Outcome of liver disease associated with alpha 1 antitrypsin deficiency (PiZ). Implications for genetic counselling and antenatal diagnosis.

We reviewed the hepatic features in 136 children with alpha 1 antitrypsin deficiency (PiZ). Eighty two were studied prospectively, 74 of whom had chronic liver disease. Sixty seven children with liver disease presented in the first four months of life, four were older infants and children with chronic liver disease, 10 (three with liver disease) were identified in studies of the family of these propositi, and one was identified when she had liver disease associated with infectious mononucleosis. By 17 years of age 20 of these 74 children with chronic liver disease had died, 20 had established cirrhosis, 19 had persisting liver disease, and only 15 had made a complete, clinical and biochemical recovery. The outcome of liver disease was similar in a further 39 previously unreported PiZ infants and children with liver disease who were not prospectively studied. Because liver disease affects only a proportion of infants with PiZ phenotype and because the severity of their liver disease is so variable, we have analysed the outcome of liver disease in 27 observed families and in 20 previously reported families with more than one child with PiZ. In 34 families the outcome of liver disease was similar in the two children. From an analysis of the families with a severely affected child, we conclude that if the first PiZ child of PiZ heterozygote parents has unresolved liver disease, there is a 78% chance that a second PiZ child will have similar liver disease. After careful counselling, fetoscopy, fetal blood sampling, and protease inhibitor phenotyping, possible termination of pregnancy should be carefully considered in these families.

Immune responses in patients with obstructive jaundice of infancy. Anti-LSP and Clq binding in sera.

To investigate possible involvement of immune responses in the pathogenesis of obstructive jaundice in infancy we measured antibody to liver specific lipoprotein (LSP) by radio immunoassay and immune complexes by their ability to bind C1q in sera from 16 patients with extrahepatic biliary atresia and 16 with neonatal hepatitis and 13 age matched controls. Anti-LSP was present in 6 of 16 with preoperative biliary atresia and 6 of 16 with hepatitis. Mean percentage C1q bound was higher in hepatitis (22 SD 15%) than preoperative biliary atresia (11.1 SD 2.3%). Nine of 16 hepatitis patients had elevated C1q binding as compared with 1 of 16 with biliary atresia. The highest value for anti-LSP and C1q binding were found in sera from patients with histologically severe hepatitis and hepatitis associated with specific viral or bacterial causes. Anti-LSP was significantly raised 5 months post-operatively in all of 6 patients with biliary atresia and poor biliary drainage but only 2 of 5 survivors. Elevated C1q binding was detected in 6 of 7 with poor drainage and 1 of 7 survivors at the same stage. Anti-LSP and C1q binding fell in 4 patients with neonatal hepatitis on recovery. These findings suggest that immunological mechanisms, possibly involving antibody to hepatocyte membrane components and immune complexes, may be involved in the pathogenesis of progressive liver disease in biliary atresia.

Radioimmunoassay of serum glycocholic acid, standard laboratory tests of liver function and liver biopsy findings: comparative study of children with liver disease.

Serum glycocholic acid (SGC) was measured by radioimmunoassay in 277 samples from 122 children with hepatobiliary disorders and from 23 healthy age-matched controls. In patients with hepatobiliary disease the SGC was more frequently abnormal (83%) than values for serum albumin (7%), prothrombin time (17%), bilirubin (22%), alkaline phosphatase (45%), aspartate transaminase (57%) and gammaglutamyl transpeptidase (63%). The cumulative frequency of abnormality of these six tests was equal to that of SGC alone. Serum glycocholic acid concentrations were raised in 13 patients in whom all other tests of liver function were normal. Two of these had clinical and histological evidence of liver disease, while four had biopsy-proven hepatic fibrosis or cirrhosis, and two of three with chronic active hepatitis in remission subsequently relapsed. Four patients have as yet, no other clinical or biochemical evidence of continuing liver disease. Serum glycocholic acid was normal in seven children with abnormal aspartate transaminase or gammaglutamyl transpeptidase in whom there is strong suspicion of significant hepatic disease. A wide range of values of SGC was found with marked overlap between the values found in the different disease entities studied. The SGC value was related to the serum concentration of aspartate transaminase and gammaglutamyl transpeptidase but not to other tests of liver function. Serum glycocholic acid concentration was considered in relation to the severity of histological abnormality in 25 percutaneous liver biopsies. The extent of the rise in SGC was related to the presence or degree of histological severity of oedema in the portal tracts, disruption of the limiting plate, parenchymal fibrosis and hepatocellular necrosis but not to other histological features. The very high incidence of abnormal SGC values found in this study does suggest that in an ordinary inpatient and outpatient service SGC determination is a practical and sensitive indicator of the presence of significant liver disease but for its comprehensive identification aspartate transaminase and gammaglutamyl transpeptidase must also be determined.

Injection sclerotherapy for oesophageal varices in children.

Oesophageal varices in 21 children with portal hypertension (intrahepatic 13, extrahepatic 8) were treated with sclerotherapy using ethanolamine oleate injected via a fibreoptic endoscope. Repeat endoscopy confirmed variceal obliteration in 18 children with a mean of 3.5 (range 1-8) injections. No patient has bled since obliteration of varices. Complications were oesophageal stricture (2 patients), oesophageal ulcer (5 patients) and haemorrhage within 3 days of injection (5 patients). The early results suggest that this is a satisfactory method for the treatment of oesophageal varices in children.

