Hepatitis A virus genotype IA-infected patient with marked elevation of aspartate aminotransferase levels.

We describe a case of acute liver failure (ALF) without hepatic encephalopathy with marked elevation of aminotransferase due to hepatitis A, according to the revised Japanese criteria of ALF. This liver biopsy of the patient showed compatible to acute viral hepatitis and she immediately recovered without intensive care. She had no comorbid disorders. Of interest, phylogenetic tree analysis using almost complete genomes of hepatitis A virus (HAV) demonstrated that the HAV isolate from her belonged to the HAV subgenotype IA strain and was similar to the HAJFF-Kan12 strain (99% nucleotide identity) or FH1 strain (98% nucleotide identity), which is associated with severe or fulminant hepatitis A. Careful interpretation of the association between HAV genome variations and severity of hepatitis A is needed and the mechanism of the severe hepatitis should be explored.

The etiology of hypertransaminasemia in Turkish children.

The aim of this study was to investigate the causes of elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in children. We analyzed the medical records for children aged 3 months to 18 years who presented to the hospital with ALT >45 IU/L and/or AST >50 IU/L, between 2012 and 2014, for various reasons, including those not related to liver disease. In total, 281 children met the study criteria. This group comprised of 125 (44.5%) females and 156 (55.5%) males. At the presentation, the most common patient complaint was fatigue (53.4%), while 15.7% of the patients reported no symptoms. The most common findings on the physical examination were jaundice and hepatomegaly. In 15% of the cases, the findings were normal. According to the diagnosis, the most common cause of the elevated transaminases were infections (34%), with hepatitis A virus (HAV) infection as the leading cause (18.9%). Drug-induced liver injury (DILI) was the cause in 18.1% of the cases and non-alcoholic fatty liver disease (NAFLD) in 11.1%. The highest transaminase levels were associated with HAV infection, while DILI and NAFLD caused only slightly elevated transaminases. Overall, our results show that the elevated transaminases in children are most often caused by infections, DILI, and NAFLD. In a majority of cases, elevated ALT and AST indicate liver disease, however, they could also be associated with conditions other than liver damage. Additionally, the elevated enzymes can be detected in completely healthy individuals.

Lysosomes serve as a platform for hepatitis A virus particle maturation and nonlytic release.

Early studies on hepatitis A virus (HAV) in cell culture demonstrated the inclusion of several viral particles in an intracellular lipid-bilayer membrane. However, the origin of these virus-associated membranes and the mechanism for the non-lytic release of HAV into bile are still unknown. Analyzing the association of this virus with cell organelles, we found that newly synthesized HAV particles accumulate in lysosomal organelles and that lysosomal enzymes are involved in the maturation cleavage of the virion. Furthermore, by inhibiting the processes of fusion of lysosomes with the plasma membrane, we found that the nonlytic release of HAV from infected cells occurs via lysosome-related organelles.

Elevació asimptomàtica de les transaminases en l’infant / No disponible

No disponible

Autoantibody response to microsomal epoxide hydrolase in hepatitis C and A.

Autoimmune responses were observed in a large proportion of hepatitis C cases and are suspected to be part of viral pathogenesis. The AN6520 antigen (AN-Ag) is a normal cellular protein mainly expressed in liver that was found associated with non-A, non-B hepatitis. To elucidate its pathogenic role in hepatitis C, we developed an IgM capture assay using purified AN-Ag and confirmed that the antibody response to AN-Ag is associated almost exclusively with hepatitis C cases (29%). Screening of a human liver expression library revealed that AN-Ag is mainly the microsomal epoxide hydrolase (mEH), a drug-metabolizing enzyme that plays an important role in the metabolism of some mutagenic and carcinogenic epoxides. Using the purified recombinant human mEH as an antigen, we now found that antibodies against this protein are associated with nearly 82% of hepatitis C virus infections and surprisingly with 46% of patients with hepatitis A. The appearance of AN-Ag/mEH in the incubation period of hepatitis C as previously reported and the antibody responses shown here indicate that this enzyme may be a marker for or even a cause of some of the pathology associated with hepatitis C and A.

