Hepatitis E: an expanding epidemic with a range of complications.

BACKGROUND: Hepatitis E virus (HEV) is a common cause of viral hepatitis worldwide. Previously considered a disease of the developing world, it is increasingly recognized that locally acquired HEV infection is common in industrialized countries. OBJECTIVES: The aim was to highlight the changing epidemiology of HEV infection, particularly in the developed world, and inform clinicians of the diverse clinical presentations and extra-hepatic complications associated with the virus. SOURCES: References for this review were identified through searches of MEDLINE/PubMed, and Google Scholar, up to January 2020. Searches were restricted to articles published in English. CONTENT: Hepatitis E virus is an under-recognized, emerging pathogen with important implications for public health in both the developing and developed world. The number of cases reported in resource-rich settings is increasing, in part due to improved case ascertainment but also as a result of increased incidence in some countries. The reasons behind these epidemiological shifts are not currently known. Chronic HEV infection has been reported in immunocompromised patients. A range of extra-hepatic manifestations have also been reported, most notably neurological and renal complications. There is evidence to suggest a causal link with Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis/myelitis. Glomerular disease has been reported in the context of both acute and chronic infection. IMPLICATIONS: HEV should be included in non-invasive liver screens and considered in the differentials for patients presenting with alanine aminotransferase elevation, suspected drug-induced liver injury or decompensated liver disease. Any patients with acute neurological injury and deranged liver function should be tested for hepatitis E, and all patients presenting with Guillain-Barré syndrome or neuralgic amyotrophy should be tested regardless of liver enzymes. Immunocompromised patients with persistently raised liver enzymes should be tested with molecular techniques and offered annual routine screening.

Hepatitis E: a largely underestimated, emerging threat.

Hepatitis E virus has two distinct clinical and epidemiological patterns based on the varying genotypes. Genotypes 3 and 4 cause widespread, sporadic infection in high-income countries and are emerging as the most common type of viral hepatitis in much of Europe. These infections carry significant morbidity and mortality in the growing numbers of immunosuppressed patients or in patients with established liver disease. Furthermore the growing extra-hepatic associations of the virus, including neurological and kidney injury, suggest that it may have been misnamed as a 'hepatitis' virus. This review explores current understanding of the epidemiology, virology and clinical presentations of hepatitis E infection and identifies vulnerable patient groups, who are at serious risk from infection. Guidance is offered regarding the diagnosis, treatment and prevention of this growing public health hazard.

Oesophageal causes of dysphagia localised only to the pharynx: Implications for the suspected head and neck cancer pathway.

OBJECTIVES: Dysphagia is a presenting symptom of both pharyngeal and oesophageal cancers. The referral pathway choice is determined by whether it is thought to be oropharyngeal or oesophageal, and this is in turn influenced by whether dysphagia is perceived to be above or below the suprasternal notch. We studied the concordance between the presence of pharynx-localised dysphagia (PLD) and the location of the underlying disease processes. DESIGN: A subset analysis of the Dysphagia Hotline Cohort, collected between 2004 and 2015, of patients with PLD and a structural diagnosis. MAIN OUTCOME MEASURES: Information about patient demography and presenting symptoms were recorded. The incisor-to-pathology distance, and the nature of the pathology, were recorded. Logistic regression analysis was used to identify independent predictors of malignancy. RESULTS: The study included 177 patients. There were 92 males, and mean age at presentation was 74 years. The commonest benign pathologies were cricopharyngeal dysfunction with or without pharyngeal pouch (n = 67), peptic stricture (n = 44) and Schatzki's ring (n = 11). There were 49 cases of cancer, including one hypopharyngeal cancer, one cervical oesophageal cancer, 28 cancers of the upper/mid-thoracic oesophagus, 15 cancers of the lower thoracic oesophagus and 4 cardio-oesophageal cancers. In 105 (59%) patients, PLD was caused by oesophageal disease. Independent predictors of malignancy were weight-change (loss >2.7 kg), a short history (<12 weeks) and presence of odynophagia. Nineteen (39%) of oesophageal cancers that presented with dysphagia that was localised only to the pharynx would have been beyond the reach of rigid oesophagoscopy. CONCLUSIONS: Pharynx-localised dysphagia is more likely to be a referred symptom of structural oesophageal disease, including cancer, than a primary symptom of structural pharyngeal disease. Absence of additional alarm symptoms such as a short history, weight-loss, and odynophagia, do not adequately exclude the possibility of oesophageal cancer. When the differential diagnosis of PLD includes malignancy, cancer should be presumed to be arising from the oesophagus or the cardio-oesophageal region until proven otherwise. This requires direct visualisation of the mucosal surfaces of the oesophagus and the cardio-oesophageal region, using either transoral or transnasal flexible endoscopy, irrespective of whether the initial assessment occurs within head and neck or upper gastrointestinal suspected cancer pathways.

