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To determine the clinical, biochemical, and histological features, and outcome of childhood autoimmune hepatitis (AIH), we reviewed the medical records of 52 children with AIH, 32 (median age: 10 [2-15] years) anti-nuclear and/or smooth muscle antibody (ANA/SMA) positive, 20 (7 [0.8-14] years) liver/kidney microsomal antibody (LKM-1) positive, with median follow-up of 5 years (range 0.3-19). At presentation: 56% had symptoms of prolonged acute hepatitis; LKM-1 positive were younger (P = .011), with higher bilirubin (P = .007), and AST (P = .047); ANA/SMA positive had lower albumin (P = .023); 69% ANA/SMA positive, and 38% LKM-1 positive were cirrhotic (P = .080). ANA/SMA positive had increased frequency of HLA haplotype A1/B8/DR3/DR52a compared with controls (53% vs. 14%, P < .001). Of six (5 LKM-1 positive) with fulminant hepatitis, four were transplanted, one died, and one ANA/SMA positive improved with immunosuppression. Of 47 treated with immunosuppression, 2 (1 LKM-1 positive) died with no remission and 4 (2 LKM-1 positive) were transplanted 8 to 14 years after diagnosis. Immunosuppression was stopped successfully in 19% of ANA/SMA positive after a median of 3 years of treatment, but in none of LKM-1 positive. Baseline bilirubin and international normalized prothrombin ratio (INR) were independent variables predictive of outcome. In conclusion, ANA/SMA positive and LKM-1 positive AIH in childhood have clinical, biochemical, and histological differences, but similar severity and long-term outcome.

Specific and sensitive diagnostic tests are now available to identify type A, B, C, D and E hepatitis. Hepatitis A and E which cause only acute, very rarely fulminant, hepatitis are spread largely by the faecal-oral route, having a brief viraemic phase. Hepatitis B, C and D which are transmitted parenterally and via secretions are often associated with chronic viraemia. Patients with chronic renal disease are at particular risk. Impaired immunity due to disease or drugs increases the propensity to develop a chronic carrier state which may progress to cirrhosis and hepatocellular carcinoma. Limited reports indicate that hepatitis C infection may cause cirrhosis more rapidly than hepatitis B. The emergence of mutants to both hepatitis B and C is a cause for concern. Treatment with interferon is of limited efficacy. Screening of blood products for viral markers and prudent handling of potentially infected materials to avoid contamination of damaged skin or mucous membrane are the best strategies to prevent infection. Hepatitis B vaccination of all newborns, young adolescents and those at risk is the most effective means of reducing the carrier frequency.

Susceptibility to autoimmune hepatitis in white patients is associated with the human leukocyte antigen class II antigens DR3 and DR4. To analyze the molecular basis of these associations, we used oligonucleotide probes to determine the DRB, DQA and DQB hypervariable nucleotide sequences in 119 patients with autoimmune hepatitis and 177 matched controls. DRB3*0101, which encodes DR52a, predisposed patients most strongly to the disease. It was present in 58% of patients and 25% of controls (corrected P < 0.000005), whereas DQA1*0101 and 0102 conferred protection in males only. The DR4 subtype, DRB1*0401, was raised in the DRB3*0101-negative patients; 81% possessed either DRB3*0101 or DRB1*0401, compared with 42% of controls (corrected P < 0.0000001). These alleles encode the amino acid sequence Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DR beta polypeptide, which was present in 94% of patients and 64% of controls (corrected P < 0.000001) and in all patients who tested positive for autoantibodies to the hepatic asialoglycoprotein receptor. The patients with DRB1*0401 had less severe disease, relapsed less frequently and were first seen significantly later in life than those patients with DRB3*0101; and whereas a single copy of DRB1*0401 predisposed to autoimmune hepatitis, DRB3*0101-associated susceptibility had a dose-related effect. These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.

Serum alpha-fetoprotein levels were measured using a sensitive radioimmunoassay in 77 infants presenting with persistent conjugated hyperbilirubinaemia. A breed range of alpha-fetoprotein concentrations occurred in both the 23 infants with extrahepatic biliary atresia and the 35 with idiopathic neonatal hepatitis but the 13 with alpha-1-antitrypsin deficiency had uniformly low levels. High alpha-fetoprotein concentrations (above 10 000 mug/1) favoured the diagnosis of neonatal hepatitis especially in the first ten weeks of life, but the overlap between neonatal hepatitis and extrahepatic biliary atresia was large and alpha-fetoprotein determination cannot be recommended as a reliable method for distinguishing the two conditions. Serial alpha-fetoprotein values showed no consistent relationship with standard liver function tests and gave no guide to prognosis. There was an association between alpha-fetoprotein production and needle biopsy evidence of hepatic giant cell transformation. The uniformly low alpha-fetoprotein levels in alpha-1-antitrypsin deficient infants with neonatal hepatitis is a new observation and possible mechanisms for disordered glycoprotein release are discussed.

