Acute hepatitis of unknown etiology in an adult female:A case report

BACKGROUND Acute liver injury(ALI)refers to inflammation of the hepatic parenchyma without hepatic encephalopathy that lasts less than 6 mo.When the etiology is unknown,Acute Hepatitis of Unknown Origin(AHUO)can present as a diagnostic and treatment challenge.AHUO in the adult population is unusual and poorly documented.It has an incidence between 11%and 75%.Currently,no treatment guidelines exist.With no identified cause,treatment is often blind,and the wrong treatment plan may have unintended consequences.CASE SUMMARY We present the case of a 58-year-old woman who presented to the emergency room for elevated liver function tests(LFTs).Her symptoms started 10 d prior to admission and included nausea,vomiting,jaundice,decreased appetite,weight loss of 10 lbs,and dark urine.She denied drinking alcohol or taking any hepatotoxic agents,including acetaminophen,statins,vitamins,or supplements.She was admitted to the hospital,and an etiologic work-up was carried out.Her initial bloodwork revealed elevated liver enzymes(alanine aminotransferase 2500 U/L,aspartate aminotransferase 3159 U/L,and alkaline phosphatase 714 U/L)and elevated total bilirubin of 6.4 mg/dL.She tested negative for common infectious etiologies such as hepatotropic viruses A,B,C,and E.Further infective work-up revealed negative serology for cytomegalovirus,Epstein-Barr virus,herpes simplex virus 1&2,and human immunodeficiency virus.Her autoanti-body test results were negative,including anti-smooth muscle antibody,anti-mitochondrial antibody,and anti-liver kidney microsome 1 antibody.Magnetic resonance cholangiopancreatography ruled out biliary causes of elevated LFTs,and her core liver biopsy proved inconclusive.Over the course of her hospital stay,the patient's LFTs improved with supportive care and without steroids.CONCLUSION Idiopathic hepatitis makes treatment challenging.It can leave patients feeling confused and unfulfilled.Thus,educating the patient thoroughly for shared decision-making and management becomes essential.

Severe acute cholestatic hepatitis of unknown etiology successfully treated with the Chinese herbal medicine Inchinko-to (TJ-135)

Severe acute hepatitis of unknown etiology is difficult to treat and often progresses to subacute fulminant hepatitis or late-onset hepatic failure. A 45-year-old wellnourished, healthy man had progressive fatigue and his liver function tests showed severe liver dysfunction. The etiology of sever acute cholestatic hepatitis was unknown. The liver function tests normalized gradually, which excluded high persistent total bilirubin after starting on predonine. A liver biopsy showed chronic active hepatitis with mild f ibrosis (A2, F1). Oral Inchinko-to, a Chinese herbal medicine, at 7.5 g daily was prescribed. The treatment was effective with no adverse effects. We present a successfully treated case and discuss hepatoprotective and choleretic effects of Inchinko-to.

Hepatitis of unknown etiology in children:Current evidence and association

Two years after the coronavirus disease 2019(COVID-19)pandemic,acute hepatitis of unknown etiology in children(AHUCD)began to be reported worldwide.The novel coronavirus and adenovirus were found in pathogen and antibody tests in AHUCD cases reported by the World Health Organization.Children are not exposed to the viruses that children are generally exposed to owing to COVID-19 infection preventive measures such as isolation and wearing masks;therefore,some researchers have speculated that this disease is related to reduced exposure to pathogens.Some scientists have also speculated that the disease is related to liver injury and adenoviral hepatitis,which are the sequelae of COVID-19.Some evidence also suggests a weak association between the disease and COVID-19 vaccination.Therefore,further research and investigation of the pathogenesis,preventive measures,and early treatment of hepatitis of unknown etiology are required.This study aimed to synthesize available evidence to further elucidate this disease in order to treat and prevent it effectively.

Adenovirus and severe acute hepatitis of unknown etiology in children:Offender or bystander?

On April 6,2022,the United Kingdom Health Security Agency(UKHSA)released an alert on cases of hepatitis of unknown etiology in children[1].On April 15,2022,World Health Organization(WHO)published the first notice of this condition[2].Later on,similar cases were reported from the UK,other European countries,and other parts of the world.

May 2022 acute hepatitis outbreak,is there a role for COVID-19 and other viruses?

