Fulminant hepatic failure in children and adolescents in Northern Brazil

The histological findings of fulminant hepatic failure were correlated to the demographic, clinical, biochemical and virological features in children and adolescents, native to the Amazonas State in Northern Brazil. 96.2% had evidence of infection by primary hepatotrophic viruses. Histological analysis revealed three distinct patterns of fulminant hepatic failure. Key-words: Hepatitis. Fulminant hepatic failure. Epidemiology. Pathology. Brazil.

Several studies have characterized the Brazilian Amazon basin as a high endemic area for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) infection 12 13 16 , and Yellow fever virus 3 .In this region, an unusual type of fulminant hepatic failure, known as Labrea Fulminant Hepatitis, has been documented in the Brazilian territory of the Amazon Basin 4 9 14 17 18 .First described over 50 years ago 8 , this disease is characterized by severe hepatitis, coursing within days to hepatic failure and death 4 9 17 18 23 .Children, adolescents and young adults are mainly affected 4 14 18 23 .
The availability of histophatological liver specimens from cases of Labrea Fulminant Hepatitis, showing a specific picture of microvesicular steatosis (morula-like cells) and eosinophilic necrosis, has been pointed out by Brazilian authors 9 11 .This pattern is different from those of massive and sub-massive necrosis found in ordinary fulminant viral hepatitis 9 11 .Similar clinical and histological features of Labrea Fulminant Hepatitis have been found in the Northern and Eastern regions of Brazil 1 22 , as well as Northern Colombia 5 , Western Venezuela 19 , Peru 6 and Central African Republics 21 .One case of non-fatal acute HDV with microvesicular steatosis in a young woman has been reported in the United States 20 .Studies in the Amazonas State (northern Brazil) have demonstrated that 63.6% of patients with Labrea Fulminant Hepatitis presented evidence of infection by HAV, HBV, HCV and HDV, either in isolation or simultaneously 14 .
The purpose of the present retrospective study was to correlate the histological findings of fulminant hepatic failure with the demographical, clinical, biochemical and virological features in children and adolescents, native to the Amazonas State.
We reviewed 23 patients admitted to our hospital between January 1984 and March 2002.A 10-mL blood sample was collected from all patients at admission, then centrifuged, aliquoted, and stored at -70°C.Sera from these patients (13 males, 10 females; aged 3 -18 years; mean 12.5 years), with post-mortem histopathological diagnosis of fulminant hepatic failure were screened for the presence of: HAV (anti-HAV HBV (HBsAg, anti-HBc IgM); HDV (HDAg, total anti-HD IgG, anti-HD IgM) with standardized ELISA assay (Hepanonostika, Organon Teknika R , B.V. Holland; and Diasorin R , Saluggia, Italy).The HBV-DNA, HCV-RNA, HDV-RNA, HEV-RNA and HGV-RNA were tested with an in-house nested polymerase chain reaction (PCR).The HCV-RNA was also investigated in sections of liver by PCR, from 4µm-thick microtome shavings of blocks of the paraffin-embedded tissues using a modification of the technique described elsewhere 24 .Antibodies to yellow fever (MAC-ELISA IgM) were investigated in serum from patients with histological diagnosis suggestive of yellow fever.Autopsy samples of liver tissue were obtained from 23 patients who died with a clinical and laboratorial picture of fulminant hepatic failure.Tissue samples were fixed in formalin, routinely processed in Auto-Technicon (Technicon Co, USA) and embedded in paraffin blocks; 4µm-thick sections were submitted to impregnation of the reticulin frame work by silver and stained by Hematoxylin and Eosin.Liver function tests, including alanine aminotransferase (ALT), were performed using automated routine laboratory procedures.The study was approved and authorized by the local Ethics Committee.
According to the histopathological aspects of the liver, the patients (see Table 1 for characteristics of patients at baseline by liver histology) were classified into three groups.
Our study demonstrates that 95.6% of children and adolescents with fulminant hepatic failure presented evidence of infection by primary hepatotropic viruses.These results are similar to those observed among children and adolescents in India (72.5%) 2 .On the other hand, our results differ from the findings among children and adolescents of developing countries where the prevalence of fulminant hepatic failure caused by primary hepatotropic viruses is very low (15%) 10 .Infection by HBV, either alone or associated with HDV or HAV, is the major pathogenic determinant in fulminant hepatic failure.In our series only one patient (4.3%) had an inconclusive diagnosis.
A high percentage was observed of coinfection or superinfection by primary hepatotropic viruses (HAV, HBV, HCV, HDV) in our patients (65%).This observation has been documented in endemic areas for HAV, HEV, HBV, HDV infection 2 11 15 16 , and the associated infection possibly explains the clinical severity and biochemical abnormalities found in fulminant hepatic failure.In our casuistic, the probable acute C hepatitis (HCV genome present in the liver tissue) can lead to fulminant hepatic failure in chronic HBV carriers (HBeAg and HBV-DNA negative in the serum).These results confirm previous findings that acute HCV superinfection can cause severe liver injury in chronic carriers of hepatitis B virus 7 .
Three distinct histological patterns of fulminant form of hepatitis were observed in children and adolescents of Amazonas State, of these, two were linked to primary hepatotropic virus, regardless of its etiology, and the other related to classic Yellow fever.These data differ from data described in the literature, with a classical histopathological pattern of fulminant hepatic failure by hepatotropic viruses: the classic picture of massive or submassive necrosis without evidence of morula-like cells 2 10 .
The demographic, clinical, biochemical and virological findings from children and adolescents with microvesicular steatosis (morula-like cells) are not different from those of massive or submassive hepatic necrosis.The microvesicular steatosis (morulalike cells) were found mostly in HDV acute superinfection, as well as in HAV/HBV acute coinfection and probably HCV acute superinfection in chronic HBV carriers.Extensive studies, including sequencing of HBV and HDV (viral genotype), are necessary to better understand whether differences in viral mutations could be responsible for severe hepatitis in Northern Brazil.Studies in Peru, found that HBV genotype F and HDV genotype III may be associated with severe cases of acute hepatitis 6 .Based on our results, we conclude that hepatotropic viruses and arboviruses in endemic areas are associated with a substantial risk of fulminant hepatic failure in children and adolescents.Finally, the high prevalence of associated infection may contribute to severe forms of fulminant hepatic failure in children and adolescents in Northern Brazil.