The zonal distribution of enzyme activities was measured by quantitative cytochemistry in cryosections of liver from three normal children and five infants with idiopathic hepatitis of infancy. Optimal conditions for cytochemical reactions were first validated in rat liver and subsequently used in human livers to quantify zonal activities of acid phosphatase (AP), succinate dehydrogenase (SDH), glutamate dehydrogenase (GDH), glucose-6-phosphatase (G6P) and NADPH-dehydrogenase (ND). In normal rat and human livers, activities were greater for SDH and G6P in periportal and for GDH and ND in perivenular hepatocytes, while AP was evenly distributed along the sinusoids. In five infants with idiopathic hepatitis of infancy (IHI), a similar trend of distribution was observed for the two mitochondrial (SDH and GDH) and the two microsomal (G6P and ND) enzymes, although the distribution gradient was less pronounced than, in normal livers. AP showed a mildly greater periportal than perivenular activity. This preliminary study shows that a similar metabolic zonation exists for these enzymes in human livers as is observed in rats.

To evaluate the role of serum procollagen III peptide as a non-invasive marker of liver damage and prognosis in hepatobiliary disorders of infancy, we have measured its concentration at presentation and serially in 30 infants with extrahepatic biliary atresia, 22 with idiopathic hepatitis of infancy, 10 with alpha 1 antitrypsin deficiency and 105 age-matched controls. Raised procollagen III peptide concentrations occurred in 51% of patients at presentation and 59% at follow up but were not related to the type of liver disease or the severity of liver damage, as assessed either by standard biochemical tests of liver function, serum glycocholic acid, semiquantitative assessment of 11 histopathological features or hepatic prolyl hydroxylase activity. Serum procollagen III peptide concentrations also gave no guide to prognosis. Although the factors determining serum procollagen III peptide concentrations in hepatobiliary disorders of infancy are unknown at the present time, we suggest that changes in growth rate may be of major importance in determining the significance of serum procollagen III peptide concentrations in infants and children.

Macroamylasaemia was found in a 12-year-old boy with persistent, severe abdominal pain and mild hepatitis. No abnormality of the pancreatic or bile ducts was demonstrated. Both the symptoms and the biochemical abnormality of macroamylasaemia settled spontaneously over 10 months. Transient, asymptomatic macroamylasaemia was found in the boy's father.

To provide an objective rapid means of excluding extrahepatic biliary atresia (atresia), a hepatic index was devised from the ratio of the net hepatic to cardiac distribution of 99mTc diisopropyl iminodiacetic acid or methylbrom iminodiacetic acid between 2.5 and 10 minutes after injection. The hepatic index was compared with subjective assessment of abdominal scintigraphy performed repeatedly over 24 hours. In 22 infants with hepatitis the hepatic index ranged from 5.03 to 14.9, one having no excretion on scintiscan. In 26 infants with atresia the index ranged from 0.49 to 4.26 and in two with paucity of intralobular bile ducts it was 1.85 and 3.69. None of these infants had excretion apparent on scintiscans. Similarly, low hepatic indices occurred in four infants with liver dysfunction but pigmented stools, three of whom had no excretion apparent on scintiscans. These preliminary studies suggest that a hepatic index of greater than 5 is much more rapid and as specific in excluding atresia as repeated abdominal scintigraphy.

Fifty four infants with hepatobiliary disease and conjugated hyperbilirubinaemia of more than two weeks' duration were identified in a defined area of south east England in a prospective study between January 1971 and December 1973. The overall incidence was one case per 2500 live births. The cases were regularly reviewed and all survivors except one were assessed at age 10 years. Nine of 11 with extrahepatic biliary atresia died from liver disease by 2 years of age, one died at 5 years, and the survivor has cirrhosis with portal hypertension. Four out of seven with alpha 1 antitrypsin deficiency died aged 1 to 3 years from liver disease and one of the survivors has cirrhosis. All three infants with intrauterine infection and one with chromosomal abnormality died in infancy. Three children with other associated factors, choledochal cyst, galactosaemia, and rhesus isoimmunisation, recovered completely with no persisting liver disease. Two of 29 with cryptogenic hepatitis died, but only a further two have signs of persisting liver disease. Perinatal complications were more common in this group. Four of the 27 children surviving to the age of 10 years are educationally subnormal. Prognosis for infants with intrahepatic liver disease in the absence of known associated factors is good and every effort should be made to minimise the short term effects of cholestasis.

