Fatal Fulminant Hepatitis Research Articles

Adipose-derived stem cells can alleviate RHDV2 induced acute liver injury in rabbits

Rabbit hemorrhagic disease virus (RHDV) can cause fatal fulminant hepatitis, which is very similar to human acute liver failure. The aim of this study was to investigate whether adipose-derived stem cells (ADSCs) could alleviate RHDV2-induced liver injury in rabbits. Twenty 50-day-old rabbits were divided randomly into two groups (RHDV2 group, ADSCs + RHDV2 group). Starting from the 1st day, two groups of rabbits were given 0.5 ml of viral suspensions by subcutaneous injection in the neck. Meanwhile, the ADSCs + RHDV2 group was injected with ADSCs cell suspension (1.5 × 107 cells/ml) via a marginal ear vein, and the RHDV2 group was injected with an equal amount of saline via a marginal ear vein. At the end of the 48 h experiment, the animals were euthanized and gross hepatic changes were observed before liver specimens were collected. Histopathological analysis was performed using hematoxylin-eosin (HE), periodic acid schiff (PAS) and Masson's trichrome staining. For RHDV2 affected rabbits, HE staining demonstrated disorganized hepatic cords, loss of cellular detail, and severe cytoplasmic vacuolation within hepatocytes. Glycogen was not observed with PAS staining, and Masson's Trichrome staining showed increased hepatic collagen deposition. For rabbits treated with ADSCs at the time of inoculation, hepatic pathological changes were significantly less severe, liver glycogen synthesis was increased, and collagen fiber deposition was decreased. For RHDV2 affected rabbits, Tunel and immunofluorescence staining showed that the number of apoptotic cells, TGF-β, and MMP-9 protein expression increased. And that in the ADSC treated group there was less hepatocyte apoptosis. In addition, RHDV2 induces liver inflammation and promotes the expression of IL-1β, IL-6, and TNF-α. In rabbits administered ADSCs at time of inoculation, the expression of inflammatory factors in liver tissue decreased significantly. Our experiments show that ADSCs can protect rabbits from liver injury by RHDV2 and reduce the pathological and inflammatory response of liver. However, the specific protective mechanism needs further study.

Immunogenicity and safety of HavisureTM vaccine developed by Human Biologicals Institute in healthy subjects of 12 months to 49 years of age: A phase II/III, randomized, single blind, non-inferiority study

BackgroundHepatitis A is an inflammation of the liver caused by the hepatitis A virus (HAV). It is transmitted mainly because of poor personal hygiene via the faecal/oral route through ingestion of contaminated food or water or through the direct contact with an infectious person. Though most of the infected individuals recover from the infection, a few may develop fatal fulminant hepatitis. In this randomized, multicenter study, immunogenicity and safety of Havisure™ vaccine of Human Biologicals Institute was compared with Havrix® vaccine. MethodsThe study was carried out in 528 eligible healthy subjects, in two age groups across eight centres in India. Group A included subjects of 19–49 years and Group B subjects of 12 months to below 19 years of age. All subjects received two doses of either Havisure™ vaccine or Havrix® vaccine as per randomization at six months interval. Blood samples for antibody titre estimation were collected before vaccination and 4–6 weeks after 2nd dose of vaccination. Immunogenicity was assessed by estimating seroconversion rate, seroprotection rate, and geometric mean titres of antibodies. Safety was evaluated by collection and analysis of data on solicited and unsolicited adverse events. ResultsOf 528 enrolled subjects, 493 subjects completed the study. There was 100% seroconversion and seroprotection in both the vaccine arms. There was no statistical difference in the geometric mean titres between the two vaccine arms. Pain and swelling at the site of injection were the most common local adverse events whereas fever and headache were the most common systemic adverse events observed in both vaccine arms. No serious adverse event was reported in the study. ConclusionThe study results indicate that the Havisure™ vaccine is immunogenic and safe when administered to healthy subjects of 12 months to 49 years of age, and is non-inferior to Havrix® Vaccine.

