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

Perspectives on Acute Hepatitis A Control in Korea

Until 1995, the incidence of symptomatic acute hepatitis A was minimal and there were no cases of national outbreak in Korea. However, there was a nationwide outbreak of hepatitis A that peaked in 2009. In 2019, a total of 10,083 cases of acute hepatitis A were reported for seven months of the year according to the Korea Center for Disease Control and Prevention. This may be attributed to the proportion of susceptible subjects in the Korean population, as about 10 years have passed since herd immunity was induced by the epidemic occurring during the late 2000s. Recent studies have shown that the rate of seropositivity for anti-hepatitis A virus antibodies (anti-HAV) is the lowest in adults in their 20s and has not changed much over the past 10 years, and seropositivity of anti-HAV in adults in their 30s has continued to decline from 69.6% in 2005 to 32.4% in 2014. Most young adults who have not yet experienced hepatitis A and are not vaccinated are vulnerable to hepatitis A infection. This year's epidemic of hepatitis A is a predictable outcome for vulnerable populations. Therefore, effective acute hepatitis A control and prevention strategies are needed, particularly for those in their 20s and 30s.

Phenotypic Characteristics of PD-1 and CTLA-4 Expression in Symptomatic Acute Hepatitis A

BACKGROUND/AIMS: The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA). METHODS: Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry. RESULTS: PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1: 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4: 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH. CONCLUSIONS: Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.

Acute hepatitis with concomitant graves' disease.

Acute hepatitis A with concomitant Graves’ disease was reported rarely in the literature. To our knowledge there is one case in the literature from New York in which acute hepatitis A infection was not thought predominant. It is difficult to manage these cases because of the limited therapy options especially when cholestasis occurs. A 36-year-old male presented with severe cholestasis who was diagnosed as acute hepatitis A infection together with Graves’ disease. He had severe cholestasis with elevated liver enzymes and bilirubin levels. Thyroid functions tests decreased to normal levels with plasmapheresis therapy and then he was sent to general surgery for thyroidectomy. Plasmapheresis is an alternative therapy option for thyrotoxicosis in patients with Graves’ disease concomitant with acute HAV infection.

Reversible splenial lesion on the corpus callosum in nonfulminant hepatitis A presenting as encephalopathy

Reversible focal lesions on the splenium of the corpus callosum (SCC) have been reported in patients with mild encephalitis/encephalopathy caused by various infectious agents, such as influenza, mumps, adenovirus, Varicella zoster, Escherichia coli, Legionella pneumophila, and Staphylococcus aureus. We report a case of a reversible SCC lesion causing reversible encephalopathy in nonfulminant hepatitis A. A 30-year-old healthy male with dysarthria and fever was admitted to our hospital. After admission his mental status became confused, and so we performed electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain, which revealed an intensified signal on diffusion-weighted imaging (DWI) at the SCC. His mental status improved 5 days after admission, and the SCC lesion had completely disappeared 15 days after admission.

Ultrasonographic Findings of the Gallbladder in Patients with Acute Hepatitis A: Do They Have Clinical Relevance?

PURPOSE: To determine the association of gallbladder (GB) abnormalities on ultrasonography (US) of patients with acute hepatitis A with demographic, clinical, and biochemical factors, and with other US findings. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board, which waived the requirement for informed consent. We retrospectively evaluated 152 consecutive patients with acute hepatitis A who underwent US. The diagnosis of acute hepatitis A was made during acute illness by demonstrating anti-HAV of the IgM class. US images were reviewed simultaneously by two abdominal radiologists and a consensus was reached for GB wall thickening, GB collapse, lymphadenopathy, and hepatic echogenicity. The associations between demographic, clinical, biochemical, and US findings and GB wall thickening or collapse were then assessed. RESULTS: GB wall thickening was present in 123 (81%) and GB collapse in 96 (63%) of the 152 patients. Total bilirubin level and GB collapse differed significantly (p < 0.05) between patients with and without GB wall thickening. Gender ratio, total and peak total bilirubin level, and GB wall thickness differed significantly (p < 0.05) between patients with and without GB collapse. Multivariate analysis showed that GB wall thickening was associated with GB collapse and vice versa. CONCLUSION: GB wall thickening and GB collapse are common US abnormalities associated with each other in patients with acute hepatitis A. However, GB wall thickening or collapse is not associated with any demographic, clinical, or biochemical factors, or with other US findings, in patients with acute hepatitis A.

