Prolonged Gut Dysbiosis and Fecal Excretion of Hepatitis A Virus in Patients Infected with Human Immunodeficiency Virus.

Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.

Mechanisms of Hepatocellular Injury in Hepatitis A.

Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8+ T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.

Autoimmune Hepatic Failure Following Acute Hepatitis A is Accompanied by Inflammatory Conversion of Regulatory T Cells.

To evaluate the pathophysiology of autoimmune hepatitis (AIH) following acute hepatitis A (AHA) in immunologic aspects, we performed multi-color flow cytometry with peripheral blood mononuclear cells of a patient who underwent liver transplantation due to AIH-induced liver failure. Unlike general AHA patients, the proportion of tumor necrosis factor-α-producing Treg cells remained high for 6 months after diagnosis of AHA until she underwent a liver transplantation. The conversion of Treg cells into mediators of inflammation may have played a role in the autoimmune pathogenesis following AHA.

Autoimmune Hepatitis A Case Report and Literature Review.

INTRODUCTION: Autoimmune hepatitis (AIH) is a cause of chronic liver disease. It is usually suspected based on clinical presentation and laboratory findings, but the diagnosis relies on the presence of specific autoantibodies and characteristic histology. Other unexplained findings should always prompt investigation for coexisting syndromes. CASE PRESENTATION: The patient is a 60-year-old Hispanic female with a history of mild asthma presented with exertional and pleuritic chest pain with weight loss, arthralgia, subjective fever, and night sweats for the last 3 months. Given the nonspecific nature of the presentation, further workup was pursued. Laboratory results indicated pancytopenia, elevated INR, and positive autoimmune panel including ANA, anti-chromatin, anti-histone, and rheumatoid factor as well as abnormal C3 and C4. Subsequent liver biopsy with interface hepatitis lead to a diagnosis of AIH with concurrent systemic lupus erythematosus suspected. CONCLUSION: The diagnostic work up for AIH is multimodal and aims to differentiate other etiologies such as congestive hepatopathy, iron overload, viral hepatitis, and other autoimmune liver diseases. In this particular case, unusual clinical and laboratory findings led to diagnosis of the overlap syndrome. Treatment for both was necessary to prevent further progression of disease.

Severe rhabdomyolysis-induced acute kidney injury following concomitant use of Genvoya® (EVG/COBI/FTC/TAF) and simvastatin; a case report.

BACKGROUND: Genvoya® (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) is a recent single regimen for the treatment of Human Immunodeficiency Virus (HIV). However, because of its complexity, it is difficult to predict drug interactions, especially when associated with HMG-CoA reductase inhibitors and/or in the setting of other comorbidities. We discuss the mechanisms of these potential drug interactions as the cause of rhabdomyolysis and acute kidney injury in the context of prior and current medication therapy with possible underlying liver and kidney dysfunction. CASE PRESENTATION: We describe the case of a 54-year-old man diagnosed with HIV who developed severe rhabdomyolysis-induced anuric acute kidney injury (AKI) requiring renal replacement therapy following introduction of Genvoya® concomitantly with simvastatin, in the context of recently diagnosed hepatitis C and hepatitis A. Haemodialysis was continued over 5 weeks followed by progressive clinical and biological improvements. Five months later, a new antiretroviral regimen was started and has been well tolerated. CONCLUSION: Simvastatin, as well as lovastatin, because of their CYP3A4 metabolism, and to a lesser extent atorvastatin, which is only partially metabolized by CYP3A4, are the HMG-CoA reductase inhibitors with the greatest risk of drug interactions and should not be used in patients under HIV-therapy. Patients receiving HMG-CoA reductase inhibitors should be monitored regularly for the occurrence of muscular adverse effects and drug interactions should be considered with each new prescription or change in clinical status. There are many online tools that enable clinicians to rapidly check for drug interactions. We recommend the one from the University of Liverpool for patients under HIV-therapy ( https://www.hiv-druginteractions.org/checker ), while for patients under hepatitis C-therapy, we advise to consult http://www.hep-druginteractions.org/ . This case illustrates the importance of multidisciplinary collaboration in the treatment of HIV-positive patients because of their complexity, associated comorbidities and the potential of multiple drug-drug interactions potentially exacerbated by underlying liver and/or kidney dysfunction.