Reversible encephalopathy secondary to paratyphoid infection and concomitant acute Hepatitis A.

Reversible encephalopathy has been described in association with typhoid fever as well as nontyphoidal salmonella infections. A diagnostic dilemma as to the cause of encephalopathy may arise when there is coexistent acute viral hepatitis and suspicion of fulminant liver failure. The authors report a patient who presented with acute icteric hepatitis A infection and a concomitant febrile illness due to Salmonella paratyphi associated with progressive encephalopathy and coma. The young man developed high-grade fever and coma. Concomitant infection with S. paratyphi was diagnosed and the patient's encephalopathy resolved rapidly with antibiotic therapy. This is the first report of a putative association of S. paratyphi infection and reversible encephalopathy. Salmonella and hepatitis A virus infection are both transmitted via the fecal-oral route, and awareness of this association is important in the management of such patients.

Inducible nitric oxide synthase (iNOS) expression in liver and splenic T lymphocyte rise are associated with liver histological damage during experimental hepatitis A virus (HAV) infection in Callithrix jacchus.

Callithrix jacchus is considered a reliable animal model for hepatitis A virus (HAV) infection. All three HAV orally inoculated marmosets developed hepatitis - the infection was monitored by continuous virus shedding, high levels of serum enzyme alanine aminotransferase, specific antibody and seroconversion 3-6 weeks after HAV inoculation. HAV antigen was detected in liver by immunofluorescence 4 days post inoculation (PI) and onwards. To gain insight into the biological role of inducible nitric oxide synthase (iNOS) during immune-related acute liver injury the enzyme was searched in frozen biopsies: immunofluorescent labeling was found in the cytoplasm of liver cells mainly Kupffer's cells and spleen macrophages (CD68+) starting 11 days PI with maximum intensity on the fifth to sixth week PI. Necroinflammatory liver lesions characteristic of viral hepatitis were also observed at 10 days PI with maximum severity at 4 to 6 weeks PI. Furthermore, T lymphocytes (CD2+) were raised at this time point. No difference was evident in the frequency of B lymphocytes (CD20+). Therefore, iNOS expression preceded necroinflammatory liver lesion and maximal immunofluorescence reaction was coincident with tissue injury, supporting the hypothesis that NO contributes to hepatic cytotoxic mechanism but also to virus clearance. The concomitant rise in T-lymphocyte population may suggest a role for these cells in this and/or other independent HAV-induced pathological changes.

[Cholinesterase in the differential diagnosis of parenchymal and obstructive icterus and in the differentiation between malignant and benign obstruction]. / Cholinesterase in der Differentialdiagnostik des parenchymatischen und obstruktiven Ikterus und bei der Differenzierung maligner und benigner Obstruktion.

Determination of CHE has already been proven as a useful test in the diagnosis of liver diseases. Our investigation included 2 groups of patients: a group suffering from parenchym hepatitis caused by virus infection A and B, and a second group of patients suffering from etiologically different obstructive hepatitis (malign and benign obstruction). Our tests show that there is lower CHE activity in patients with hepatitis B. There is a remarkable difference of CHE activity in benign and malign obstructive hepatitis.

Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised trial.

BACKGROUND: Hepatitis A vaccination stops outbreaks of hepatitis A infection, but its efficacy against infection after exposure has not been proven. We investigated the use of hepatitis A vaccine to prevent secondary infections with hepatitis A virus (HAV). METHODS: We did a randomised controlled trial of hepatitis A vaccine in household contacts of people with sporadic HAV infection (index cases). Households (index cases and contacts) were randomly assigned to the vaccine group or unvaccinated group, according to the study week in which they were enrolled. All household contacts in the vaccine group received vaccination at the time of entry to the study. FINDINGS: During 45 days of follow-up, secondary infection had occurred in ten (13.3%) of 75 households (two families had two cases each) in the untreated group and in two (2.8%) of 71 households in the vaccine group. The protective efficacy of the vaccine was 79% (95% CI 7-95). The number of secondary infections among household contacts was 12 (5.8%) of 207 in the unvaccinated group and two (1.0%) of 197 in the vaccinated group. Therefore, 18 individuals needed to be vaccinated to prevent one secondary infection. INTERPRETATION: Hepatitis A vaccine is effective in the prevention of secondary infection of HAV and should be recommended for household contacts of primary cases of HAV infection.

