Biomedical subjects
Publications and source records attributed to M Hadchouel.
Three children with Kawasaki disease had liver biopsies because of evidence of hepatic disease. Cholangitis or bile duct injury and proliferation were found. Similar damage to the hepatic ductular system may explain the hydrops of the gallbladder sometimes seen in this disease.
Previous reports have demonstrated that tumor necrosis factor alpha (TNF-alpha) plays an important role in the pathogenesis of fulminant hepatic necrosis. The purpose of this experimental study was to measure TNF-alpha blood activity in paracetamol-induced liver necrosis and in coronavirus (MHV3)-induced fulminant hepatitis in mice. No elevation of TNF-alpha activity was found in hepatic failure complicating paracetamol poisoning. In contrast, TNF-alpha activity significantly increased in response to MHV3, reaching 16.3 +/- 5.5 U/ml from 24 h post infection (P less than 0.01). This augmentation was observed even though the virus was not detectable in the liver. Serum alanine aminotransferase levels were low and no histological lesion was observed. In conclusion, our study further supports the implication of TNF-alpha in virus-induced hepatitis failure and confirms that paracetamol poisoning does not cause increased TNF-alpha activity in the circulation.
We report a cytogenetic and molecular study of a series of patients with Alagille syndrome. All 14 patients were studied with high resolution banding techniques and eight of them were also analysed with non-radioactive in situ hybridisation of the cosmid probe D20S6. Seven of these eight patients were also studied for allelic losses at the D20S6 locus. No microdeletion of chromosome 20 was found in this series.
Paucity of interlobular bile ducts (PIBD) is defined as the reduction in the number of interlobular bile ducts. Paucity could be defined using the ratio of the number of portal tracts devoid of bile duct to the total number of portal tracts. At least 10 complete portal areas must be examined. In the past, only wedge biopsies could provide such samples, but now it can be achieved with needle biopsy. Usually, two types of PIBD, syndromatic and nonsyndromatic, are considered. In the syndromatic type, paucity is a major feature of the disease. In the nonsyndromatic type, paucity is only a part of the disease, as in peroxisomal disorders or alpha 1-antitrypsine (A1AT) deficiency, and is an inconstant finding. Opacification of the intrahepatic bile ducts in infants with nonsyndromatic paucity with no associated disorder demonstrates sclerosing cholangitis in at least half of patients in whom the diagnosis of "idiopathic paucity" would have been made a few years ago. The remaining patients must be considered as waiting for the identification of new disorders associated with paucity.
Bacterial cholangitis is a frequent complication of successful surgical repair of biliary atresia, occurring in 93% of patients before the age of 1 year, but thought to be rare after 2 years of age. Among 76 children free of jaundice more than 5 years after operation, four presented with late cholangitis (7 to 13.5 years old), consisting of fever, jaundice, and abdominal pain with biochemical features of an inflammatory process and cholestasis. Liver biopsy specimens consistently demonstrated histological features of cholangitis, growth of microorganism, or both. Cholangitis subsided spontaneously in one patient or in response to intravenous administration of antibiotics. Cholangiography consistently demonstrated biliary abnormalities but no definite obstruction to the bilioenteric anastomosis. All the children had good hepatic function 3 weeks to 4 years after the episode of cholangitis. These results suggest that cholangitis may occur several years after surgery but does not seem to alter prognosis.
The clinical usefulness of serum gamma-glutamyl transpeptidase (gamma GT) assay for the diagnosis of liver disease in children was assessed retrospectively in 398 children investigated from 1981 to 1986, in whom diagnosis was ascertained according to currently accepted criteria including liver histology in each case. Serum gamma GT activity was within normal limits in 10 controls, in 19 children with portal vein obstruction, and in 10 of 12 children with congenital hepatic fibrosis. Serum gamma GT was raised in all children with biliary atresia, sclerosing cholangitis, paucity of interlobular bile ducts, and alpha 1-antitrypsin deficiency with jaundice. Serum gamma GT was normal in spite of patent clinical signs of cholestasis in 3 patients with benign recurrent intrahepatic cholestasis, 1 infant with post-hemolytic neonatal cholestasis, and in 22 of 28 patients with progressive idiopathic cholestasis akin to Byler disease. In the latter group, children with raised serum gamma GT displayed extensive portal fibrosis and bile duct proliferation on liver histology, while this was not a prominent feature in children with normal serum gamma GT. These results indicate (a) the value and limits of the assay for serum gamma GT activity in children with liver disease, (b) that raised serum gamma GT may be considered a fairly reliable index of bile duct damage, and (c) that serum gamma GT may prove a useful tool in separating two forms of progressive idiopathic cholestasis, with or without bile duct involvement.