Knowledge gaps and research priorities in the prevention and control of hepatitis E virus infection.

Hepatitis E virus (HEV), family Hepeviridae, is a main cause of epidemic hepatitis in developing countries and sporadic and cluster cases of hepatitis in industrialized countries. There are an increasing number of reported cases in humans especially in industrialized countries, and there is a high potential for transboundary spread of zoonotic genotypes of the virus through the transport of pigs, pig products and by-products. Bloodborne transmission of the virus has been reported with a significant medical concern. To better coordinate HEV research and design better control measures of HEV infections in animals, a group of HEV experts reviewed the current knowledge on the disease and considered the existing disease control tools. It was concluded that there is a lack of in-depth information about the spread of the virus from pigs to humans. The role of animals other than pigs in the zoonotic transmission of the virus to humans and the extent of foodborne transmission are poorly understood. Factors involved in development of clinical disease such as infectious dose, susceptibility and virulence of virus strains need to be studied more extensively. However, such studies are greatly hindered by the absence of a broadly applicable, efficient and sensitive in vitro cell culture system for HEV. Diagnostic tools for HEV are available but need to be further validated, harmonized and standardized. Commercially available HEV vaccines for the control of HEV infection in animal populations are needed as such vaccines can minimize the zoonotic risk for humans. Anti-HEV drugs for treatment of HEV-infected patients need to be studied more extensively. The detailed expert review can be downloaded from the project website at http://www.discontools.eu/.

Hepatitis E virus in patients with decompensated chronic liver disease: a prospective UK/French study.

BACKGROUND: In developed countries, hepatitis E is a porcine zoonosis caused by hepatitis E virus (HEV) genotype 3. In developing countries, hepatitis E is mainly caused by genotype 1, and causes increased mortality in patients with pre-existing chronic liver disease (CLD). AIM: To determine the role of HEV in patients with decompensated CLD. METHODS: Prospective HEV testing of 343 patients with decompensated CLD at three UK centres and Toulouse France, with follow-up for 6 months or death. IgG seroprevalence was compared with 911 controls. RESULTS: 11/343 patients (3.2%) had acute hepatitis E infection, and three died. There were no differences in mortality (27% vs. 26%, OR 1.1, 95% CI 0.28-4.1), age (P = 0.9), bilirubin (P = 0.5), alanine aminotransferase (P = 0.06) albumin (P = 0.5) or international normalised ratio (P = 0.6) in patients with and without hepatitis E infection. Five cases were polymerase chain reaction (PCR) positive (genotype 3). Hepatitis E was more common in Toulouse (7.9%) compared to the UK cohort (1.2%, P = 0.003). HEV IgG seroprevalence was higher in Toulouse (OR 17, 95% CI 9.2-30) and Truro (OR 2.5, 95% CI 1.4-4.6) than in Glasgow, but lower in cases, compared to controls (OR 0.59, 95% CI 0.41-0.86). CONCLUSIONS: Hepatitis E occurs in a minority of patients with decompensated chronic liver disease. The mortality is no different to the mortality in patients without hepatitis E infection. The diagnosis can only be established by a combination of serology and PCR, the yield and utility of which vary by geographical location.

Unusual serological response to hepatitis E virus in plasma donors consistent with re-infection.

Hepatitis E virus (HEV)-positive plasma donations, identified by a plasma mini-pool screening approach, were analysed using serological methods for the presence of anti-HEV IgM and IgG. Avidity testing was performed on the IgG-reactive donations. Anti-HEV IgG with high avidity was observed in two donors together with high viral loads, but with the absence of anti-HEV IgM. These data are suggestive of re-infection in a small proportion of plasma donors, which has not previously been reported.

Extra-hepatic manifestations of autochthonous hepatitis E infection.

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.

Hepatitis E: An emerging infection in high income countries.

Hepatitis E virus (HEV) genotype 3 is the most recently characterized hepatotropic virus and is increasingly being recognized as the cause of unexplained liver disease in many western countries. Although asymptomatic in most cases, HEV GT3 may be responsible for a wide range of illnesses, from mild to fulminant acute hepatitis, and also chronic hepatitis in immunocompromised patients. Extrahepatic manifestations have been occasionally described. Anti-HEV antibody detection by immunoassays is hampered by moderate test accuracy particularly in immunocompromised hosts while a WHO international standard for molecular detection of HEV RNA by RT-PCR has recently been introduced. This review describes the basic virology, epidemiology, clinical virology and treatment of HEV GT3 infections in high income countries.

Hepatitis E virus in Scottish blood donors.