Optimal time for repeating the IgM anti-hepatitis A virus antibody test in acute hepatitis A patients with a negative initial test / 대한간학회지

BACKGROUND/AIMS: The nonspecific clinical presentation of acute hepatitis A (AHA) mandates the detection of anti-hepatitis A virus IgM antibodies (IgM anti-HAV) in the serum for obtaining a definitive diagnosis. However, IgM anti-HAV might not be present during the early phase of the disease. The aim of this study was to determine the optimal time for repeating the IgM anti-HAV test (HAV test) in AHA patients with a negative initial test. METHODS: In total, 261 patients hospitalized with AHA were enrolled for this retrospective study. AHA was diagnosed when the test for IgM anti-HAV was positive and the serum alanine aminotransferase (ALT) level was > or =400 IU/L. Repeat HAV test was conducted after 1-2 weeks if the initial HAV test was negative but AHA was still clinically suspected. RESULTS: The results of the initial HAV test were negative in 28 (10.7%) patients. The intervals from symptom onset to the initial-HAV-test day and from the peak-ALT day to the initial-HAV-test day were significantly shorter in the negative-initial-HAV-test group, but on multivariate analysis only the latter was significantly associated with negative results for the initial HAV test (beta=-0.978; odds ratio [95% confidence interval]=0.376 [0.189-0.747]; P=0.005). The HAV test was positive in all patients when it was performed at least 2 days after the peak-ALT day. CONCLUSIONS: The results of HAV tests were significantly associated with the interval from the peak-ALT day to the HAV-test day. The optimal time for repeating the HAV test in clinically suspicious AHA patients with a negative initial HAV test appears to be at least 2 days after the peak-ALT day.

Influenza A (H1N1) 2009 Pandemic Calm Down the Prevalence of Acute Hepatitis A in the Latter Half of 2009: Korean Population Study / 대한소화기학회지

BACKGROUND/AIMS: There was a spiking incidence of acute hepatitis A (AHA) in 2009 summer, but it went down drastically after an outbreak of influenza A (H1N1). We assessed the relationship between 2009 H1N1 pandemic and AHA prevalence from August to December 2009. METHODS: We compared AHA cases nationwide and in our hospital for the period from the latter half of 2008 to the end of 2010. H1N1 cases in our hospital from August 2009 to December 2009 were included in the study and the correlation between 2009 H1N1 pandemic and AHA prevalence was assessed. RESULTS: The national surveillance system reported 2,233, 7,895, 15,231 and 7,660 AHA cases from 2007 to 2010, respectively. A similar trend was noted in our hospital in the same periods. Although the national total incidence was increased in 2009, it showed steep decreasing trend line in the final 21 weeks of 2009 (weeks 32-52), as compared with 2008 and 2010. The mean weekly incidence percentage (AHA cases in a week/total in a year) in weeks 32-52 of 2009 was 1.17+/-0.55%, significantly lower than that in 2008 and 2010 (1.61+/-0.43% and 1.56+/-0.51%; p<0.001). Furthermore, we found a significant negative correlation between 2009 H1N1 pandemic and AHA in our hospital for weeks 32-52 of 2009 (r=-0.597; p<0.001). CONCLUSIONS: The widespread occurrence of 2009 H1N1 pandemic highlighted the benefits of health care and good hygiene, such as effective hand washing and wearing of masks, which may have also interrupted hepatitis A virus transmission.

Effects of Reactivation of Latent Epstein-Barr Virus Using Polymerase Chain Reaction on Acute Hepatitis A in Children / 대한소아소화기영양학회지

PURPOSE: We previously reported that concurrent reactivation of latent Epstein-Barr virus (EBV) in children with hepatitis A virus (HAV) infection is common and EBV reactivation with HAV infection adversely affects the clinical features of hepatitis. However, the incidence of concurrent reactivation was not accurate because the detection of EBV reactivation was based on serologic methods. Therefore, we studied the effects of polymerase chain reaction (PCR)-proven EBV reactivation, thus a more precise concurrence, on acute HAV infection in children. METHODS: PCR were conducted in 34 patients, who had enrolled previous study and diagnosed with acute HAV infection between January 2008 and June 2010. Their medical records were reviewed. RESULTS: Among 34 patients with acute HAV infection, 12 patients (35.3%) had EBV reactivation which was proven using serologic and molecular biologic techniques. There were significant differences in the peak levels of AST and ALT between the reactivated and non-reactivated groups (p=0.001 and p10 years of age revealed more liver dysfunction compared to the non-reactivated sub-group. A comparison with a previous study was performed. CONCLUSION: PCR-proven reactivation of latent EBV in children with HAV infection is common and EBV reactivation with HAV infection adversely affects the clinical features of hepatitis, especially in older children.

A Case of Pleural Effusion Associated with Acute Hepatitis A / 대한소화기학회지

Hepatitis A virus (HAV) infection is common in developing countries, including Korea. It can be accompanied by extrahepatic complications such as renal failure, arthritis, and vasculitis. Pleural effusion is a very rare complication of HAV infection, which has been reported usually in children, and has benign clinical courses. Here we report a case of pleural effusion with ascites which occurred in an adult hepatitis A patient. A 26-year-old-woman presented generalized myalgia and fever and was diagnosed as acute hepatitis A. Despite of the improvement of laboratory findings, fever and cough persisted. Pleural effusion newly appeared on the serial chest radiologic images. After the fever settled down, the pleural effusion resolved spontaneously at 13th day of admission.

