Aetiology,clinical course and outcome of sporadic acute viral hepatitis in pregnancy

Hepatitis E causes large-scale epidemics in endemic areas. The disease, during epidemics, has increased incidence and severity in pregnant women. Sporadic acute viral hepatitis (AVH) is common in endemic areas. The relationship of sporadic AVH and pregnancy has not been well studied. Over a 3-year period we prospectively studied 76 pregnant women and 337 non-pregnant women of childbearing age with sporadic acute viral hepatitis for aetiology, clinical course and outcome of disease. The aetiology in sporadic AVH was hepatitis A virus (HAV) in six (1.5%), hepatitis B virus (HBV) in 62 (15%), hepatitis C virus (HCV) in seven (1.7%), hepatitis D virus (HDV) co-infection in six (1.5%), hepatitis E virus (HEV) in 205 (49.6%), and hepatitis non-A-to-E (HNAE) in 127 (30.7%). Sixty-five (85.5%) pregnant women and 140 (41.5%) nonpregnant women had hepatitis E. The proportion of pregnant women was 31.7% in HEV group and 5.3% in non-HEV group [P < 0.001; OR=8.3 (95%C1 4.2-16.3)]. The prevalence of HEV in pregnant women in first trimester (76.9%), second trimester (88.9%), third trimester (83.8%) and puerperium (100%) did not differ significantly (P=0.09). Forty-seven (61.8%) of the 76 pregnant women developed fulminant hepatic failure (FHF), 69.2% in HEV group and 10% in non-HEV group (P < 0.001). Thirty-four (10.1%) nonpregnant women developed fulminant hepatic failure, 10% in HEV group and 9.7% in non-HEV group (P=0.86). FHF had occurred in four (40%) of 10 patients with HE in first trimester as against 41 (74.5%) of 55 patients in second trimester and beyond (P=0.015). Amongst the major complications of fulminant hepatic failure, cerebral oedema (53.2%) and disseminated intravascular coagulation (21.3%) occurred more often in pregnant women than in nonpregnant women (29.4% and 2.8%; P=0.03 and 0.016, respectively) while infections occurred more often in nonpregnant women (36.1%) than in pregnant women (10.6%; P=0.003). Fifty (61.7%) patients with FHF died [25 (53.2%) pregnant women and 25 (69.5%) nonpregnant women (P=0.06)]. Cerebral oedema and HEV aetiology were independent variables of survival in patients with FHF. Patients with cerebral oedema had worse prognosis and patients with HEV aetiology had best chances of survival. Hence HEV was the most common cause of sporadic AVH in this endemic area. High proportion of pregnant women and increased severity of disease in pregnancy were limited to patients with hepatitis E. Sporadic AVH caused by agents other than HEV did not show any special predilection to or increased severity in pregnancy. FHF in pregnant women caused by HEV was an explosive disease with short pre- encephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation and may represent a severe manifestation of a Schwartzmann-like phenomenon.     

Changing aetiologic patterns of acute viral hepatitis in Taiwanese children

During 1981-86, 76 children were diagnosed as having acute viral hepatitis at the Department of Pediatrics, National Taiwan University Hospital, which is a major referral centre for hepatitis in children in northern Taiwan. The majority (64%) of children had acute hepatitis B which had occurred mainly during infancy. Perinatal transmission from a hepatitis B e negative surface antigen (HBsAg) carrier mother or infection through blood transfusion from a donor who had escaped notice by a less sensitive screening test (reverse passive haemagglutination test) for HBsAg were the two important modes of transmission of hepatitis B virus. The number of cases of acute hepatitis B declined after 1984, with the beginning of the nation-wide hepatitis B vaccination programme. Due to an outbreak of hepatitis A in northern Taiwan in 1982, the number of cases of hepatitis A peaked that year. Subsequently, cases of acute hepatitis A decreased remarkably. Better socio-economic conditions and improved hygiene might have contributed to the marked decrease of viral hepatitis A. The frequency of non-A, non-B hepatitis remained stable during the study period. It is possible to conclude that the aetiologic pattern of acute hepatitis in Taiwanese children changed during the past 6 years: clinical cases of hepatitis A and B decreased, probably because of more effective control of hepatitis A and B virus infections, whereas the control of non-A, non-B virus apparently requires further efforts.     