There has been an increasing number of reported cases of acute hepatitis of unknown origin in previously healthy children since first reported on March 31,2022.This clinical syndrome is identified by jaundice and markedly elevated liver enzymes with increased aspartate transaminase and/or alanine aminotransa-minase(greater than 500 IU/L).We conducted an inclusive literature review with respect to acute hepatitis outbreaks in children using the search terms acute hepatitis,outbreak,children,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),coronavirus disease 2019(COVID-19),and adenovirus.According to the cumulative data presented in four main studies,the median age is 4 years,with a male predominance(1.3:1).Jaundice was the most common clinical manifestation(69%),followed by vomiting(63%),anorexia(52.9%),diarrhea(47.2%),abdominal pain(39%),pyrexia(33.3%),pale stool(30%),and dark urine(30%).Coryza and lethargy were reported in 16.6%,while pruritus was reported in 2%of cases.Acute liver failure was observed in 25%of cases.The exact mechanism of this acute hepatitis outbreak is still not entirely clear.Adenoviruses and SARS-CoV-2 were detected in a significant number of patients.Coinfection with adenovirus and SARS-CoV-2 could be a possible underlying mechanism.However,other possible infections and mechanisms must be considered in the pathogenesis of this condition.Acute hepatitis of unknown origin in children has been a serious problem since the start of the COVID-19 pandemic but has not yet been sufficiently addressed.Many questions remain regarding the underlying mechanisms leading to acute liver failure in children,and it is likely that extensive future research is needed.

Hepatitis C and B Virus Infection in Chinese Patients with Extrahepatic Bile Duct Carcinoma

Objective In China, the incidence of extrahepatic bile duct carcinoma (EBDC) tends to increase over the past decades. The etiology of the noted increase in EBDC is not identified. Approximately, in a half of the overall Chinese patients with EBDC, the causative factors in the development of EBDC have not been demonstrated.There is a high prevalence of hepatitis C virus (HCV) or hepatitis B virus (HBV) in China, both of which can induce malignant transformation of infected cells and strongly associated with hepatocellular carcinoma (HCC). In this study, EBDC tissues from Chinese patients were examined for the presence of HCV and HBV infection to investigate further the potential causes of EBDC.Methods HCV NS5 protein and HBsAg were detected by labeled streptavidin biotin (LSAB) method; HCV RNA and HBV DNA were detected by in situ polymerase chain reaction (IS-PCR) in formalin fixed, paraffin embedded specimens from 51 Chinese patients with EBDC. HCV RNA and HBV DNA were detected by IS-PCR in 34 Chinese patients with specimens of benign lesions of hepatobiliary tract (control group) .Results In 51 case tissue sections of EBDC, NS5 protein was detected in 14 (27.5%), and HBsAg in 5 (9.8%), HCV RNA in 18 (35.4%) and HBV DNA in 8 (15.9%) .respectively, of which HCV and HBV co-infection was detected in 2 (3.9%). In 34 case tissue sections of the control group, HCV RNA was detected in 2 (5.9 % ), and HBV DNA in 3 (8.8%).Conclusion In this study using standard histochemical and PCR techniques, HCV and HBV genomes and their encoding proteins were detected in the tissues of EBDC. The data show that there is a higher than expected incidence of HCV and HBV presence in EBDC tissues than would be expected on serologic grounds. The detectable rate of HCV RNA in EBDC tissues was significantly higher than in control group (x2 = 9.808, P = 0.002). As a result, this study indicates that there is a correlation between the presence of HCV infection and EBDC, and HCV infection has possible etiologic significance in the development of EBDC in China. While HBV DNA was detected in EBDC tissues with the difference in the detectable rate of HBV, DNA being not significance between EBDC tissues and the control group (x2 = 0.853, P = 0.356) . Further research is necessary to determine the presence of a causal relationship between HCV/HBV infection and the development of EBDC.