A Case of Acute Renal Failure Associated with Non-fulminant Acute Hepatitis A / 영남의대학술지

Acute hepatitis A is a generally self-limiting disease of the liver. Acute renal failure is rare in patients with acute non-fulminant hepatitis A. Acute tubular necrosis is the most common form of renal injury found in such patients. The 36 years old male patient visited our hospital with complaint of general weakness, fatigue, nausea, vomiting and myalgia. He was diagnosed with acute renal failure associated with acute non-fulminant hepatitis A. We report here on a case of acute renal failure associated with non-fulminant hepatitis A, and we include a review of the literature.

Clinical courses after administration of oral corticosteroids in patients with severely cholestatic acute hepatitis A; three cases / 대한간학회지

Acute hepatitis A is currently outbreaking in Korea. Although prognosis of acute hepatitis A is generally favorable, a minority of patients are accompanied by fatal complications. Severe cholestasis is one of the important causes of prolonged hospitalization in patients with acute hepatitis A. In such cases, higher chances of additional complications and increased medical costs are inevitable. We report three cases of severely cholestatic hepatitis A, who showed favorable responses to oral corticosteroids. Thirty milligram of prednisolone was initiated and tapered according to the responses. Rapid improvement was observed in all cases without side effects. We suggest that corticosteroid administration can be useful in hepatitis A patients with severe cholestasis who do not show improvement by conservative managements. Clinical trial will be needed to evaluate effectiveness of corticosteroids in these patients.

A Case Report of Acute Hepatitis A Infection in Pregnancy / 대한주산의학회잡지

Hepatitis A virus infection is the most common cause of acute hepatitis but is rarely reported during pregnancy. We report a case of acute hepatitis A in a 28-year old pregnant woman at 40 weeks of gestation. Her initial complaint was fever. Three days after, she developed spontaneous labor and delivered a healthy baby vaginally. Her laboratory examination showed thrombocytopenia, elevated D-dimer and decreased Fibrinogen level as well as markedly elevated liver enzymes. In addition, oliguria and pulmonary effusion were also noted. Hepatitis A infection during pregnancy may be associated with development of labor. And the differential diagnosis with preeclampsia and acute fatty liver of pregnancy is very important for the management.

Hemophagocytic Syndrome in a Patient with Acute Tubulointerstitial Nephritis Secondary to Hepatitis A Virus Infection

Hepatitis A virus (HAV) infection is generally a self-limited disease, but the infection in adults can be serious, to be often complicated by acute kidney injury (AKI) and rarely by virus-associated hemophagocytic syndrome (VAHS). Our patient, a 48-yr-old man, was diagnosed with HAV infection complicated by dialysis-dependent AKI. His kidney biopsy showed acute tubulointerstitial nephritis with massive infiltration of activated macrophages and T cells, and he progressively demonstrated features of VAHS. With hemodialysis and steroid treatment, he was successfully recovered.

Guillain-Barre Syndrome With anti-GM1 and GD1b Antibodies Following Acute Hepatitis A

Guillain-Barre syndrome (GBS) rarely develops following acute viral hepatitis, and there has been no report on the association with anti-ganglioside antibodies. Herein, we report a 36-year-old man who presented with rapidly progressive areflexic quadriparesis following acute viral hepatitis A. The results of nerve conduction study were consistent with demyelinating motor polyneuropathy, and IgG anti-GM1 and anti-GD1b antibodies were positive. Immune responses towards gangliosides may also be important mediators in acute hepatitis A-associated GBS.

A case of acute renal failure associated with non-fulminant acute hepatitis A / 대한내과학회지

Acute hepatitis A is generally a mild, self-limiting disease of the liver. Acute renal failure is extremely rare in patients with acute non-fulminant hepatitis A. Acute tubular necrosis is the most common form of renal injury found in such patients. The 27 years old male patient visited our hospital with complaint of fatigue, nausea and vomiting. He was diagnosed with acute renal failure associated with acute non-fulminant hepatitis A. The renal biopsy demonstrates tubulointerstitial nephritis with focal tubular necrosis on light microscopy. We report here on a case of acute renal failure associated with non-fulminant hepatitis A, and we include a review of the literature.

