at eight centres (Scotland, England, USA, Canada, Denmark, Italy, Singapore & New Zealand) were prospectively included over 12 months. Data recorded included the full Rockall score (FRS); AT use (Aspirin, Adenosine Diphosphate Receptor Inhibitors (ADP-RI), Vitamin-K Antagonists (VKA), Low Molecular Weight Heparin (LMWH), Thrombin inhibitors and Factor Xa inhibitors); endoscopic findings; blood transfusion; interventional radiology; surgery; rebleeding; 30 day mortality and length of hospital stay.
Results
Out of 3154 patients, 619 required endotherapy (44% for ulcer bleeding and 21% for varices). 187 (30%) patients were on aspirin, 61 (11%) ADP-RI, 57 (9%) VKA, 8 (1%) LMWH, 7 (1%) factor Xa-inhibitor and 1 patient a thrombin-inhibitor. 63 (11%) patients were treated with >1 type of AT. Patients treated with ATs were older (p < 0.0001), had higher ASA-score (p = 0.001), lower haemoglobin (P = 0.04), higher FRS (p < 0.0001), more frequently had ischaemic heart disease (IHD; p < 0.001), less frequently had cirrhosis (P < 0.001), more frequently bled from ulcers (p < 0.001) but less frequently from varices (p < 0.001) compared with those not taking ATs. There were no differences in sex, systolic blood pressure, frequency of malignancies, need for surgery/embolisation or rebleeding rate. Patients taking ATs had lower mortality than those not taking these drugs: all cause (11/253 [4%] vs 37/315 [12%]; p = 0.006) and bleeding-related (3/253 [1%] vs 19/315 [6%]; p = 0.01). However, when excluding patients with liver cirrhosis (n = 151) there were no differences in mortality between groups.
Conclusion
Patients with UGIB who require endoscopic therapy whilst on ATs do not experience a higher rate of rebleeding or mortality compared with UGIB patients who do not use ATs. We observed excess mortality in patients not taking ATs, which is likely due to the high rates of cirrhosis (40%) and variceal bleeding (33%) in these patients. Further studies are needed to clarify the risk of adverse outcome following UGIB in patients taking novel ATs.
Summary Background Autochthonous (locally acquired) hepatitis E is increasingly recognised in developed countries, and is thought to be a porcine zoonosis. A range of extra‐hepatic manifestations of hepatitis E infection have been described, but have never been systematically studied. Aim To report the extra‐hepatic manifestations of hepatitis E virus. Methods Retrospective review of data of 106 cases of autochthonous hepatitis E (acute n = 105, chronic n = 1). Results Eight (7.5%) cases presented with neurological syndromes, which included brachial neuritis, Guillain‐Barré syndrome, peripheral neuropathy, neuromyopathy and vestibular neuritis. Patients with neurological syndromes were younger (median age 40 years, range 34–92 years, P = 0.048) and had a more modest transaminitis (median ALT 471 IU/L, P = 0.015) compared to cases without neurological symptoms [median age 64 years (range 18–88 years), median ALT 1135 IU/L]. One patient presented with a cardiac arrhythmia,twelve patients (11.3%) presented with thrombocytopenia, fourteen (13.2%) with lymphocytosis and eight (7.5%) with a lymphopenia, none of which had any clinical consequence. Serum electrophoresis was performed in 65 patients at presentation, of whom 17 (26%) had a monoclonal gammopathy of uncertain significance. Two cases developed haematological malignancies, acute myeloid leukaemia and duodenal plasmacytoma, 18 and 36 months after presenting with acute hepatitis E infection. Conclusions A range of extra‐hepatic manifestations can occur with hepatitis E. Neurological and haematological features of hepatitis E infection are relatively frequent in this UK cohort, and result in significant morbidity which warrants further study.
Until recently, HEV was thought not to occur in developed countries such as the UK, except in travellers returning from endemic areas.However, it has now become clear that autochthonous (locally acquired) HEV is common in developed countries, and is considered an "emerging disease".Autochthonous HEV has been documented in Europe, the USA, Canada, Japan, and New Zealand.HEV infection acquired in these areas differs from that in developing countries in a number of important aspects: it is caused by genotype 3 (and 4 in China and Japan); it most commonly affects middle-aged/ elderly males; it is zoonotic with a porcine primary host.Although pig herds worldwide are infected with HEV genotype 3, and HEV has been detected in retail meats in the human food chain in a number of developed countries, the route of transmission is not fully understood since most cases of autochthonous infection are not obviously associated with pigs or pig products.HEV has also been transmitted by blood transfusion in a number of countries, and surprisingly high numbers of asymptomatic blood donors are viraemic at the time of donation: Germany 1:1200, Netherlands 1:2671, England 1:7000 and Sweden 1:7986.Our understanding of the clinical range of HEV infection in humans has undergone a sea-change in recent years.Until 2008, HEV was thought to cause only acute selflimiting infection.However, it is now evident that HEV may cause persistent disease in immune-compromised solid organ transplant recipients, individuals with HIV and patients with haematological malignancy.Patients with chronic HEV infection have no symptoms, but some develop rapidly progressive liver cirrhosis.The full clinical spectrum of HEV in developed countries is still emerging.In Cornwall (UK), we have been studying the disease prospectively for over a decade, one of the longest studies of its type in a developed country.HEV has important extra-hepatic manifestations, which deserve further investigation.For example, we have shown that HEV is neuropathogenic, and can cause a wide range of neurological illness.In particular, very recent data suggests that Guillain-Barré syndrome and neuralgic amyotrophy are associated with locally acquired HEV in approximately 5% and 10% of cases respectively.
Clinic Handbook: Gastroenterology provides practical guidelines on the medical and administrative issues associated with running a gastroenterology-based outpatient clinic.Written with all members of the outpatient team in mind, the book provides key information on diagnosis; planning and implementation of treatment; patient education and resource
HLA-DR+ gut epithelial cells may present antigen to intraepithelial lymphocytes (IEL). This study aimed to isolate an IEL population from the human colon to activate CD3 + IEL by a human colonic epithelial cell line (HT-29), bearing different concentrations of class II antigen (HLA-DR). IEL were isolated by a mechanical method from six patients with ulcerative colitis (UC) and from 14 control patients. IEL were cocultured with HT-29 which had been induced to express class II molecules by gamma-interferon (IFN-gamma) in a dose dependent manner. The phenotype and the subsequent expression of activation markers by the IEL were determined to two colour flow cytometry. The IEL population had a CD4/CD8 ratio similar to that seen in tissue sections. In the mixed cell culture, the degree of IEL activation showed a positive correlation with the degree of HLA-DR expression by the HT29 cells and the IEL secreted a IFN-gamma like factor that in turn stimulated the HT-29. Thus, depending on their expression of HLA molecules, colonic epithelial cells are able to activate CD3+CD8+IEL.
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