[Characteristics of experimental models of hepatitis A in Papio hamadryas]. / Kharakteristika éksperimental'nykh modelei gepatita A na pavianakh gamadrilakh.

Hepatitis A (HA) was induced in 14 Papio hamadryas by strain VHA-PH isolated from this species of monkeys with spontaneous infection, strain VHA-MM isolated from Macaca mulatta, and a unique strain VHA-H3 isolated from a patient; this latter strain is pathogenic for Macaca mulatta in experiment. All infected seronegative animals developed a disease with virological, serological, biochemical, and morphological signs characteristic of human HA, but the duration of these signs manifestation varied. Virus in the feces and an increased level of SGPT were detected periodically starting from days 3-26 to 24-135, and in 4 monkeys even later (up to days 163-238). Morphologic changes in the liver, typical of acute hepatitis, were observed from days 10-46 to days 16-130. Strain VHA-H3 is less pathogenic for papios. HA models on Papio hamadryas infected with strains VHA-PH and VHA-MM can help solve many research and practical problems.

Hepatitis A impairs the function of human hepatic CYP2A6 in vivo.

Hepatitis virus A (HVA) is a worldwide sporadic disease but its effects on pharmacokinetics and individual drug responses have not been studied. In this study, the 7-hydroxycoumarin (7OHC) excretion test used in vivo as a bioindex of hepatic CYP2A6 activity was performed in 20, previously healthy, acute jaundice HVA patients. Volunteers with an acute HVA were treated with one p.o. administration of 5 mg coumarin (Venalot). Among the patients, 11 were children (6-10 years; two girls and nine boys), the rest (15-40 years old) consisted of two men and seven women. Urinary excretion of 7OHC was measured after overnight fasting in four fractions: 0 h before any medication (to detect if any basal 7OHC excretion exits), and after a 5-mg coumarin capsule p.o., 0-2, 2-4 and 4-8 h fractions were collected and urine volumes were recorded. Urinary excretion of 7-hydroxycoumarin occurred to a similar extent in healthy adults and children. The first 2-h 7OHC excretion was decreased by 26% (P < 0.05) and total (0-8 h) 7OHC excretion was decreased by 37% (P<0.01) among HVA-positive adults (age range 15-40 years) compared with the values obtained from healthy volunteers. In 11 HVA-positive children (age 6-10 years), the first 2-h 7OHC excretion was only 20% (P < 0.0001) and the total 7OHC excretion 28% (P < 0.0001) of the value observed in healthy controls. These results suggest that (i) an acute HVA decreases the metabolic clearance of drugs such as coumarin which are rapidly metabolised by CYP2A6 and (ii) this decrease is even more prominent in children. Such metabolic responses may be of clinical importance and may also interfere with other drug therapy in these patients.

Analysis of serum hepatitis A virus antibody response in different courses of hepatitis A virus infection.

Changes in the serum hepatitis A virus antibody (anti-HAV) response in patients with different clinical courses of HAV infection were examined using immune adherence hemagglutination (IAHA). Anti-HAV was detected 2-6 weeks after the onset of clinical symptoms in patients with the typical course of acute hepatitis A and 1-4 weeks after the onset in those with fulminant hepatitis A. Maximal anti-HAV titers were observed 8-20 weeks after the onset of clinical symptoms, and changes in anti-HAV were similar in the typical and the prolonged course of acute hepatitis A, but maximal antibody titers were higher in the prolonged course. Maximal anti-HAV titers in patients with subclinical HAV infection were significantly lower than titers in patients with the typical and prolonged courses of acute hepatitis A, and in those with fulminant hepatitis A. High titers of anti-HAV remained positive for at least 6 years after infection in patients with clinical infection and for at least 4 years in patients with subclinical infection on follow-up. These findings suggest that the maximum anti-HAV titer correlates with the clinical severity of HAV infection; knowledge of the antibody response should be useful for analyzing the pathogenesis of HAV infection.