Effect of hepatitis C virus infection on expression of several cancer-associated gene products in hepatocellular carcinoma

AIM To study hepatocarcinogenesis of hepatitis C virus (HCV). METHODS Expression of HCV antigens (CP10, NS3 and NS5) and several cancer associated gene products (ras p21, c myc, c erbB 2, mutated p53 and p16 protein) in the tissues of hepatocellular carcinoma (HCC, n =46) and its surrounding liver tissue were studied by the ABC (avidin biotin complex) immunohistochemical method. The effect of HCV infection on expression of those gene products in HCC was analyzed by comparing HCV antigen positive group with HCV antigen negative group. RESULTS Positive immunostaining with one, two or three HCV antigens was found in 20 (43 5%) cases, with either of two or three HCV antigens in 16 (34 8%) cases, and with three HCV antigens in 9 (19 6%) cases. Deletion rate of p16 protein expression in HCC with positive HCV antigen (80%, 16/20) was significantly higher than that in HCC with negative HCV antigen. Whereas no significant difference of the other gene product expression was observed between the two groups. CONCLUSION HCV appears related to about one third of cases of HCC in Chongqing, the southwest of China, and it may be involved in hepatocarcinogenesis by inhibiting the function of p16 gene, which acts as a negative regulator of cell cycle.

Low serum albumin predicts early mortality in patients with severe hypoxic hepatitis

To evaluate the incidence, etiology, and predictors of mortality of severe hypoxic hepatitis. METHODSWe used computerized patient records to identify consecutive cases of severe hypoxic hepatitis admitted to a tertiary hospital in Singapore over a one-year period. We defined severe hypoxic hepatitis as elevation of serum transaminases more than 100 times upper limit of normal in the clinical setting of cardiac, circulatory or respiratory failure after exclusion of other causes of hepatitis. We used multivariable regression analysis to determine predictors for mortality. RESULTSWe identified 75 cases of severe hypoxic hepatitis out of 71380 hospital admissions over one year, providing an incidence of 1.05 cases per 1000 admissions. Median age was 65 years (range 19-88); 57.3% males. The most common etiologies of severe hypoxic hepatitis were acute myocardial infarction and sepsis. Fifty-three patients (71%) died during the hospitalization. The sole independent predictive factor for mortality was serum albumin measured at the onset of severe hypoxic hepatitis. Patients with low serum albumin of less than 28 g/L have more than five-fold increase risk of death (OR = 5.39, 95%CI: 1.85-15.71). CONCLUSIONSevere hypoxic hepatitis is uncommon but has a high mortality rate. Patients with low serum albumin are at highest risk of death.

Hepatitis C virus genotype 3a infection and hepatocellular carcinoma: Pakistan experience

AIM: To assess the association between chronic hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) in Pakistan, and the genotype distribution among these HCC patients.METHODS: One hundred and sixty-one subjects with HCC were included in this study. Liver biopsy was performed on 145 of the patients; sixteen were excluded because they failed to fulfill the inclusion criteria. Qualitative polymerase chain reaction (PCR) was performed for hepatitis B virus and HCV. Samples positive for HCV RNA were genotyped using genotype-specif ic PCR and conf irmed by HCV 5' noncoding region sequencing analysis. RESULTS: Chronic HCV infection was identified a major risk factor (63.44% of tested HCC patients) forthe development of HCC. The time from HCV infection to appearance of cancer was 10-50 years. In the HCC patient population, broader distributions of genotypes were present with genotype 3a as the predominant genotype. Using the type-specific genotyping method, we found HCV genotype 3a in 40.96%, 3b in 15.66%, 1a in 9.63%, and 1b in 2.40% of HCC tissue samples. About 28% of cases were found with mixed genotypes. Two cases were unable to be genotyped because of low viral load. Sixty-six percent of treated patients with cirrhosis had an end of treatment response, but unfortunately they relapsed quickly when the treatment was discontin-ued, and HCC developed during a median 3.8 years. CONCLUSION: There was a strong association between chronic HCV infection and HCC in Pakistan, and between HCV genotype 3a and HCC.

Etiology of Fulminant Viral Hepatitis in Shenyang

Serological methods were used to determine the cause of fulminant hepatitisin 207 patients. They were admitted to the isolation wards of 4 hospitals inShenyang between 1986-1990. The final diagnoses were: hepatitis type A 4 cas-es (2.0%), type B 144 cases (69.4% ),superinfections with A and B 3 cases (1.5%), hepatitis non-A non-B (NANB) 51 cases (24.6%), type D 2 cases (1.0%), type E 2 cases (1.0%) and cytomegalovirus (CW) infection 1 case (0.5%). The risk factors were found to be concerned with type D and several typesuper infections (prognosis poor).