An Unusual Cause of Acute Isolated Hepatitis in a Cancer Patient Post-COVID Pneumonia: HSV-2

Herpes simplex virus is a rare cause of hepatitis in immunosuppressed and immunocompetent individuals. It can cause clinical pictures in patients ranging from an asymptomatic course to fatal acute fulminant hepatitis. Early diagnosis and treatment may be delayed if it is not suspected because of the patients’ nonspecific clinic. This study presents a case of isolated HSV-2 hepatitis in a patient with a history of cancer chemotherapy and a recent diagnosis of COVID-19 who received steroid therapy.

Novel monocyclic amide-linked phenol derivatives without mitochondrial toxicity have potent uric acid-lowering activity

Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal tubule epithelial cells. We also evaluated their inhibitory activity against mitochondrial respiration as a critical mitochondrial toxicity parameter. Some derivatives with UUI activity had no mitochondrial toxicity, including compound 3f, which effectively lowered the plasma uric acid level in Cebus apella. Thus, 3f is a promising candidate for further development as a uricosuric agent.

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Benzbromarone.

Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. Although the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly regarded as a key molecular initiating event. However, apart from causing aberrant toxicities, reactive metabolites may result in mechanism-based inactivation (MBI) of cytochrome P450. Here, we investigated and confirmed that BBR inactivated CYP3A4 in a time-, concentration-, and NADPH-dependent manner with K I, k inact, and partition ratio of 11.61 µM, 0.10 minutes-1, and 110, respectively. Coincubation with ketoconazole, a competitive inhibitor of CYP3A4, attenuated the MBI of CYP3A4 by BBR, whereas the presence of glutathione and catalase did not confer such protection. The lack of substantial recovery of enzyme activity postdialysis and after oxidation with potassium ferricyanide, combined with the absence of a Soret peak in spectral difference scans, implied that MBI of CYP3A4 by BBR did not occur through the formation of quasi-irreversible metabolite-intermediate complexes. Analysis of the reduced CO-difference spectrum revealed an ∼44% reduction in ferrous-CO binding and hinted that inactivation is mediated via irreversible covalent adduction to both the prosthetic heme moiety and the apoprotein. Finally, our in silico covalent docking analysis further suggested the modulation of substrate binding to CYP3A4 via the covalent adduction of epoxide-derived reactive intermediates of BBR to two key cysteine residues (Cys239 and Cys58) vicinal to the entrance of the orthosteric binding site. SIGNIFICANCE STATEMENT: Although the bioactivation of benzbromarone (BBR) to reactive metabolites has been well characterized, its potential to cause mechanism-based inactivation (MBI) of cytochrome P450 has not been fully investigated. This study reports the MBI of CYP3A4 by BBR via irreversible covalent adduction and develops a unique covalent docking methodology to predict the structural molecular determinants underpinning the inactivation for the first time. These findings lay the groundwork for future investigation of clinically relevant drug-drug interactions implicating BBR and mechanisms of BBR-induced idiosyncratic hepatotoxicity.

Hepatitis B Screening Prior to Chemotherapy in the Middle East: A Retrospective Cohort Study

Background: Hepatitis B virus (HBV) reactivation can be asymptomatic or manifest as fatal fulminant hepatitis. Most international guidelines recommend screening patients prior to immunosuppressive therapy.
 Aims: To determine HBV screening rates and modalities in patients receiving chemotherapy at the American University of Beirut Medical Center.
 Methods: A retrospective cohort review of electronic health records of adult patients who received chemotherapeutic agents, between June 2015 and June 2016. Patients clinical characteristics were documented. Adequate screening was defined as performing all: HBsAg, HBs Abs, and anti HBc Abs(total).
 Results: A total of 1547 patients were initially assessed. 45.6% were males with a mean age of 56. 382(30%) had hematologic malignancies, of whom 111 underwent HSCT. Of those included, 303(24%) patients were screened by at least one test for HBV and 42(3.3%) for HBsAg, anti HBc Abs and HBs Abs.
 Patients who were appropriately screened were significantly younger(p=0.008) and more likely to have hematologic malignancies (n=35, 83.3%, p<0.0001). Among patients with hematologic malignancies, appropriately screened patients (n=35) were younger (p=0.042) and had a history of HSCT(n=19, 54.3%, p=0.001).
 Conclusion: Rates of screening for HBV prior to chemotherapy at our medical center are low, and not always complete or adequate. There is an urgent need to implement a better screening policy.