Transient abnormality in carbohydrate metabolism during enterically transmitted non-A, non-B acute viral hepatitis

Blood glucose, plasma insulin and free fatty acids (FFA) responses, during the 2 h oral glucose tolerance test (OGTT) with 75 g of dextrose, were measured in 30 consecutive patients with acute enterically transmitted non-A, non-B hepatitis. All of these parameters during the OGTT were compared with 10 age-, sex- and weight-matched healthy volunteers from the same community. The fasting blood sugar, insulin and FFA were not different from normal controls (P greater than 0.05). According to the WHO criteria, the blood glucose response during OGTT in these patients was normal in 23%, impaired in 33% and diabetic in 43%. There was significant hyperinsulinaemia (P less than 0.001) in patients with impaired and diabetic GGT and it persisted even at the end of 2 h. None of the abnormal liver function tests correlated with blood sugar, insulin and FFA response during the OGTT. All abnormal responses during the OGTT were, however, transient and returned to normal in all the patients after the recovery from acute hepatitis.     

Possible infectious causes in 651 patients with acute viral hepatitis during a 10-year period (1976–1985)

ABSTRACT— Six hundred and fifty-one patients with acute viral hepatitis were identified serologically between January 1976 and December 1985. Of these, 109 (17%) had hepatitis A, 135 (21%) had hepatitis B, and 407 (62%) had hepatitis non-A, non-B. The possible infectious causes for acquisition of viral hepatitis occurring within 6 months before the onset of hepatitis were analysed. Approximately 80% of cases of hepatitis A and 70% of hepatitis B had no known risk factor, while in 67% of cases of hepatitis non-A, non-B possible risk factors for infection were documented. Infectious causes for hepatitis A were ingestion of raw shellfish (11%) and previous familial contact with patients with hepatitis A (10%). For hepatitis B, risk factors included medicare (24%), such as transfusion, surgical operation, accidental needle stick and acupuncture, and sexual contact (6%). For hepatitis non-A, non-B, the most important infectious cause was medical procedures (65%). The numbers of hospital employees were 2 (2%) with hepatitis A, 15 (11%) with hepatitis B and 14 (3%) with hepatitis non-A, non-B. These data suggest that hepatitis non-A, non-B can be a kind of nosocomial disease.     

Non-A,non-B fulminant viral hepatitis in France in returnees from Asia and Africa

Among 61 patients admitted for non-A, non-B fulminant viral hepatitis to Hôpital Beaujon, 10 had returned from Asia or Africa, and 51 had not been outside France, within the month preceding jaundice. This suggests that hepatitis might have been contracted in Asia or Africa in the former, and in France in the latter. The interval between the onset of jaundice and the onset of hepatic encephalopathy was 10 days in the former and 26 days in the latter (P<0.03). The serum of the patient returning from Asia contained, and the sera of the nine patients returning from Africa did not contain, antibodies to a virus isolated from the stools of patients suffering from an epidemic fecal-oral non-A, non-B viral hepatitis in Central Asia. It is concluded that infection with Asian-African non-A, non-B viruses can be the cause of fulminant hepatitis in persons returning from these countries, that the course of this type of non-A, non-B fulminant viral hepatitis is shorter than that of non-A, non-B fulminant hepatitis contracted in France, and that different viruses might be responsible for non-A, non-B hepatitis in Asia and Africa.     

Prevalence of antibody to hepatitis C virus in prospectively followed acute non-A,non-B hepatitis,from different epidemiological categories

ABSTRACT— We have studied the prevalence of antibody against hepatitis C virus (anti-HCV) and its relation to the time of onset of the symptoms in 57 patients with acute non-A, non-B hepatitis: 16 post-transfusion, 25 drug addicts and 16 sporadic cases. In the 1st month after the onset of illness, anti-HCV was positive in 25% of patients with post-transfusion hepatitis, 44% of drug addicts and 25% of sporadic hepatitis. In the 3rd month this antibody was detected in 75%, 88% and 31.2%, and in the 6th month in 87.5%, 96% and 31.2%, respectively. The prevalence in the 3rd and 6th months was significantly higher in post-transfusion patients and drug addicts than in sporadic cases. In the 6th month the prevalence of anti-HCV in patients who progressed towards chronicity was also significantly higher than in those with acute resolving non-A, non-B hepatitis (94% vs 50%, p<0.001). These results show that HCV is probably the main agent in acute post-tranfusion non-A, non-B hepatitis and in those occurring in drug addicts, and that in a high proportion of these patients the anti-HCV can be detected in the 3rd month after the beginning of the symptoms. On the other hand, the relation of hepatitis C virus with sporadic acute non-A, non-B hepatitis may be doubtful.     