Serum lactic dehydrogenase in the differential diagnosis of acute hepatocellular injury.

Acute hepatocellular injury, whether due to viral hepatitis, hepatic ischemia, or drug hepatotoxicity, results in elevated levels of serum aminotransferases (AST and ALT). Serum lactate dehydrogenase (LD) is reported to be markedly elevated in ischemic hepatitis. Thus, comparisons of the degree of elevation of serum levels of LD, ALT, and AST may be helpful in the differential diagnosis of acute liver injury. To study this, we reviewed serum enzyme patterns early in the course of acute liver injury in patients with acute viral hepatitis A and B (n = 51), ischemic hepatitis (n = 20), and acetaminophen injury (n = 26). All patients had serum ALT and/or AST at least five times the upper limit of normal. For a given ALT and AST level, LD was higher in ischemic hepatitis and acetaminophen injury than in viral hepatitis. The mean ALT/LD ratio for acute viral hepatitis was 4.65, for ischemic hepatitis 0.87, and for acetaminophen injury 1.46. Mean ALT/LD ratio for viral hepatitis was significantly higher (p < 0.0001) than for the other two groups combined. An ALT/LD ratio of 1.5 differentiated acute viral hepatitis from ischemic hepatitis and acetaminophen injury with a sensitivity of 94% and a specificity of 84%.

A patient with hepatic granuloma formation and angiotensin-converting enzyme production by granuloma cells during clinical relapse of hepatitis A.

Elevation of the serum angiotensin-converting enzyme (sACE) level and hepatic granulomas were found during a clinical relapse in a 22 year old patient with acute viral hepatitis type A (AVH-A). The serum transaminase level and sACE level remained high for more than 6 months. In the biopsied specimen of the liver, fibrous rings of granulomas composed of collagen types I, III, and V were observed. Furthermore, the localization of ACE was visible in the rough endoplasmic reticulum of epithelioid cells of granulomas in the liver under electron microscopy using the indirect immunoperoxidase method. These results suggest that granuloma cells in the liver caused by hepatitis A may be involved in ACE production. In addition, other diseases associated with the presence of granulomas in the liver, such as lymphoma, cytomegalovirus infection, visceral leishmaniasis, and lupoid hepatitis, were ruled out. However, the hepatic granulomas disappeared with the healing of AVH-A. In this regard, the present case is considered to be one of the very few cases of hepatic sarcoidosis.

Elevated serum thymidine kinase activity in patients with acute viral hepatitis.

To evaluate the clinical applications of serum thymidine kinase (TK) activity, we compared the results obtained with this parameter with those of other liver function tests in 27 patients with acute viral hepatitis and 16 normal controls. In those in the acute stage, the serum TK activity increased significantly to 55.5 +/- 66.5 U/L. There was no significant correlation between serum TK activity and findings for serum albumin, bilirubin, alkaline phosphatase or r-glutamyl transpeptidase. However, it did correlate significantly well with the serum activity of aspartate aminotransferase (AST) (r = 0.621, P < 0.01), alanine aminotransferase (ALT) (r = 0.551, P < 0.01), and lactate dehydrogenase (LDH) (r = 0.620, P < 0.01). Serum TK activity reached higher than 70 U/L in 8 of 11 patients with hepatitis A; however, no patients with the other types of hepatitis reached such a high level. During the recovery stage, the serum TK activity decreased significantly to 5.9 +/- 1.7 U/L (P < 0.01), and did not correlate with AST, ALT, LDH or other conventional liver function parameters. The data suggest that an elevation of serum TK in patients with acute viral hepatitis results from hepatocellular damage. A marked elevation of serum TK activity may thus provide a marker for acute hepatitis A infection.

[The role of liver in muscular dystrophy]. / Il ruolo del fegato nella distrofia muscolare.