Clinical and virological features of acute hepatitis A during an ongoing outbreak among men who have sex with men in the North of France.

OBJECTIVES: Since February 2017, an increase of acute hepatitis A (AHA) cases has been notified in North of France. We aimed to report clinical and virological features of 49 cases treated in three hospitals in Lille European Metropolis (LEM). METHODS: All adult patients treated for AHA in 3 LEM hospitals between 20 February and 5 July 2017 were included. Demographic characteristics, exposure risk factors to hepatitis A virus (HAV), AHA manifestations and concomitant sexually transmitted infections (STI) were retrospectively recorded. RESULTS: Forty-nine cases of AHA were diagnosed among which 34 (69%) were hospitalised. Severe AHA occurred in 7 (14%) patients. The median age of cases was 36 years. All cases except 1 were men and 32 (65%) were identified as men having sex with men (MSM). Eleven (23%) patients were HIV-infected, 5 were under HIV pre-exposure prophylaxis (PrEP), 6 had a history of HIV postexposure prophylaxis and 19 had a history of at least one STI. Only three patients had received HAV vaccine. Proportion of patients tested for syphilis, chlamydial and gonococcal infections was 75% (18/24) in those seen by sexual health specialists and 21% (6/29) in those seen by other specialists. At least one concomitant STI was diagnosed in 13 out of 24 tested patients (54%). RT-PCR sequencing was available for 38 cases and confirmed co-circulation of 3 different strains of subgenotype IA (VRD 521 2016: n=24, RIVM-HAV16-090: n=13, V16-25801: n=1), already identified in several European countries. CONCLUSIONS: We are facing an outbreak of AHA among MSM in the North of France with a high rate of hospitalisation. Analysis of cases highlighted missed opportunities of vaccination and lack of concomitant STI screening. Awareness among healthcare providers and MSM should be increased and HAV vaccination promoted.

Atypical manifestations of hepatitis A virus infection. / Manifestaciones atípicas de la infección por el virus de la hepatitis A.

Acute hepatitis due to the hepatitis A virus usually has a short, benign and self-limited course, without causing chronic hepatitis. However, some cases have an atypical presentation, such as relapsing hepatitis, prolonged or persistent cholestasis, fulminant hepatic failure, or liver failure associated with autoimmune hepatitis. The typical clinical course of acute hepatitis A virus infection is spontaneous remission in 90% of the cases, but atypical cases have a prevalence that varies from less than 1 to 20%, depending on the manifestation (overall prevalence ∼7%). There is little information on the atypical clinical courses of hepatitis A virus infection and the lack of recognizing those presentations in clinical practice often results in carrying out numerous studies and treatments that not only are unnecessary, but can also be harmful. The aim of the present article was to describe 3 clinical cases of atypical hepatitis A infection and provide a literature review of such cases.

Experimental infection of Marmota monax with a novel hepatitis A virus.

To establish an animal model for the newly identified Marmota Himalayana hepatovirus, MHHAV, so as to develop a better understanding of the infection of hepatitis A viruses. Five experimental woodchucks (Marmota monax) were inoculated intravenously with the purified MHHAV from wild woodchuck feces. One animal injected with PBS was defined as a control. Feces and blood were routinely collected. After the animals were subjected to necropsy, different tissues were collected. The presence of viral RNA and negative sense viral RNA was analyzed in all the samples and histopathological and in situ hybridization analysis was performed for the tissues. MHHAV infection caused fever but no severe symptoms or death. Virus was shed in feces beginning at 2 dpi, and MHHAV RNA persisted in feces for ~2 months, with a biphasic increase, and in blood for ~30 days. Viral RNA was detected in all the tissues, with high levels in the liver and spleen. Negative-strand viral RNA was detected only in the liver. Furthermore, the animals showed histological signs of hepatitis at 45 dpi. MHHAV can infect M. monax and is associated with hepatic disease. Therefore, this animal can be used as a model of HAV pathogenesis and to evaluate antiviral and anticancer therapeutics.