Acute hepatitis non-A,non-B; are there any specific light microscopic features?

ABSTRACT— Coded examination of liver biopsies from a total of 24 patients with acute hepatitis non-A, non-B revealed two main histological trends: (a) acute viral hepatitis with confluent necrosis (sublobular and bridging) carrying a relatively good prognosis and taking a chronic course in only four out of 14 patients (29%); and (b) acute viral hepatitis with severe portal infiltration rich in lymphocytes and plasma cells, lymph follicles with germinal centers and bile duct lesions, as described by Poulsen & Christoffersen. The latter group showed a very high tendency to transition to chronic hepatitis (six out of seven patients, 86%) or a course characterized by one or multiple acute relapses (one out of seven patients, 14%). Bile duct lesions, if present in biopsies of patients with acute hepatitis, are of diagnostic and prognostic value. They point to the etiological possibility of a hepatitis non-A, non-B and, at the same time, they indicate a high likelihood of evolution to chronic liver disease.     

Fulminant viral hepatitis: Indian experience

Thirty-six patients with fulminant viral hepatitis were studied. Enzyme immunoassay was used to detect the presence of HBsAg, IgM anti-HBc, and IgM anti-HAV. Non-A, non-B virus was the most common aetiological agent (61.1%) followed by hepatitis B virus (HBV; 30.6%) and hepatitis A virus (8.3%). Presence of IgM anti-HBc confirmed the diagnosis of HBV infection in three cases who were negative for HBsAg. Similarly, in one case who was positive for HBsAg, absence of IgM anti-HBc suggested superinfection with some other agent. Survival was significantly higher (P less than 0.01) in the hepatitis A virus (HAV) group (66.6%) compared with non-A, non-B (31.2%) and HBV groups (27.3%). Fever at the onset of illness was seen in all patients with HAV, 54.5% of patients with HBV and 38.88% of patients with non-A, non-B infection (P less than 0.01). The median time interval between the first symptom and the onset of encephalopathy was 16, 13 and 8 days in HAV, HBV and non-A, non-B groups, respectively, but this difference was statistically not significant (P greater than 0.05).     

Predictors of outcome in children with acute viral hepatitis and coagulopathy

The presence of coagulopathy in acute viral hepatitis (AVH) in children raises issues about prognosis and need for liver transplantation. We evaluated factors predicting outcome in such patients and determined the applicability of the paediatric acute liver failure study group (PALFSG) definition of acute liver failure (ALF) of coagulopathy alone in comparison with coagulopathy and encephalopathy. Children with AVH (clinical features, raised transaminases and positive viral serology) with uncorrectable coagulopathy [prothrombin time (PT) > 15 s] with or without hepatic encephalopathy (HE) were enrolled. Comparative analysis was based on (i) outcome: survivors/nonsurvivors and (ii) ALF criteria: group A coagulopathy (PT > 15 s) and encephalopathy and group B coagulopathy (PT > 20 s). We studied 130 children (86 boys, mean age 7.5 ± 4.5 years): 86 recovered and 44 died. Single virus infection was present in 96 (74%), hepatitis A being the commonest (n-69). On multiple stepwise logistic regression analysis, age <3.5 years, serum bilirubin ≥ 16.7 mg/dL, PT ≥ 40.5 s and clinical signs of cerebral oedema were independent predictors of mortality. Mortality increased from 0% with single to 100% with four risk factors. Ninety-seven cases met the PALFSG criteria: group A-79 and group B-18. Group A subjects had higher mortality (55.6%vs 0%) and poorer liver functions (bilirubin 18.1 ± 8.9 vs 13.8 ± 6.9 mg/dL, PT 63.9 ± 35.1 vs 27.2 ± 5.2 s) than group B. PT deteriorated significantly with the appearance and progression of HE. One-third of children with AVH with coagulopathy die without transplantation. Age <3.5 years, bilirubin ≥ 16.7 mg/dL, PT ≥ 40.5 s and signs of cerebral oedema are predictors of poor outcome. Children with encephalopathy and coagulopathy have a poorer outcome than those with coagulopathy alone.     