Five out of 28 infants investigated in a regional survey of neonatal hepatitis were found to have genetically-determined deficiency of alpha(1)-antitrypsin (ZZ phenotype). The clinical course and pathological changes varied considerably. All five infants had an acute hepatitis-like illness, and although this subsided cirrhosis later developed in three cases. The remaining two infants had minimal abnormalities of the liver function tests at 12 and 18 months of age, and one had increased hepatic fibrosis. Australia antigen was found in the serum of three infants, and Australia antigen or antibody in one or both parents of these and of one further case whose serum was negative. It is suggested that the association of neonatal hepatitis with alpha(1)-antitrypsin deficiency may be commoner than previously realized and that Australia antigen acts as a trigger factor in these cases.

Chronic hepatitis implies that clinical and biochemical features of hepatitis have been present for at least 6 months; but irreversible liver damage may occur with subclinical disease suggesting that pathological features should also define chronicity. We examined 28 children with hepatitis B negative chronic active hepatitis to determine whether the severity of abnormal biochemical tests of liver function, raised serum immunoglobulin concentrations, and positive serum autoantibodies, which are characteristic features in immunosuppressant responsive disease, varied with the duration of symptoms. The pattern of abnormality in these patients was similar whether the disease had been present for less than three months, from three to 6 months, or for more than 6 months, and apart from lack of hyperbilirubinaemia was similar in patients presenting with complications of cirrhosis without previous symptoms of liver disease. Two children died of liver disease. The remainder showed a clinical, biochemical, and immunological response to prednisolone or azathioprine, or both. These drugs have now been withdrawn in 8 patients without relapse, and disease activity is completely suppressed in 13. Unfortunately, 15 survivors have definite cirrhosis and a further five have possible cirrhosis. Eight of 10 survivors with symptoms of more than 6 months duration before treatment have cirrhosis compared with two of 12 with symptoms of less than 6 months. It is suggested that consideration of this diagnosis at onset of symptoms and immediate immunosuppressant treatment after appropriate confirmatory investigations may reduce the incidence of cirrhosis in hepatitis B negative chronic active hepatitis in children. [ABSTRACT FROM AUTHOR]

Anti-lymphocytic antibodies (ALA) have been described in a variety of autoimmune disorders. We have investigated the presence of ALA in autoimmune chronic active hepatitis (aCAH) starting in childhood. Using a modified Terasaki technique ALA were found in 17 of 18 patients with aCAH but in only one of 15 patients with alpha-1-anti-trypsin deficiency or Wilson's disease and three of 27 aged-matched healthy controls (P < 0.0005 for both). Sera from 12 patients with uncontrolled aCAH had significantly higher cytotoxicity values than sera from six children with inactive disease (P < 0.01). ALA were directed to T but not B lymphocytes and were not reactive with specific HLA antigens. No preferential killing was observed against CD4 or CD8 positive T lymphocytes. Characterization of ALA revealed them to be cold-reactive IgM. The possible role of ALA in aCAH is discussed. [ABSTRACT FROM AUTHOR]

An indirect immunofluorescence technique was used to investigate the immunoglobulin class, IgG subclass, light chain type and complement fixing ability of anti-liver kidney microsomal antibody (anti-LKM) in the sera of six children and five adults with autoimmune chronic active hepatitis (aCAH), Anti-LKM titres ranged from 1/80 to 20,480. In the children, the antibody belonged to the IgG1 subclass alone (titre l/80-1/20,480) and was able to fix complement (titre 1/40 -1/5120). In the adult group, antibody belonged to the IgG1 subclass in three cases (titre 1 40-1 640 whilst two belonged to both IgG1 (titre 1/640) and lgG4 (titre 1/40, 1/640). Such subclass restriction is similar to that found in other autoimmune disorders and may be genetically determined. Investigation of' the light chain constituent of anti-LKM revealed that the kappa to lambda ratio was consistent with a polyclonal antibody response. To investigate the nature of the antigen to which anti-LKM is directed, the ability of these sera to bind to the surface membrane of isolated human hepatoma cells (Alexander cells) was investigated. Four of the eleven sera showed significant binding activity. Prior incubation of these four sera with Alexander cells abolished their membrane binding activity, but did not alter the anti-LKM titre. These results suggest that anti-LKM binds to cytoplasmic constituents alone and does not cross-react with surface antigens. [ABSTRACT FROM AUTHOR]

To investigate the function of activated T lymphocytes in autoimmune chronic active hepatitis, 7 of 15 T-cell clones from the peripheral blood of 8 patients were studied. These clones showed specificity for liver-membrane antigen with proliferation when stimulated by rabbit liver cell membranes. 6 of these clones reacted with liver-specific lipoprotein complex, and 1 clone (and 3 subclones) responded to the asialoglycoprotein receptor (ASGPR), both known targets of immune attack in autoimmune chronic active hepatitis. 2 of these clones stimulated autologous B lymphocytes to produce liver-membrane-specific autoantibodies and antibody to the ASGPR. These results suggest that liver-membrane-specific activated T lymphocytes in peripheral blood may be important in the autoimmune attack of chronic active hepatitis. [ABSTRACT FROM AUTHOR]