Hepatitis A and B Infections.

Hepatitis A virus causes acute viral hepatitis, presenting with jaundice, nausea, and vomiting. Symptoms are self-limited and treated symptomatically. Routine vaccination of infants has greatly reduced the incidence in the United States. Vaccination is recommended for all infants and adults at increased risk. Hepatitis B virus can cause acute and chronic viral hepatitis. Acute hepatitis B is usually self-limited, but can develop into a chronic infection. Patients are at highest risk for developing chronic disease if they are infected at a younger age. Routine vaccination and universal screening of pregnant women has decreased the transmission of hepatitis B virus.

Evaluation of adults with acute viral hepatitis a and review of the literature.

AIM: In developing countries HAV infection is very common in the first years of life and it is often asymptomatic. However especially in regions of intermediate endemicity, exposure to the virus may delay and outbreaks of hepatitis A may be encountered in adults. The aim of this study is to evaluate the clinical and laboratory findings and risk factors of adults with acute viral hepatitis A. MATERIALS AND METHODS: In present study we evaluated 203 patient with acute viral hepatitis A, who were admitted to four different hospitals of three cities of Turkey between January 2000-December 2011, retrospectively. The diagnosis of acute viral hepatitis A was performed by laboratory findings and clinically. RESULTS: In a total of 203 patients, 120 (59.1%) patients were male and 83 (40.9%) were female. Mean age of cases with acute viral hepatitis A was 24.7 +11.8 years (ranged 15 to 82 years old). Acute viral hepatitis A were seen in patient who were 15-20 years and 21-30 years old, commonly. Jaundice (74%), fatigue (68%), nausea- vomiting (56%) and dark urine (48%) were the most common symptoms in cases. Prolonged cholestasis (6.8%) was the most common atypical manifestation. Prolonged jaundice was more frequent in the cases with positive HBsAg (P < 0.001). CONCLUSIONS: Acute viral hepatitis A can cause atypical presentations such as prolonged cholestasis, acute kidney injury and fulminant hepatitis. Some precautions such as routine vaccination program, improvement of hygiene conditions and informing people about it, should be taken for reducing of acute viral hepatitis A infection incidence.

[Serological tests of functional activity of the digestive system (gastrin, pepsinogen-I, trypsin), general IgE and serum cortisol levels in children with hepatitis A and B].

The mild form of hepatitis A and B with children is attended by a functional activity of pancreatic gland (tripsin), mucous coats of stomach and duodenum (gastrin) which permits to consider them as a factor of the risk of digestive organs combined pathology starting with the disease acuity. Differences in gastrin levels with children depending on hepatitis etiology were specified. Highest levels of gastrin were observed with persons suffering from hepatitis B.

Clinical significance of elevated serum alpha-fetoprotein (AFP) level in acute viral hepatitis A (AHA).

BACKGROUND/AIMS: The clinical course of acute viral hepatitis A (AHA) is highly variable. Serum alphafetoprotein (AFP) level is often elevated in various types of acute liver injuries, indicating active liver regeneration. This study was aimed to investigate the clinical significance of serum AFP level in the aspect of the early recovery in AHA. METHODOLOGY: A total of 238 patients with AHA, confirmed by IgM anti-hepatitis A virus, were included. The patients were classified according to serum AFP level. Multivariate analysis by Cox proportional hazards model using dichotomized clinical variables was performed to identify the independent predictors for early recovery (ALT normalization within 2 weeks). RESULTS: The median age (range) was 30 (17-50) years and male dominant (62%, 147/238). Compared to low AFP group, high AFP group (>10 ng/mL) had significantly lower platelet counts (p <0.0001), lower albumin (p =0.003), lower AST (p <0.001), lower ALT (p = 0.001), higher total bilirubin level (p <0.0001) on univariate analysis. On Cox regression analysis, high AFP level (>10 ng/mL) was the only independent predictor for early recovery (Hazard ratio (HR); 2.392, 95% CI; 1.564-3.659, p = 0.0001). CONCLUSIONS: High serum AFP level (>10 ng/mL) may indicate the already-started recovery through active liver regeneration or the early recovery within 2 weeks in AHA.