Liver biopsy features of acute hepatitis C compared with hepatitis A,B, and non-A,non-B,non-C

ABSTRACT— The diagnosis of acute hepatitis C (AHC) often can only be suspected because current serologic tests remain negative for over 3 months. Because histologic features might provide useful clues, we reviewed 85 liver biopsy specimens from 85 patients with acute viral hepatitis, comparing 22 cases of AHC with 23 cases of acute hepatitis A (AHA), 30 cases of acute hepatitis B (AHB), and 10 cases of acute hepatitis non-A, non-B, non-C (AHNC). AHC was characterized by dense portal lymphoid aggregates (7 cases) and Poulsen-Christoffersen-type cholangitis (8 cases); these lesions were not found in any other type of acute viral hepatitis, and thus appeared to be diagnostic. Sinusoidal inflammatory infiltrates also were common in AHC, particularly in biopsy specimens obtained during the early phase of the disease. These inflammatory infiltrates did not appear to affect adjacent hepatocytes. Necrosis in AHC usually was spotty and accompanied by mixed inflammatory cells. In AHNC, necrosis was also spotty but, as an added feature, pigmented macrophages predominated in them. In AHA, necrosis was predominantly periportal, whereas in AHB, severe zone-3 necrosis predominated. Fatty changes were predominantly microvesicular; they were common in AHC but were also found in other groups. Collectively, the described histologic features allowed diagnosis of AHC in biopsy specimens with reasonable confidence. However, histologic findings failed to predict the prognosis in individual cases.     

Antibody to the hepatitis C virus in acute hepatitis and chronic liver diseases in Japan

ABSTRACT— In a 6-month follow-up study of acute hepatitis in Japan, 31 out of 41 (75.6%) cases of post-transfusion non-A and non-B hepatitis (NANB-PTH) and 14 out of 40 (35.0%) cases of sporadic non-A non-B hepatitis (NANB-SPO) were found to be positive for antibody to the hepatitis C virus (HCVAb). After 12 months of follow-up, 30 cases (81.1%) became chronic among 37 HCVAb positive acute NANB hepatitis cases. This figure shows a significantly higher rate of chronicity as compared with HCVAb negative acute NANB hepatitis. The prevalences of HCVAb in hepatitis B surface antigen (HBsAg) negative cases of chronic hepatitis and liver cirrhosis were 76.3% (200/262) and 66.7% (106/159), respectively, which were significantly different from the values of 5.1% (13/255) and 10.6% (13/123) observed in HBsAg positive cases. Of chronic liver disease cases positive for HCVAb, 45.8% (152/332) had a history of blood transfusion, in contrast to the value of 3.7% (13/352) observed in HBsAg positive cases of chronic liver disease that were negative for HCVAb.     

Detection by immunofluorescence of an antigen-antibody system in patients with acute and chronic non-A,non-B hepatitis

ABSTRACT— An antigen-antibody system has been identified by immunofluorescence in patients with non-A, non-B hepatitis. The non-A, non-B antigen was localized in the hepatocyte nuclei of liver biopsies from patients with acute post-transfusion or sporadic non-A, non-B hepatitis and in those from patients with chronic post-transfusion non-A, non-B hepatitis, the percentage of positive cells being most prominent in patients receiving immunosuppressive treatment. Absence of the antigen in normal livers and in livers from patients with type B hepatitis infection indicated its specific association with non-A, non-B infection. Antibody reacting with the nuclear antigen became detectable in serum during post-transfusion acute non-A, non-B hepatitis in 11 out of 15 cases; it was absent before transfusion. Six out of 12 cases of sporadic acute non-A, non-B hepatitis were also found to produce the antibody, which was repeatedly found to be absent during the acute phase in five patients with type A and in eight with type B hepatitis. The non-A, non-B antibody, mainly an IgM antibody, persisted in serum for prolonged periods of time after onset, both in patients showing biochemical resolution of their illness and in those who continued to have liver damage after the acute phase. Accordingly, eight out of nine patients withchronic non-A, non-B hepatitis were found positive for the antibody in serum, seven at the time the non-A, non-B antigen was detected in their liver. Thus this non-A, non-B associated antigen-antibody system shares remarkable similarities of behaviour with the “core” system of the hepatitis B virus.     