In children with acute hepatitis the main concern is to identify the cause since prognosis and therefore management largely depend on the specific causative agent. Since HAV is the most frequent in children, it should be investigated first. If there are no IGM anti-HAV antibodies, hepatitis B should be investigated. The value of anti-HCV antibodies, during acute hepatitis is not clear. Whatever the virus, severe evolution may occur, and symptoms of poor significance must be detected early. There is no risk of chronic evolution for hepatitis A. Follow-up studies of patients with hepatitis B should be performed to ensure clearance of HBSAg or to recognize the development of a chronic carrier state. Preventive measures include a search for a chronic carrier in the family and vaccination of the negative sibling or parents. In infancy, the diagnosis of "neonatal hepatitis" must be asserted by the presence of serological markers of viral infection. In the absence of such markers, other causes of cholestasis in infancy must be investigated. Perinatal transmission of hepatitis B virus should be now prevented by screening for women from high-risk groups and administration of immunoglobulins and vaccine to the neonates.
To define long-term prognosis of children who underwent surgery for biliary atresia, a retrospective study was undertaken in 122 children who underwent one of the Kasaï procedures between 1968 and 1977. Forty of the 122 children (32.7%) were alive after 10 years. Firm hepatomegaly was present in 31 and splenomegaly in 29 children. Serum bilirubin or all liver function tests were normal in 21 and 11 children, respectively; survival rate decreased with the age at operation, but no significant difference was observed in the rate of children surviving with normal serum bilirubin whether they underwent surgery before age 2 months or between 2 and 3 months. Twenty-four had esophageal varices and 15 experienced gastrointestinal bleeding. Normal liver-function tests and absence of portal hypertension were observed in 11 of 122 children. These results indicate that Kasaï's procedures were helpful in a significant proportion of children with biliary atresia who underwent surgery during this period. However, 80% of children who initially underwent surgery with Kasaï's procedures should eventually undergo liver transplantation.
To determine the incidence of liver cirrhosis in children with chronic hepatitis, we investigated 92 children (64 were girls; mean age was 8 years 2 months) with chronic hepatitis for the presence of cirrhosis by the combined use of laparoscopy and needle liver biopsy, between 1975 and 1985. Forty-six children had hepatitis B virus-related chronic hepatitis; cirrhosis was present in 13 (32%). Cirrhosis was diagnosed by laparoscopy in 14 children and by needle liver biopsy in eight. In six patients, cirrhosis was diagnosed within the first 12 months after the clinical onset of liver disease. Forty-six children had autoimmune hepatitis; cirrhosis was present in 41 (89%). Cirrhosis was diagnosed by laparoscopy in all 41 children and by needle liver biopsy in 23 children. Cirrhosis was already present in all 10 children studied 2 to 5 months after the first sign of liver disease. Our results indicate that the incidence of cirrhosis is high in children with chronic hepatitis, especially of the autoimmune type, and that cirrhosis may occur early, irrespective of cause. A combination of laparoscopy and biopsy is more reliable than biopsy alone for the diagnosis of cirrhosis in children with chronic hepatitis.
An autosomal dominant transmission of arteriohepatic dysplasia, or Alagille syndrome, with reduced penetrance and variable expressivity has been suggested from familial pedigrees, but the nature of the genetic defect and its chromosomal localization are not firmly established. We report the case of an 8-year-old boy with arteriohepatic dysplasia, in whom high-resolution chromosome study showed a partial deletion of the short arm of chromosome 20, which encompasses subbands p11.23 to p12.3. In situ hybridization and Southern blotting localized four restriction fragment length polymorphism probes within the deletion and another one distal to the deletion. Because one patient has already been reported to have arteriohepatic dysplasia and deletion of the short arm of chromosome 20, and six additional patients with such a deletion had major features of Alagille syndrome, this syndrome should now be assigned to chromosome 20p.
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We used an in situ hybridization technique using single-stranded RNA probes to study the expression pattern of gamma-glutamyl transpeptidase (GGT) in rat liver and kidney during development. The results were compared to those obtained with an immunoperoxidase technique and with Northern blot analysis of GGT mRNA. In the kidney, northern blot revealed a 20-fold increase of GGT mRNA between day 18 of gestation and adulthood. Protein and mRNA localization clearly identified the proximal tubules as the site of synthesis of GGT. In the liver, the expression was lower than in the kidney and Northern blot showed a dramatic decrease of expression after birth. Using immunohistochemistry, the protein was detected within parenchymal cells in embryo and hepatocyte membranes and bile ducts in adults. Using in situ hybridization, GGT mRNA was only detected on days 1 and 2 after birth and exclusively in hepatocytes. Immunoperoxidase may be more sensitive than in situ hybridization to study the expression of minor liver protein such as GGT. However, the study of GGT expression using in situ hybridization is possible in cases of increased expression such as alcoholism, cholestasis, and carcinogenesis.