Pseudothrombocytopenia or platelet clumping as a possible cause of low platelet count in patients with viral infection: a case series from single institution focusing on hepatitis A virus infection.

INTRODUCTION: Pseudothrombocytopenia (PTCP) is the phenomenon of ethylenediaminetetraacetic acid anticoagulant-activated platelet clumping, which results in artificially low platelet counts. Other investigators have reported a few cases of PTCP associated with viral infections. The objective of this study was to demonstrate the association of viral infection with PTCP. METHODS: Medical records of patients with thrombocytopenia who were tested for peripheral blood smear examination between March 2009 and February 2011 were reviewed for platelet clumping and viral infection. RESULTS: Thrombocytopenic patients with viral infection had a higher frequency of platelet clumping than those with other diseases, which was statistically significant (13.8% vs. 6.5%, respectively: P = 0.003). Among the 18 cases where PTCP or platelet clumping was related to viral infection, hepatitis A virus infection (72.2%) was most common, followed by cytomegalovirus (11.1%) and influenza A H1N1 infections (5.6%). A third (33.3%) of the patients had platelet counts <100 × 109/L. CONCLUSION: Pseudothrombocytopenia or platelet clumping should be considered in patients with acute viral infection, particularly if the platelet count is unexpectedly low, because failure to recognize PTCP may lead to unnecessary diagnostic tests and patient mismanagement.

Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses.

Hepatitis A and hepatitis C viruses (HAV and HCV) are both positive-strand ribonucleic acid (RNA) viruses with hepatotropic lifestyles. Despite several important differences, they share many biological and molecular features and similar genome replication schemes. Despite this, HAV infections are usually effectively controlled by the host with elimination of the virus, whereas HCV most often is able to establish lifelong persistent infection. The mechanisms underlying this difference are unknown. The cellular helicases RIG-I and MDA5, and Toll-like receptor 3, are pattern recognition receptors that sense virus-derived RNAs within hepatocytes in the liver. Activation of these receptors leads to their interaction with specific adaptor proteins, mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing adapter-inducing interferon-ß (TRIF), respectively, which engage downstream kinases to activate two crucial transcription factors, nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). This results in the induction of interferons (IFNs) and IFN-stimulated genes that ultimately establish an antiviral state. These signaling pathways are central to host antiviral defense and thus frequent targets for viral interference. Both HAV and HCV express proteases that target signal transduction through these pathways and that block the induction of IFNs upon sensing of viral RNA by these receptors. An understanding of the differences and similarities in the early innate immune responses to these infections is likely to provide important insights into the mechanism underlying the long-term persistence of HCV.

Hepatitis A in Pohnpei State, Federated States of Micronesia, 2008-2009.

An epidemic of infectious hepatitis caused by the hepatitis A virus was detected in Pohnpei State, Federated States of Micronesia (FSM), beginning in November 2008. Epidemiologic investigation revealed that the index case occurred in late June 2008 in a traveler from nearby Chuuk State, which itself had experienced an epidemic of hepatitis A in the first half of 2008. Most cases have been confirmed by IgM serology, the rest by a clinically compatible syndrome with either jaundice or elevated liver enzymes. The most commonly affected group has been school-aged children; it is likely that the paucity of patients in the 40-50 year age group represents immunity conferred during the previous epidemic of hepatitis A in the early 1970's, as hepatitis A is not thought to be endemic in Pohnpei. As of September 17, 2009 there have been 300 reported cases with 17 hospitalizations (6%) and one death (0.3%). The epidemic peaked in April 2009, with a sharp decline in cases in June attributable with the end of the school year, as schools were found to be the major focus of infection. Efforts to control the outbreak have centered on public awareness and improved hygiene initiatives, particularly in schools. The greatest challenge to ongoing diminution of the outbreak is the recent resumption of the school year; control efforts, especially improved hygiene, will need to be sustained with renewed vigor if we are to extinguish the outbreak.