A Case of Hemophagocytic Lymphohistiocytosis Accompanied by Acute Hepatitis A: Review of the Literature / 대한혈액학회지

A previously healthy 26-year-old female was referred to our hospital because of fever and abnormalities of her blood biochemistry. Her laboratory results displayed leukopenia (1.79x103/microliter), thrombocytopenia (85x103/microliter), the serum aspartate aminotransferase and alanine aminotransferase levels were elevated to more than 2,000 IU/L, and the serum levels of lactate dehydrogenase and ferritin were markedly increased. Mild hepatosplenomegaly was reported on the abdomen-pelvis computed tomography. The bone marrow smears revealed proliferation of mature histiocytes that were ingesting platelets and erythrocytes, which is consistent with hemophagocytic lymphohistiocytosis. Although the other viral markers were all negative, the anti-hepatitis A IgM was positive and the anti-hepatitis A IgG was negative. Therefore, the patient was diagnosed as hepatitis A-associated hemophagocytic lymphohistiocytosis. Since a fulminant clinical course was suspected, 2 cycles of cyclosporine (3mg/kg iv from day 1 to day 5), dexamethasone (30mg iv qd from day1 to day 4) and immunoglobulin (500mg/kg iv day 1) therapy was started from the seventh day after onset and a favorable clinical outcome resulted.

Fulminant Guillain-Barre Syndrome Mimicking Cerebral Death Following Acute Viral Hepatitis A

A 32-year-old man was transferred to an intensive care unit due to respiratory difficulties with a 4-day history of progressive areflexic quadriparesis following acute hepatitis A. A nerve-conduction study revealed inexcitability of most nerves. The cerebrospinal fluid showed albuminocytologic dissociation, suggesting Guillain-Barre syndrome (GBS). The patient appeared brain dead on day 4, showing absent brainstem reflexes, respiratory failure, and fully dilated and fixed pupils. This case is an example of how GBS can evolve and simulate a brain-dead state from fulminant deafferentation following acute hepatitis A.

Clinical Characteristics of Adult Patients with Acute Hepatitis A / 영남의대학술지

BACKGROUND: The incidence of acute hepatitis A in adults has recently been increasing. This study was conducted to investigate the epidemiology and clinical characteristics of acute hepatitis A in Daegu province over the past 10 years. MATERIALS AND METHODS: We reviewed the medical records of 55 patients (male/female: 34/21), who were diagnosed with acute hepatitis A by confirmation of the IgM anti-HAV between January 1998 and June 2007. RESULTS: The mean age was 29.7+/-10.3 years (range; 17-65 years). The incidence was most common between March and June (56.1%), in the third and fourth decades of life (78.2%) and 90.9% (50/55) of the patients were diagnosed from 2003 to present. The common symptoms included anorexia, nausea or vomiting (69.1%), fever and chills (49.1%), myalgia (47.3%), weight loss (47.3%), fatigue (40.0%), abdominal pain (36.4%), diarrhea (9.1%) and pruritus (5.5%). The mean duration of hospital stay was 8.6+/-3.4 days (range; 3-20 days). The route of transmission was identified in only 11 patients (20.0%); 7 patients (12.7%) traveled (abroad or domestic), 2 patients (3.6%) ingested raw food and 2 patients (3.6%) had friends with acute hepatitis A. Fifty four patients recovered without complication; one patient developed fulminant hepatitis and recovered after a liver transplantation. CONCLUSION: The incidence of acute hepatitis A in adults is increasing. Because of the cost of treatment and potential for serious disease, persons, under 40 are recommened to have hepatitis A vaccination and confirmation of IgG anti-HAV.

Two Cases of Acute Renal Failure Associated with Nonfulminant Acute Hepatitis A / 대한소화기학회지

We report two cases of acute renal failure in patients with nonfulminant acute hepatitis A. First case is a healthy 25 year-old man complained of myalgia and jaundice. Initial laboratory results showed BUN 40 mg/dL, creatinine 5.23 mg/dL, AST 2,220 IU/L, ALT 3,530 IU/L, total bilirubin 6.26 mg/dL, and positive anti-HAV IgM antibody. Supportive treatments including fluid therapy were started. Serum creatinine and total bilirubin levels were 7.98 mg/dL and 7.66 mg/dL respectively on the 5th hospital day, and decreased gradually. He was discharged on the 12th hospital day, and was being followed up in outpatient department. Second case is a 33 year-old woman who admitted for bilateral flank pain, high fever, nausea, and vomiting. She was diagnosed as acute pyelonephritis and acute hepatitis A. On admission, BUN 13 mg/dL, creatinine 0.74 mg/dL, AST 3,720 IU/L, ALT 2,280 IU/L, total bilirubin 0.9 mg/dL were noted, and acute renal failure developed next day. Fluid therapy with antibiotics administration were started, and maximal BUN and creatinine was 41.7 and 8.09 mg/dL respectively on the 8th day. She recovered without dialysis and was discharged on the 19th hospital day. Proper and prompt comprehensive supportive measures would decrease the need for dialysis in patient of acute renal failue associated with acute hepatitis A.