Aetiology and prognostic factors in acute liver failure in India

The early prognostic indicators for acute liver failure in endemic zones for hepatitis E virus have not been determined. All consecutive patients with acute liver failure from a geographically defined region endemic for hepatitis E virus were studied over the period April 1989-April 1996. Demographic, clinical and biochemical parameters were recorded at presentation and serum samples were analysed for known viral hepatitis (A-E) markers. Multiple parameters were compared in survivors and non-survivors in a univariate analysis. All significant factors on univariate analysis were entered into a stepwise logistic regression analysis to identify independent variables of prognosis. The sensitivity and specificity of significant prognostic factors was then assessed. A total of 180 [69 males and 111 females: age (mean +/- SD) 31.1 +/- 14.7 years] with acute liver failure were studied. Of these, 131 (72.8%) patients died. Hepatitis E virus was the aetiological cause in 79 (43.9%) patients, while hepatitis A virus, hepatitis B virus, hepatitis C virus and non-A, non-E agent/'s could be incriminated in four (2.1%), 25 (13.9%), 13 (7.2%) and 56 (31.1%) patients respectively. Of 83 women in childbearing age, 49 (59.0%) were pregnant, 33 (67.3%) of these were in the third trimester. Forty-seven (95.8%) pregnant women had HEV infection. Nine variables differed significantly between survivors and non-survivors on univariate analysis. Of these, four variables which predicted the adverse outcome on multivariate analysis were non-hepatitis-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years in that order of significance. Pregnancy per se or duration of gestation did not adversely affect the prognosis. In endemic areas, hepatitis E virus is the commonest cause of acute liver failure. Acute liver failure occurs in a high proportion of pregnant women, mostly in third trimester. Early predictors of a poor outcome are non-E aetiology, prothrombin time >30 s, grade of coma >2 and age >40 years.     

Detection of hepatitis C virus-specific antigens in semen from non-A,non-B hepatitis patients

Semen samples from nine patients clinically diagnosed as having non-A, non-B hepatitis (NANBH) were tested by an ELISA using antibodies raised in rabbits against HCV-specific specific antigens. The semen from all nine patients had elevated levels of HCV-specific antigen in comparison to semen from five healthy donors. Semen from five of the nine patients had significant levels of the HCV-specific antigen. Seven of the eight serum samples from these patients were reactive with the standard C-100 HCV ELISA. Eight of these nine patients had serum reactive for HCV-specific antibodies in our ELISA using HCV-specific antigens. This more direct evidence for viral presence supports the earlier epidemiological data suggesting that HCV could be transmitted sexually.     

Aetiology and prognosis of fulminant viral hepatitis in Japan: A multicentre study

In 236 patients with fulminant viral hepatitis (FVH), type B (FBH) was most common (47.5%), followed by non-A non-B hepatitis (FNANB, 44.9%) and hepatitis type A (FAH, 7.6%). The survival rate was significantly higher in the FAH group than in the FBH and FNANB groups (61.1, 36.6 and 18.9% respectively), and was significantly higher in the FBH group than in the FNANB group. In spite of screening for hepatitis B virus (HBV), FBH was prevalent (27 of 41) in post-transfusion cases; this phenomenon is discussed in relation to a recently revealed mutation of HBV. Within a month after the onset of hepatitis symptoms all cases in the FAH, 93% in the FBH and 79% in the FNANB group, developed encephalopathy. When the duration of illness before the onset of encephalopathy was more than 10 days (a subacute form), the survival rate was significantly lower than when encephalopathy developed in less than 11 days (an acute form). This difference could be accounted for by the difference in the relative frequency of aetiological viruses in the two forms and the higher survival rate in the acute, than the subacute, form in the FNANB group.     