Hepatitis E in patients with hematological disorders

Hepatitis E virus (HEV), a causative agent of hepatitis E, is indigenous to Japan, and pigs and wild boars are established as primary reservoirs of HEV. As HEV is present in the circulating blood of infected hosts, blood-borne HEV transmission is possible. Patients with hematological disorders are at considerable risk of transmission from blood-borne sources. Although HEV viremia is typically transient, cases of chronic HEV infection are increasingly reported in immunocompromised patients, including solid-organ transplant recipients and patients with hematological disorders. In Japan, although nationwide studies have reported the presence of chronic HEV infection in solid-organ transplant recipients, no such study has been conducted on patients with hematological disorders, including those after hematopoietic stem cell transplantation (HSCT). To date, at least 13 cases with hematological disorders acquiring HEV infection have been reported in Japan, mostly through blood transfusion, including those with chronic hepatitis E and fatal fulminant hepatitis E. Thus, clinicians should be aware of the potential for HEV to present as either acute or chronic infection, with mild or absent clinical symptoms. Overall, HEV testing should be considered in at-risk immunosuppressed patients with hematological disorders, even when the liver function test reveals only moderate elevation or should better be performed as part of routine testing.

Fatal case report of concomitant hepatitis E and Salmonella paratyphi A infection in a sub-Himalayan patient

We report a case of fatal fulminant hepatitis E and Salmonella paratyphi A coinfection in a patient of the sub-Himalayan region. The patient presented with acute febrile illness accompanied with sudden unconsciousness. Concomitant infection can result an illness having overlapping symptom, resulting in a situation where the diagnosis and treatment of patient may be difficult.

Fulminant Hepatitis Following Crizotinib Administration for ALK-positive Non-small-cell Lung Carcinoma

We herein report a case of fatal fulminant hepatitis secondary to crizotinib administration. The patient was 54-year-old female with a history of Hepatitis C infection (not current), dermatomyositis and steroid-induced diabetes mellitus. She was diagnosed with advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement. We began 400 mg of crizotinib as first-line therapy. No adverse effects were seen until Day 16. On Day 29, she was admitted to hospital with elevated liver enzymes (aspartate aminotransferase 3236 IU/l, alanine aminotransferase 5201 IU/l) and coagulopathy (prothrombin time <10%), and was diagnosed with crizotinib-induced fulminant hepatitis. We started intensive care, using plasma exchange, continuous hemodiafiltration and high-dose steroid therapy. Unfortunately, she did not respond to therapies, and died on Day 36. The mechanism and risk factors of crizotinib-induced hepatotoxicity are uncertain. Physicians should be aware of possible adverse effects of crizotinib. A systemic survey is imperative to identify possible risk factors of crizotinib-related hepatotoxicity.

Fatal Fulminant Hepatitis E Associated with Autoimmune Hepatitis and Excessive Paracetamol Intake in Southeastern France

We present, to our knowledge, the first case of fatal fulminant liver failure associated with hepatitis E virus infection, autoimmune hepatitis, and excessive paracetamol intake, which occurred in a 77-year-old woman. Hepatitis E testing should be performed in severe acute liver failure cases, even when another cause has been identified.

Fatal Nocardia cyriacigeorgica spontaneous bacterial peritonitis.

We report the first case of fatal spontaneous bacterial peritonitis and fulminant hepatitis caused by Nocardia cyriacigeorgica in a patient with hepatitis C-related liver cirrhosis.

An outbreak of lethal adenovirus infection among different otariid species

An outbreak of fatal fulminant hepatitis at a Japanese aquarium involved 3 otariids: a California sea lion (Zalophus californianus), a South African fur seal (Arctocephalus pusillus) and a South American sea lion (Otaria flavescens). In a span of about a week in February 2012, 3 otariids showed diarrhea and were acutely low-spirited; subsequently, all three animals died within a period of 3 days. Markedly increased aspartate amino transferase and alanine amino transferase activities were observed. Necrotic hepatitis and eosinophilic intranuclear inclusion bodies in liver hepatocytes and intestinal epithelial cells were observed in the South American sea lion on histological examination. Otarine adenovirus DNA was detected from the livers of all three animals by polymerase chain reaction and determination of the sequences showed that all were identical. These results suggest that a single otarine adenovirus strain may have been the etiological agent of this outbreak of fatal fulminant hepatitis among the different otariid species, and it may be a lethal threat to wild and captive otariids. This is the first evidence of an outbreak of lethal adenovirus infection among different otariid species.