BACKGROUND AND OBJECTIVES: Published prevalence figures for hepatitis E virus (HEV) reveal significant regional differences. Several studies have reported virus transmission via blood transfusion. The aim of this study was to establish HEV seroprevalence and investigate a potential HEV RNA presence in Scottish blood donors. MATERIALS AND METHODS: IgG and IgM were determined in individual serum samples. HEV RNA was investigated in plasma mini-pools corresponding to 43 560 individual donations using nested PCR. Samples amenable to reamplification with primers from a different region were considered confirmed positives, sequenced and analysed. RESULTS: A total of 73 of 1559 tested individual sera (4·7%) were IgG positive, none tested positive for IgM. Plasma mini-pool testing revealed an HEV RNA frequency of 1 in 14 520 donations. Three confirmed positives belonged, as expected to genotype 3. CONCLUSIONS: HEV IgG and RNA figures in Scottish blood donors are lower than those published for the rest of the UK, but sufficiently high to prompt further studies on potential transmission rates and effects of HEV infection, especially for immunosuppressed individuals.

Autochthonous hepatitis E in developed countries and HEV/HIV coinfection.

A novel hepatitis virus was long suspected as the cause of outbreaks of unexplained hepatitis with high maternal mortality in Asia. An outbreak of unexplained hepatitis in a Soviet military camp in Afghanistan led one investigator to ingest a pooled fecal extract from affected service personnel. This resulted in the discovery of the hepatitis E virus (HEV) in 1983. Subsequent studies showed that HEV was endemic in large parts of the developing world. Its incidence in industrialized nations was initially attributed to travel-related exposure. For many years after the discovery of HEV, it was considered a "new" virus, and of no relevance to developed countries. This perceived wisdom has proven to be hopelessly inaccurate. Human infections with HEV are not "new," and are of considerable global importance, including in developed countries.

Hepatitis E: source and route of infection, clinical manifestations and new developments.

Hepatitis E was previously thought to be a disease of developing countries causing significant morbidity and mortality in young adults, particularly among pregnant women and patients with pre-existing chronic liver disease. Recent studies have shown that hepatitis E is also an issue in developed countries. In this setting, hepatitis E is a zoonotic infection and causes acute infection mainly in middle-aged and elderly men; and chronic infection in the immunosuppressed. The scope and burden of disease are still emerging. The diagnosis of hepatitis E should be considered in any patient with hepatitis, irrespective of their age or travel history.

Characteristics of Epstein-Barr virus hepatitis among patients with jaundice or acute hepatitis.

BACKGROUND: Abnormal liver blood tests are common in Epstein-Barr virus (EBV) infection, but symptomatic hepatitis is rare. The demographics, clinical features and outcome of EBV hepatitis are incompletely understood, particularly in the elderly people. AIM: To identify the demographics, presenting features and natural history of EBV hepatitis. METHODS: Retrospective review of 1995 consecutive patients attending the jaundice hotline clinic over a 13-year period. Data collected included demographic information, presenting features, clinical and laboratory parameters, radiology imaging and clinical outcome. RESULTS: Seventeen of 1995 (0.85%) had EBV hepatitis. The median age was 40 years (range 18-68 years). Ten of 17 (59%) patients were aged >30 years, and seven of 17 (41%) patients were aged ≥60 years. Fifteen of 17 (88%) patients presented with clinical/biochemical evidence of jaundice. Seventeen of 17 (100%) patients had a serum lymphocytosis at presentation. 2/17 (12%) patients with EBV hepatitis presented with the classical features of infectious mononucleosis (fever, sore throat and lymphadenopathy). Splenomegaly was present in 15/17 (88%) of patients. Symptoms lasted for a median 8 weeks (range 1-12 weeks). Three of 17 (18%) patients required a brief hospital admission. CONCLUSIONS: In patients presenting with jaundice/hepatitis, EBV hepatitis is an uncommon diagnosis and causes a self-limiting hepatitis. The diagnosis is suggested by the presence of a lymphocytosis and/or splenomegaly. The majority of patients do not have infectious mononucleosis. Compared with infectious mononucleosis, EBV hepatitis affects an older age group, with nearly half of patients being aged more than 60 years. The diagnosis should be considered in all patients with unexplained hepatitis irrespective of their age.

Multicentre comparison of the Glasgow Blatchford and Rockall Scores in the prediction of clinical end-points after upper gastrointestinal haemorrhage.