Outcome of acute symptomatic non-A,non-B hepatitis: a 13-year follow-up study of hepatitis C virus markers

ABSTRACT— Thirty-nine of 61 prospectively followed patients who had had acute non-A, non-B hepatitis in 1978 were clinically reexamined in 1991 and tested for antibodies to hepatitis C virus (anti-HCV) with a second generation ELISA and RIBA and for HCV RNA by PCR. Acute hepatitis C was diagnosed in stored sera from 1978 in 24 patients, who were found still to be anti-HCV positive in 1991, and 16 of them were also HCV RNA positive. The majority of anti-HCV positive patients with or without HCV RNA had elevated serum ALT levels 13 years after onset of their acute hepatitis C. After 13 years follow-up, 1.6% of the patients had died of end-stage liver disease, 8% of anti-HCV positive patients had histologically confirmed liver cirrhosis, 79% of anti-HCV positive patients were judged to have chronic infection, whereas 21% seemed to have recovered. To conclude, we found that a majority of our patients with acute symptomatic hepatitis C continued to be viraemic 13 years after onset of hepatitis C, and that all continued to be anti-HCV positive by second-generation ELISA.     

Clinico-pathological study of acute non-A,non-B post-transfusion hepatitis: histological features of liver biopsies in acute phase

ABSTRACT— A follow-up study of acute non-A, non-B post-transfusion hepatitis with a mean follow-up period of 30 months was carried out in 24 patients in whom liver biopsy was done within 3 months of onset. Of the 24, 13 patients (54%) developed chronic biochemical liver disease with elevated serum aminotransferases for more than 6 months, and in 11 the elevated liver enzymes were normalized within 6 months. Although there were no statistically significant differences in the mean peak values of liver enzymes, length of incubation period and number of transfusions between the chronic and resolved groups, the former tended to have a slow rise and multiple peaks of serum liver enzymes. Analysis of the liver biopsies made in the acute phase revealed that limiting plate erosion, hepatocellular degeneration, and poor regenerative activities were indicative of subsequent transition to chronicity. Multiple biopsies were taken in five patients who were followed for an average of 29 months, and the subsequent histological diagnosis was chronic persistent hepatitis in two, chronic active hepatitis in two and cirrhosis in one.     

Lack of evidence for hepatitis B virus (HBV) infection in fulminant non-A,non-B hepatitis

We studied eight patients who had orthotopic liver transplantation for fulminant hepatic failure in the course of acute non-A, non-B hepatitis. HBV DNA was searched for extensively in the liver tissue by PCR using several sets of primers in conventional and heminested reactions. All patients were negative for HBV DNA in liver tissue by all assays employed; furthermore, they were negative for HEV RNA, HCV RNA, and HBV DNA in serum. Although the causative role of HEV and HCV in fulminant non-A, non-B hepatitis cannot be excluded, our data do not support a causative association between this syndrome and HBV infection.This study was supported by Grant CR20 from the Mayo Clinic and Foundation. D.H.P. is supported by Public Health Service grants AI 32403, AR 41497, and AI 30548 from the National Institutes of Health.     

Light microscopic morphology of acute hepatitis non-A,non-B. A comparison with hepatitis type A and B

ABSTRACT— Liver biopsies from a total of 240 patients with acute hepatitis A (86 patients), B (78 patients) and non-A, non-B (76 patients) were blindly evaluated for quantitative and qualitative light microscopic differences. No qualitative differences separate the three types of hepatitis, but the frequency and degree of some histological features seem to be characteristic of acute human non-A, non-B hepatitis. The degree of focal necrosis and portal inflammation was less pronounced in the non-A, non-B group as compared to the hepatitis A and B groups (P<0.01). Twenty-six percent of the non-A, non-B liver biopsies showed steatosis as compared with 10% and 6% in the hepatitis A and B groups, respectively (P<0.01). Bridging necrosis only occurred in liver biopsies from patients with non-A, non-B and B hepatitis. Abnormal bile ducts were detected in a total of five patients, three of whom were found in the non-A, non-B group. A comparison between histological findings in non-A, non-B patients with and without a possible intravenous exposure revealed that steatosis, cholestasis, large piecemeal necrosis and confluent necrosis occurred with the highest incidence in the patients without intravenous exposure, indicating that non-A, non-B hepatitis may be caused by more than one etiological agent.