SARS-CoV-2:Possible role in children with acute hepatitis of unknown origin

The UK raised an alert with the World Health Organization(WHO)in April 2022 concerning a significant surge in the num-ber of children diagnosed with acute hepatitis of unknown origin(AHUO).Despite an ongoing investigation attributing its etiology to adenovirus infection,the absence of adenovirus inclusions in liver biopsies and the remarkably low viral load raised doubts.Concurrently,reports of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infections in children coincided with the surge in acute hepatitis cases,prompting the need for a thorough examination of the poten-tial connection between current or past SARS-CoV-2 infections and pediatric hepatitis epidemics.Epidemiological data suggests that acute hepatitis is a notable manifestation of the multiple-system inflammatory syndrome in children following the global SARS-CoV-2 pandemic.However,the precise role of the SARS-CoV-2 virus in liver injury etiology remains uncertain.To shed light on the potential association between SARS-CoV-2 and AHUO in children,we conduct-ed a systematic review of epidemiological links,potential pathogenesis,and recent research findings,aiming to raise awareness and vigilance among clinicians.Convincing and definitive evidence will be essential in the future to confirm the direct impact of SARS-CoV-2 infection on children with AHUO.

Severe acute hepatitis of unknown causes in children–Current findings,questions,opinions,and recommendations,a mini-review

Since October 2021 in Alabama,the United States,and March 2022 in central Scotland,the United Kingdom,the number of cases of severe acute hepatitis of unknown etiology/causes in children was found to increase,and the total number of cases has reached 920 worldwide by June 22 this year,45 cases(5%)required liver transplantation,and 18 cases(2%)died according to World Health Organization(WHO).To understand the basic characteristics of this disease/syndrome,a literature search was performed at PubMed,websites of WHO,UK Health Security Agency,and US and European Centers for Disease Control and Prevention,and more than 20 reports were enrolled as references for this review.The main clinical manifestations are anorexia,vomiting,fatigue,jaundice,and so forth.Most of the cases seemed to have a self-limited course of the disease,about 6%of cases may develop life-threatening acute liver failure.The disease seems to be transmissible from person to person.Human adenovirus was detected in up to 75%of cases,but this virus seems not to be the only and major etiologic agent,other cofactors probably are involved.Researchers proposed many hypotheses concerning the etiology and pathogenesis,and many important works and studies are ongoing.This mini-review is aimed at summarizing,reviewing,and further understanding the characteristics of the disease,raising some clinically relevant questions,and trying to discuss some questions that may be related to the treatment of the disease for consideration.

Severe Acute Hepatitis of Unknown Origin in Children: What Do We Know Today?

In May 2022, the UK International Health Regulations National Focal Point notified World Health Organization of 176 cases of severe acute hepatitis of unknown etiology in children under 10 years of age. From that moment on, cases of severe acute hepatitis of unknown origin in children began to be reported in several countries. As of June 17, 2022, a total of 991 cases had been reported in 35 countries worldwide, 50 children needed a liver transplant and 28 patients died. According to information published by ECDC, 449 cases have been detected in 21 EU countries. The children were between 1 month and 16 years of age. Adenovirus was detected in 62.2% of the analyzed samples. So far, the cause of these cases is unknown and many hypotheses remain open, but hepatitis A-E viruses and COVID-19 vaccines have been ruled out. A possible hypothesis has been published to explain the cause of these cases of severe hepatitis, according to which it could be a consequence of adenovirus infection in the intestine in healthy children previously infected with SARS-CoV-2. No other clear epidemiological risk factors have been identified to date. Thus, at this time, the etiology of the current cases of hepatitis remains under active investigation.

Expert symposium on severe acute hepatitis of unknown cause in children,a paradigm of exchanges and sharing between Chinese and Western medicine professionals

Recently,cases of severe acute hepatitis of unknown cause(SAHUC)in children have suddenly increased in the United States,the United Kingdom,and other countries.In order to understand the progress in the diagnosis and treatment of this disease,and to prepare for the relevant plans in advance,the“Expert Symposium on the Severe Acute Hepatitis of Unknown Cause in Children”was successfully held on May 13,2022,online organized by Beijing Children's Hospital(BCH),Capital Medical University,Beijing Institute of Pediatrics Integrated Chinese and Western Medicine,Futang Research Center of Pediatric Development,and Branch of Hepatobiliary Diseases,China Association of Chinese Medicine.More than 9200 people watched the meeting online.Professors Yan Hu,Yan Yang,and Jing Hao,from the Department of Traditional Chinese Medicine(TCM),BCH,Capital Medical University,hosted the symposium.