We have previously described a rearrangement of the proto-oncogene c-myc with a new cellular sequence of unknown function in a woodchuck primary liver tumor. We have now cloned and further analysed the normal woodchuck locus (termed hcr) of the sequence involved in the rearrangement with c-myc. The hcr locus is highly expressed in hepatocytes but not in other cell types examined and is conserved in mammals. Two unspliced hcr transcripts 4.5 and 4.7 kb long accumulate in liver cell nuclei. These transcripts differ only in their 3' extremities, located 180 bases apart, and by additional poly(A) tailing of the longer RNA species. The genomic sequence flanking the transcription start site contains variant elements of a classical eukaryotic promoter. Nucleotide sequence analysis of cDNA clones for the hcr RNA reveals that the 5' end of the hcr transcripts contains a short open reading frame of only 3 gamma codons initiated by an ATG. The biological function of her RNA remains to be determined.
In situ hybridisation was used to detect RNA of Hepatitis B virus (HBV) in peripheral mononuclear blood cells. Presence of HBV-RNA was detected in 10/17 HBsAg positive HBeAg positive patients, in 8/18 HBsAg positive HBeAg negative patients, in 1/3 anti-HBs positive subjects. Four control subjects were negative. The frequency of labelled cells varied from 1 to 10% of mononuclear cells. These results indicate that the DNA detected so far in mononuclear blood cells may be transcriptionally active.
Clinical, radiologic, and histologic features in 22 children with Budd-Chiari syndrome are reported. Three children had acute refractory ascites; all the others had hepatomegaly, which was detected either fortuitously or because of abdominal pain or distention. Results of liver function tests were normal or only moderately abnormal. In most cases a combination of ultrasonography and needle liver biopsy pointed to the diagnosis of Budd-Chiari syndrome, which was confirmed by angiography. Eighteen children underwent surgery involving various techniques, depending on the degree of patency of the inferior vena cava. Five children died postoperatively. Histologic studies of the liver, carried out in 12 of the surviving children, showed disappearance or regression of centrilobular hemorrhagic infiltration. Half of the surviving surgical patients are now free of complications after a follow-up of 7 months to 7 years; the others have either secondary thrombosis of the inferior vena cava or stenosis of the shunt or have experienced late pulmonary complications. Our results suggest that (1) Budd-Chiari syndrome must be considered a possible diagnosis in children with firm hepatomegaly and normal or near normal liver function, (2) surgery provides good results in many instances, and (3) the possibility of late complications requires careful follow-up.
Ichthyosis and neutral lipid storage disease (INLSD) is a nonlysosomal, multisystemic, triglyceride storage disorder. It is characterized by nonbullous congenital ichthyosiform erythroderma (NBCIE), leukocyte vacuoles, and variable involvement of the liver, muscles, eyes, and central nervous system. In our patient fat-containing vacuoles were also demonstrated in the epidermis. In patients with NBCIE, the diagnosis of INLSD is readily made by direct examination of a peripheral blood smear demonstrating cytoplasmic lipid vacuoles within most granulocytes and monocytes.
We have sought to address the problem of the host and tissue specificity of the hepatitis B virus (HBV) by using transgenic mice obtained after injection of head-to-tail dimers of the HBV genome. Viral DNA replication and protein synthesis were obtained in one of nine transgenic mice containing integrated HBV DNA. The RNAs encoding the HBV surface antigen and the core antigen were synthesized in the liver, the kidney, and the heart. In these organs, DNA replicative intermediates similar to those found during normal infection were associated with corelike structures. Large amounts of core polypeptides and capsids were detected in the nuclei in the absence of any pathological effect. These results show that the different steps of HBV multiplication can take place in nonliver nonhuman cells once the problem of entry into the host cell is overcome. In the absence of a small laboratory animal infectable by HBV, such transgenic mice should be helpful for the study of many aspects of viral multiplication.
Hepatitis B virus (HBV) DNA integration has been shown to occur frequently in human hepatocellular carcinomas. We have investigated whether common cellular DNA domains might be rearranged, possibly by HBV integration, in human primary liver tumors. Unique cellular DNA sequences adjacent to an HBV integration site were isolated from a patient with hepatitis B surface antigen-positive hepatocellular carcinoma. These probes detected rearrangement of this cellular region of chromosomal DNA in 3 of 50 additional primary liver tumors studied. Of these three tumor samples, two contained HBV DNA, without an apparent link between the viral DNA and the rearranged allele; HBV DNA sequences were not detected in the third tumor sample. By use of a panel of somatic cell hybrids, these unique cellular DNA sequences were shown to be located on chromosome 4. Therefore, this region of chromosomal DNA might be implicated in the formation of different tumors at one step of liver cell transformation, possibly related to HBV integration.