Hepatitis B reactivation related to everolimus

Reactivation of hepatitis B virus (HBV) during chemotherapy is a well known complication in patients with chronic hepatitis B and cancer. The clinical manifestations range from subclinical elevation of liver enzymes to severe, potentially fatal fulminant hepatitis. Reactivation can occur in a patient with previous inactive HBV infection; either an inactive carrier or a patient with resolved hepatitis. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved in renal cell carcinoma, neuroendocrine tumours and breast cancer. mTOR inhibitors are a new generation of drugs for targeted treatment; therefore, little about their side effects is known. Here, we report a patient with renal cell carcinoma who experienced a flare of hepatitis B infection during treatment with everolimus. Clinicians should be aware of HBV reactivation in patients who are undergoing treatment with everolimus, and screening for hepatitis B infection and prophylactic antiviral treatment should be considered.

Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy

With the increasing use of potent immunosuppressive therapy, reactivation of hepatitis B virus (HBV) in endemic regions is becoming a clinical problem requiring special attention. A recent annual nationwide survey clarified that HBV reactivation related to immunosuppressive therapy has been increasing in patients with malignant lymphoma, other hematological malignancies, oncological or rheumatological disease. In the survey, rituximab plus steroid-containing chemotherapy was identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg) negative patients with malignant lymphoma. In this setting, HBV reactivation resulted in fatal fulminant hepatitis regardless of the treatment of nucleoside analog. The Intractable Hepatobiliary Disease Study Group and the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis jointly developed guidelines for preventing HBV reactivation. The essential features of the guideline are as follows. All patients should be screened for HBsAg by a sensitive method before the start of immunosuppressive therapy. Second, hepatitis B core antigen (HBcAb) and hepatitis B surface antibody (HBsAb) testing should be performed in HBsAg negative patients, especially those receiving intensive immunosuppressive therapy. Prophylaxis with nucleoside analogs is essential for preventing HBV reactivation in HBsAg positive patients. In contrast, HBsAg negative with HBcAb and/or HBsAb positive patients should be monitored monthly for an increase in serum HBV DNA during and 12 months after completion of chemotherapy. Nucleoside analogs should be administrated immediately when HBV DNA becomes positive during this period. This strategy facilitates commencement of nucleoside analogs at an early stage of HBV reactivation and results in prevention of severe hepatitis.

Histological and immunohistochemical features in fatal acute fulminant hepatitis E

Hepatitis E is being increasingly recognized as an emerging infection in developed countries. Data on histological findings and nature of inflammatory cell infiltrate in liver in this disease are quite sparse. This study was planned to study the histological features and the type of inflammatory infiltrate in liver biopsies of patients with acute fulminant hepatitis E. We retrieved postmortem liver biopsies of 11 Indian patients with fulminant hepatitis E, and compared these with biopsies from seven patients with fulminant hepatitis B. Biopsies from acute fulminant hepatitis E showed varying degrees of hepatocyte necrosis, mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo-rosette formation, steatosis, and presence of plasma cells in portal tracts. Interface hepatitis was more frequent in acute hepatitis B than in acute hepatitis E (100% vs 20%; P<0.05). These findings differ from those reported in cases with autochthonous hepatitis E in Europe. On immunohistochemistry, lymphocyte infiltrate consisted predominantly of CD3 + T cells in both hepatitis E and hepatitis B; these cells contained a predominant cytotoxic (CD8 + ) cell subpopulation in 81.8% of cases with hepatitis E and in 50% of cases with hepatitis B. Our findings suggest that histological changes in HEV infection may vary with geographical location because of prevalent HEV genotypes, and that CD8 + lymphocytes play a role in HEV-induced liver injury.