Diagnosis and Clinical Management of Acute Severe Hepatitis of Unknown Origin: Operational Recommendation of Peking Union Medical College Hospital

Around 450 cases of acute severe hepatitis of unknown origin in children have been reported in 21 countries and region globally since April 2022,which has exceeded the past annual incidences of related regions,and has aroused wide concern.Affected patients were predominantly children under 16years of age,presented with symptoms of acute hepatitis with markedly elevated liver enzymes,and had been ruled out of common viral infections such as hepatitis A,B,C,D,and E.Similar cases have not been reported in China yet.However,considering that the severe acute hepatitis has involved worldwide areas,still with unknown origin,and incidences of severity is relatively high,we formulated this recommendation to standardize diagnosis and treatment of acute severe hepatitis of unknown origin in Peking Union Medical College Hospital,to get fully prepared to the possible public health events.

Clinical characteristics and possible etiology in children with acute severe hepatitis of unknown etiology

To the Editor:According to the data released by the World Health Organization(WHO)on July 12,2022,around 1010 cases of children with acute hepatitis of unknown etiology have been reported in five regions and 35 countries globally;these reports include new and retrospectively identified cases since October 1,2021.Most patients presented with acute severe hepatitis and significantly high transaminase levels;the most common symptoms and signs were nausea or vomiting(60%).

Severe acute hepatitis in children with unknown aetiology,etiology analysis and the next action

On April 5,2022,United Kingdom(UK)reported 10 cases of severe acute hepatitis with unknown cause among children under 10 years old.The initial symptoms of these cases could date back to March 2022.A rapidly increasing number of cases lasted for a month and the growth seems to be slightly slowing down in May.As of May 27,2022,the total number of children with acute hepatitis in UK reached to 222(UKHSA,2022a).European Union and European Economic Area reported 305 cases across 17 countries and none as epidemiologically linked as of May 31,2022(ECDC-WHO,2022).

Non-hepatotropic viral hepatitis and its causative pathogens:The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology

ELEVATEDINCIDENCEOFSEVERE ACUTEHEPATITISOFUNKNOWN ETIOLOGYINCHILDRENIN2022 As of June 22,2022,920 probable cases of severe acute hepatitis of unknown etiology had been reported in 33 countries.l The numbers of reported cases were the highest in the United States and the United Kingdom.

Viral diseases in Africa: Preventing the outbreak of acute hepatitis of unknown etiology

Hepatitis is an inflammation of the liver.There had been an outbreak of hepatitis of unknown origin among children,where nine pediatric patients in Alabama,United States of America,tested negative for hepatitis viruses(A,B,C,D,and E)and autoimmune conditions.So far,no case has been recorded in Africa.This article seeks to give guidelines on how to prevent its occurrence in Africa.Various literatures were reviewed on the background of hepatitis of unknown origin while focusing on World Health Organization publication as regards the outbreaks in other European countries.Therefore,it is worthy to state that Africa needs to keep its healthcare systems ready to take care of the mechanism by which the outbreak may occur and protect the vulnerable pediatric population from such an outbreak.

Trained innate immunity and human adenovirus infection as a novel mechanism linked to the severe acute hepatitis of unknown origin in children during the COVID‐19 pandemic

1|OUTBREAK OF SEVERE ACUTE HEPATITIS OF UNKNOWN ORIGIN IN CHILDREN Severe acute hepatitis of unknown origin in children was first reported by the United Kingdom to the World Health Organization on April 5,2022.Subsequently,650 probable cases were reported worldwide by May 26,2022,1 and four patients were analyzed after reviewing the clinical records of a children's hospital in Alabama since October 1,2021.2 Although most patients recovered,the disease progressed to acute liver failure in several patients,who further required liver transplantation;thus,additional research is required to determine the disease pathogenesis.