Hepatic complications of cystic fibrosis.

74 patients with cystic fibrosis aged 1-19 years were assessed prospectively for 1-7 years for evidence of liver involvement. 20 of these patients were referred primarily because of hepatic problems. 3 of 4 with neonatal hepatitis recovered. Chronic active hepatitis developed in a further child but resolved spontaneously. 6 patients had abnormal liver-function tests without clinical evidence of liver disease. In 18 cirrhosis was detected at age 4-13 years. Liver disease was stable in these except terminally in 3 with cor pulmonale. The principal hepatic problem was variceal bleeding, which occurred in 6 patients. 50% of bleeds followed aspirin ingestion. This drug therefore should be avoided in such patients. 13 had hypersplenism. 2 had severe splenic pain necessitating splenectomy with lienorenal shunt, which was performed also in 2 patients who had bled. 3 remain well up to 5 years later. In 3 patients seen in the past 3 years injection sclerotherapy has controlled bleeding. This technique was well tolerated without the pain associated with, or intensive physiotherapy necessary after, shunt surgery; and this may be the method of choice for controlling variceal bleeding in cystic fibrosis.

Extrahepatic biliary atresia: preoperative assessment and surgical results in 47 consecutive cases.

Of 47 consecutive infants with extrahepatic biliary atresia, effective bile drainage with the return of the serum bilirubin concentration to normal, was achieved in 17 (38%). Direct bile duct-to-bowl anastomosis, attempted in 15 infants, produced bile drainage in only those 4 (9%) in whom bile could be seen within the bile duct remnants at laparotomy. 13 (45%) of 29 infants subjected to portoenterostomy (direct liver-to-bowel anastomosis) had satisfactory prolonged bile drainage with normal serum bilirubin values. Although a correct preoperative diagnosis was made in each case, in 3 (6%) the 72-hour faecal rose bengal 131I excretion was greater than 10% of the injected dose, and in 5 (11%) the hepatic histology did not indicate bile duct obstruction, showing that both investigations are necessary for preoperative diagnosis. Preoperative clinical, laboratory, and hepatic histological features in the 16 jaundice-free survivors showed no significant difference when compared with the 31 infants in whom surgery was successful. Cholangitis occurred in only 7 (43%) of 16 infants with satisfactory bile drainage and was easily controlled with antibiotic treatment. No cutaneous enterostomies were performed. In most survivors liver function tests remain abnormal, but the patients are symptom-free. While it is too early to predict a long-term prognosis for these children, our eldest survivors are healthy and show normal development.

Immune responses to liver membrane antigens in patients with cystic fibrosis and liver disease.

Biliary obstruction by viscid mucus, although important, may not be the only factor for the development of liver disease in some patients with cystic fibrosis. In the present study the relationship between immune responses to liver antigens and the presence of liver damage was investigated using the leucocyte migration test and lymphocyte cytotoxicity to isolated rabbit hepatocytes. Inhibition of leucocyte migration by purified liver-specific lipoprotein, derived from hepatocyte plasma membrane, was found in 9 of 11 children with liver disease, but in only 5 of 14 with cystic fibrosis and no overt liver disease (P < 0.025). Lymphocyte toxicity to isolated rabbit hepatocytes was significantly increased in 10 of 13 children with liver disease, but in only 6 of 29 children without liver disease (P < 0.001). Experiments using lymphocyte subpopulations showed that the cytotoxicity was mediated by a non-T-cell population and could be blocked with liver-specific lipoprotein in 7 out of 10 cases, suggesting that the reaction in these patients was specifically directed against liver-specific lipoprotein. The study suggests that sensitisation against liver membrane antigens, whether arising primarily or secondarily in some way to other hepatic lesions, may contribute to the progression of liver damage in cystic fibrosis.

Extrahepatic biliary atresia versus neonatal hepatitis. Review of 137 prospectively investigated infants.

In a prospective regional survey of neonatal hepatitis syndrome 32 infants had extrahepatic biliary atresia (EHBA) and 103 had hepatitis. No cause for the lesion was found in infants with extrahepatic biliary atresia, but in 32 with hepatitis a specific cause was identified, 24 having genetic deficiency of the serum protein alpha1-antitrypsin. No differences were observed in parental age, mother's health in pregnancy, month of birth, birth order, or sex of the infants. Familial idiopathic hepatitis occurred in 3 of 67 sibs of patients with idiopathic hepatitis, but the 33 sibs of EHBA patients had no liver disease. Of the infants with hepatitis, 36 were of low birthweight, less than 2.5 kg, and 23 were born prematurely. Infants with biliary atresia were all of normal birthweight and only one was born prematurely. Consideration of clinical and biochemical abnormalities in the first 2 months of life showed no differences between the two groups except that infants with EHBA were more commonly jaundiced from birth (80%) and had more frequently acholic stools (83%). The frequency of these features in patients with hepatitis being 68% and 52%. Standard tests of liver function were not discriminatory. Percutaneous liver biopsies were diagnostic in 75% of those with EHBA and in 92% of those with hepatitis. The I131 Rose Bengal faecal excretion was less than 10% in 26 of 28 infants with EHBA and in only 5 of 18 with hepatitis. These latter two investigations together allowed a correct preoperativer diagnosis of EHBA in all instances. Bile drainage was achieved surgically in only 3 cases. A major reason for these poor results may have been the late referral of cases for diagnosis and laparotomy, which should be performed as soon as the diagnosis is suspected and always by 70 days of age.