Fatal fulminant primary hepatitis B virus infections with G1896A precore viral mutants in southeastern France

Fulminant hepatitis has been shown to occur in about 1% of acute hepatitis B virus (HBV) infections, and its mortality rate is nearly 70%. Specific HBV genotypic features have been pointed out in fulminant acute hepatitis B worldwide, but these associations remain controversial. We describe all four primary HBV infections diagnosed in 2008 in our institution in Marseille, southeastern France, including two fatal cases. HBV genotypes were D or E. Precore G1896A HBV mutants were detected in both fatal fulminant primary HBV infections. Hepatitis B surface antigen and hepatitis B e antigen (HBeAg) were negative in two and three cases, respectively, despite HBV DNA detection. Primary HBV infection remains a cause of death in France. The impact of the precore G1896A mutation on the severity of AHB deserves to be assessed in larger studies in this country.

Safety of anti-TNF therapy: 10 year experience in pediatric patients from a single tertiary center

Methods Time of exposure, dose and reason for discontinuation were recorded Analysis involved incidence rate, outcome, and causal relationship. Statiscal analysis were performed using SPSS software. Results Data from 131 clinical records were analyzed . 87(66.4%) were female, median age at diagnosis 7.2 (RIQ 3.8-11.3), median follow up 7.9 ys (SD±4.8). 111 pts had JIA,5 JDM ,4 vasculitis, 3 sarcoidosis, 2MCTD,1SLE and 5 idiopathic uveitis. Most of the AEs were mild: 28,2% and 13,5 upper respiratory and skin infections respectively. Four pts developed autoinmune events: Lupus –like syndrome, Psoriasis and 2 other ,optic neuritis .One pt under IFX + MTX developed Non-Hodgkin Limphoma and another on IFX fatal fulminant hepatitis.

Chemoprevention of Patients with Hepatitis B Receiving Chemotherapy or Bone Marrow Transplant

Hepatitis B virus (HBV) reactivation is a common but preventable complication of immunosuppression. With the advent of new therapies that provide efficient and prolonged immunosuppression, the incidence of HBV reactivation is likely to increase. The clinical presentation can range from mildly elevated aminotransferase values to fatal fulminant hepatitis. Despite prompt antiviral therapy, the mortality rates remain high, and it can adversely affect the outcome of immunosuppressive therapy for the underlying hematological disease. Over the past decade, several studies evaluated the risk of HBV reactivation, role of serological tests, and effectiveness of antiviral therapies in preventing severe hepatic dysfunction among patients undergoing immunosuppressive therapy. Studies show that HBV antiviral therapy given prior to chemotherapy may prevent HBV replication, and reduce the risk of HBV reactivation during the immunosuppression period. This article reviews the current literature and society guidelines on HBV reactivation, risk factors, and prophylaxis for HBV reactivation in patients undergoing chemo-/immunosuppressive therapy.

Rifampicin-isoniazid induced fatal fulminant hepatitis during treatment of latent tuberculosis: A case report and literature review

A 42-year-old Indian man received 450 mg rifampicin (RIF) and 150 mg isoniazid (INH) daily after being diagnosed of a latent tuberculosis infection. Baseline serum aminotransferase and total bilirubin levels were within normal limits. On day 31 of treatment, the patient experienced epigastric discomfort and general malaise and one week later he developed nausea and episodic vomiting. The patient missed his first scheduled clinic appointment and he continued taking RIF-INH despite his symptoms. He visited the tuberculosis clinic on day 47 of treatment where he was found to be jaundiced and his liver enzymes were elevated. RIF-INH was stopped and the patient was admitted to our hospital as a case of RIF-INH induced hepatitis. On the 7th day of hospitalization, the patient developed consciousness disturbance with flapping tremor and high ammonia level. The patient was diagnosed with fulminant hepatic failure and transferred immediately to the medical intensive care unit, where he died 4 days later.

Fatal Fulminant Hepatitis in a Chimpanzee (Pan troglodytes) Receiving Cyproterone Acetate

Cyproterone acetate is a steroidal anti-androgen that has been used in human medicine for contraceptive purposes as well as treatment of medical conditions responsive to suppression of testosterone production. While serious side effects are considered to be rare, sporadic cases of severe hepatitis have been reported, including several fatal cases. This report describes a case of fatal fulminant hepatitis in one of four male chimpanzees (Pan troglodytes) that were undergoing trial treatment with cyproterone acetate to decrease inter-male aggression.