BACKGROUND: The Glasgow Blatchford Score (GBS) is increasingly being used to predict intervention and outcome following upper gastrointestinal haemorrhage (UGIH). AIM: To compare the GBS with both the admission and full Rockall scores in predicting specific clinical end-points following UGIH. PATIENTS AND METHODS: Data on consecutive patients presenting to four UK hospitals were collected. Admission history, clinical and laboratory data, endoscopic findings, treatment and clinical follow-up were recorded. Using ROC curves, we compared the three scores in the prediction of death, endoscopic or surgical intervention and transfusion. Results A total of 1555 patients (mean age 56.7years) presented with UGIH during the study period. Seventy-four (4.8%) died, 223 (14.3%) had endoscopic or surgical intervention and 363 (23.3%) required transfusion. The GBS was similar at predicting death compared with both the admission Rockall (area under ROC curve 0.804 vs. 0.801) and full Rockall score (AUROC 0.741 vs. 0.790). In predicting endo-surgical intervention, the GBS was superior to the admission Rockall (AUROC 0.858 vs. 0.705; P<0.00005) and similar to the full Rockall score (AUROC 0.822 vs. 0.797). The GBS was superior to both admission Rockall (AUROC 0.944 vs. 0.756; P<0.00005) and full Rockall scores (AUROC 0.935 vs. 0.792; P<0.00005) in predicting need for transfusion. CONCLUSIONS: Despite not incorporating age, the GBS is as effective as the admission and full Rockall scores in predicting death after UGIH. It is superior to both the admission and full Rockall scores in predicting need for transfusion, and superior to the admission Rockall score in predicting endoscopic or surgical intervention.

National mortality rates from chronic liver disease and consumption of alcohol and pig meat.

A correlation between national pig-meat consumption and mortality rates from chronic liver disease (CLD) across developed countries was reported in 1985. One possible mechanism explaining this may be hepatitis E infection spread via pig meat. We aimed to re-examine the original association in more recent international data. Regression models were used to estimate associations between national pig-meat consumption and CLD mortality, adjusting for confounders. Data on CLD mortality, alcohol consumption, hepatitis B virus (HBV) and hepatitis C virus (HCV) seroprevalence for 18 developed countries (1990-2000) were obtained from WHO databases. Data on national pig-meat and beef consumption were obtained from the UN database. Univariate regression showed that alcohol and pig-meat consumption were associated with mortality from CLD, but beef consumption, HBV and HCV seroprevalence were not. A 1 litre per capita increase in alcohol consumption was associated with an increase in mortality from CLD in excess of 1.6 deaths/100,000 population. A 10 kg higher national annual average per capita consumption of pork meat was associated with an increase in mortality from CLD of between 4 and 5 deaths/100,000 population. Multivariate regression showed that alcohol, pig-meat consumption and HBV seroprevalence were independently associated with mortality from CLD, but HCV seroprevalence was not. Pig-meat consumption remained independently associated with mortality from CLD in developed countries in the 1990-2000 period. Further work is needed to establish the mechanism.

Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation.

BACKGROUND: Upper-gastrointestinal haemorrhage is a frequent reason for hospital admission. Although most risk scoring systems for this disorder incorporate endoscopic findings, the Glasgow-Blatchford bleeding score (GBS) is based on simple clinical and laboratory variables; a score of 0 identifies low-risk patients who might be suitable for outpatient management. We aimed to evaluate the GBS then assess the effect of a protocol based on this score for non-admission of low-risk individuals. METHODS: Our study was undertaken at four hospitals in the UK. We calculated GBS and admission (pre-endoscopy) and full (post-endoscopy) Rockall scores for consecutive patients presenting with upper-gastrointestinal haemorrhage. With receiver-operating characteristic (ROC) curves, we compared the ability of these scores to predict either need for clinical intervention or death. We then prospectively assessed at two hospitals the introduction of GBS scoring to avoid admission of low-risk patients. FINDINGS: Of 676 people presenting with upper-gastrointestinal haemorrhage, we identified 105 (16%) who scored 0 on the GBS. For prediction of need for intervention or death, GBS (area under ROC curve 0.90 [95% CI 0.88-0.93]) was superior to full Rockall score (0.81 [0.77-0.84]), which in turn was better than the admission Rockall score (0.70 [0.65-0.75]). When introduced into clinical practice, 123 patients (22%) with upper-gastrointestinal haemorrhage were classified as low risk, of whom 84 (68%) were managed as outpatients without adverse events. The proportion of individuals with this condition admitted to hospital also fell (96% to 71%, p<0.00001). INTERPRETATION: The GBS identifies many patients presenting to general hospitals with upper-gastrointestinal haemorrhage who can be managed safely as outpatients. This score reduces admissions for this condition, allowing more appropriate use of in-patient resources.

Case report: Thromboembolic and septic complications of migrated cyanoacrylate injected for bleeding gastric varices.

Endoscopic injection of N-butyl-2-cyanoacrylate combined with radio-opaque lipiodol is widely used to achieve haemostasis in bleeding gastric varices. We present a case of migration of injected cyanoacrylate, thrombus formation and subsequent septic embolisation.