Epidemiological or anamnestical data may either help or confuse the differential diagnosis of various diseases mainly characterized by asymptomatic hypertransaminasemia. Occasional finding of transaminase elevation may lead to suppose chronic or persistent hepatopathy, particularly when the patient seems to be asymptomatic and presents anamnestic data suggesting intoxication, acquired infection from blood derivatives, origin from geographic areas with high prevalence of viral hepatitis. However, the true existence of hepatic damage, concurrent to a myopathy, may be also related to the primitive diseases. There is evidence, in fact, that in the presence of muscular dystrophy, a disease caused by structural defects of muscular membranes, also hepatocytes show ultrastructural defects. The present work reports the cases of 5 children, hospitalized at the 1st Clinic of Infectious Diseases of the University of Genoa, affected by persistent hypertransaminasemia and showing anamnestical data suggesting hepatitis; histological findings of hepatitis were effectively shown in 3 patients after needle biopsy. All patients proved to be affected by muscular dystrophy. Hepatic damage results cannot be correlated to known causes of hepatopathy. During disease courses heralded by asthenia and hypertransaminasemia, differential diagnosis must take into account non-hepatic diseases, like muscular dystrophy. Although this disease mainly affects the muscle, also the liver seems to be involved, as suggested by histological changes found in some patients.

In situ hybridization studies in hepatitis A infection.

An in situ hybridization method using radiolabeled oligonucleotide probes was developed to study primary sites of hepatitis A virus replication in an experimental animal model of infection. Hepatitis A genomic sequences were demonstrated in hepatocytes of four marmosets with acute hepatitis A by use of antisense probes. In two of these animals, staining was also found when a sense probe was used, which is consistent with active replication in the hepatocytes. The specificity of the hybridization signal was confirmed by neutralization with "cold" (i.e., unlabeled) probes and by absence of hybridization with non-A hepatitis and reverse antisense probes. The hepatocyte appeared to be the only cell type showing staining. No hybridization was found in other organs, including the intestine (n = 4) and, in one animal, the kidney and spleen.

Serum adenosine deaminase: isoenzymes and diagnostic application.

Human adenosine deaminase (ADA; EC 3.5.4.4) consists of three isoenzymes: ADA1, ADA1+CP, and ADA2. We developed an electrophoretic technique to distinguish between these three isoenzymes. The isoenzyme pattern was studied in tissue and cell homogenates, as well as in serum from normal subjects and from patients with increased serum ADA who had either hepatitis, infectious mononucleosis, tuberculosis, pneumonia, rheumatoid arthritis, or acute lymphoblastic leukemia (ALL). The highest ADA activity was found in lymphocytes and monocytes. ADA2 could be detected only in monocytes (18% of total ADA activity). It was also the predominant isoenzyme in the sera of controls and all disease groups, except for ALL--the only condition evaluated that is not of an inflammatory nature. We conclude that serum ADA reflects monocyte/macrophage activity or turnover in most diseases studied. The exception is ALL, where serum ADA most probably originates from lymphocyte precursors.

Dissociation of alanine aminotransferase values in acute hepatitis A patients with and without past experience to the hepatitis B virus.

Serological markers and peak serum alanine aminotransferase (ALT) values of 140 in-patients with acute hepatitis, either type A (n = 90), or type B (n = 50) were prospectively assessed. In 23 out of the 90 patients with acute hepatitis A, evidence of previous experience with hepatitis B virus (HBV) was found, whereas 35 out of the 50 patients with acute hepatitis B had past contact with hepatitis A virus (HAV). The mean peak ALT values [S.D.] were significantly higher in hepatitis A patients with previous experience with HBV (1413 [704] i.u./l), when compared to those without such experience (842 [464] i.u./l, P less than 0.001). Such a difference was not evident between acute hepatitis B patients, whether or not they had previous contact with HAV. We conclude that when acute hepatitis A is superimposed on past HBV infection an augmented transaminaemia, indicative of enhanced liver cell necrosis, takes place although a definite explanation is lacking. We suggest that individuals with markers of HBV infection should be early candidates for HAV immunization.