Niemann-Pick disease type C: diagnosis and outcome in children, with particular reference to liver disease.

The records of 52 children with Niemann-Pick disease type C were reviewed to establish whether the disease process and outcome varied with the initial clinical pattern; 34 children (65%) had cholestatic liver disease and hepatosplenomegaly in infancy; 18 were seen at a mean age of 4 years with splenomegaly or neurologic disease or both. Of the 34 children with early cholestatic liver disease, three died in the neonatal period; cholestasis and hepatomegaly subsided in the remaining 31 children, although splenomegaly persisted. Of these 31 children, 15 had persistent liver disease with elevated aminotransferase values. Serial liver biopsy specimens showed that 3 of the 15 children had normal architecture and 12 had hepatic fibrosis, with progression to cirrhosis in 5. No other significant morbidity or additional deaths were associated with the liver disease. The clinical importance of persistent liver disease was overshadowed by the subsequent development of severe neurologic disease. There was no difference in the age at onset of the disease (mean, 4.5 years) or in the pattern of neurologic disease, including supranuclear ophthalmoplegia, whether or not the child had early liver disease. Overt neurologic disease has not yet developed in seven surviving children with liver disease at onset. Sixty-seven percent of children died during the study; the main cause of death was bronchopneumonia. We conclude that the diagnosis of Niemann-Pick disease type C should be considered in patients with unexplained neonatal hepatitis, especially if splenomegaly is a persistent feature. Because liver biopsy specimens may not demonstrate storage cells, bone marrow aspiration to detect the characteristic storage cells is recommended in such patients.

Association between HLA and extrahepatic biliary atresia.

The etiopathogenesis of extrahepatic biliary atresia (EHBA) remains undefined. There are clinical and pathological suggestions supporting the idea that EHBA could consist of at least two forms: the congenital (embryonic or fetal) and the acquired (perinatal) types. To test the hypothesis that susceptibility to this disease would be influenced by host genetic factors, we studied the human leukocyte antigen (HLA) system in 55 patients with and without major extrahepatic congenital anomalies. We found, especially in those without associated malformations, a significantly higher frequency of HLA-B12, of haplotypes A9-B5 and A28-B35, and of their disequilibrium values, as compared with the 8th International Histocompatibility Workshop controls. This study suggests that immunogenetic factors may play a role in determining susceptibility to EHBA, and the different HLA frequencies in those with and without anomalies lend support to the hypothesis that biliary atresia may be an etiologically heterogeneous disorder.

The relative importance of familial, reproductive and environmental factors in biliary atresia: etiological implications and effect on patient survival.

1. The clinical records of 237 patients with extrahepatic biliary atresia (EHBA) attending King's College Hospital, London, between March 1973 and October 1985 were analyzed in terms of familial and reproductive factors, as well as of their possible effect on patient survival. 2. The male:female ratio was 0.93, and the ages of the patients' mothers and fathers were significantly higher than would have been expected from sibship data. Similarly, the number of first-born children having EHBA was less than expected. 3. In a subsample of 189 mothers, the obstetrical histories of women who had children with associated EHBA (20% of the total) showed: 1) a higher frequency of illness before and during pregnancy; 2) a higher level of pharmaceutical drug consumption during pregnancy, and 3) more fetal losses, especially in the gestation immediately preceding the patient's birth. 4. Age at death (average 15.1 +/- 13.2 months) and survival rates depend critically on surgical intervention and were not related to the presence or absence of extrahepatic malformations or to the type of atresia. 5. The present observations, taken together with those of others, indicate that problems in the reproductive process or exposure to noxious environmental agents may be etiological factors in associated EHBA.

The relative importance of familial, reproductive and environmental factors in biliary atresia: etiological implications and effect on patient survival

The clinical records of 237 patients with extrahepatic biliary atresia (EHBA) attendi9ng King's College Hospital, London, between March 1973 and October 1985 were analyzed in terms of familial and reproductive factors, as well as of their possible effect on patient survival. The male: female ratio was 0.93, and the ages of the patients'mothers and fathers were significantly higher than would have been expected from sibship data. Similarly, the number of first-born children having EHBA was less than expected. In a subsample of 189 mothers, the obstetrical histories of women who had children with associated EHBA (20% of the total) showed: 1) a higher frequency of illness before and during pregnancy; 2) a higher level of pharmaceutical drug consumption during pregnancy, and 3) more fetal losses, especially in the gestation immediately preceding the patient's birth. Age at death (average 15.1 ñ 13.2 monthjs) and survival rates depend critically on surgical intervention and were not related to the presence or absence of extrahepatic malformations or to the type of atresia. The present observations, taken together with those of others, indicate that problems in the reproductive process or exposure to noxious environmental agents may be etiological factors in associated EHBA

Congenital structural abnormalities in biliary atresia: evidence for etiopathogenic heterogeneity and therapeutic implications.

The clinical, surgical, laboratory and histological data of 237 children with extrahepatic biliary atresia were reviewed. Forty-seven patients (20%) had associated congenital anomalies, and of these, 28 had cardiovascular, 22 digestive and 19 splenic malformations. Of the 19 patients with splenic malformations, 13 showed the polysplenia syndrome and two had asplenia. Chromosome studies were performed in eight children, six having associated anomalies, and two of them showed karyotype abnormalities (46,XX,del 18 p- and 49,XXXXY). These observations indicated that biliary atresia could be subdivided into four distinct etiopathogenic subgroups, three involving a congenital form that could arise through a malformation, a disruption or a chromosome abnormality, and the remaining to agents active in the perinatal period (the acquired form). The surgical outcome in 171 patients operated on by an experienced surgeon was not influenced by the presence of anomalies but by the timing of surgery. Seventy-one percent of 24 patients operated on by 8 weeks of age were jaundice-free as opposed to only 34% of those who had later surgery (p less than 0.01).

Extrahepatic biliary atresia and twinning

Four pairs of discordant twins were observed in a series of 237 extrahepatic biliary atresia patients ascertained in London. The twinning prevalence (1.7%) was as expedcted considering the ethnic composition of the sample. Out of a total of 17 other twin pairs reported in the literature only one was concordant for the disease. Since only 17 instances of familial cases have been described, the conclusion is that any influence of genetic factors in this condition is likely to be manifested indirectly, possibly in the form of increased susceptibility of the biliary epithelium to infectious or toxic agents

Extrahepatic biliary atresia and twinning.

1. Four pairs of discordant twins were observed in a series of 237 extrahepatic biliary atresia patients ascertained in London. 2. The twinning prevalence (1.7%) was as expected considering the ethnic composition of the sample. 3. Out of a total of 17 other twin pairs reported in the literature, only one was concordant for the disease. Since only 17 instances of familial cases have been described, the conclusion is that any influence of genetic factors in this condition is likely to be manifested indirectly, possibly in the form of increased susceptibility of the biliary epithelium to infectious or toxic agents.

Growth velocity, growth hormone therapy, and serum concentrations of the amino-terminal propeptide of type III procollagen.

The relationship between serum concentrations of the amino-terminal propeptide of type III procollagen (PIIINP) and growth was assessed in 307 healthy subjects and 82 children with disorders of growth (41 with insufficient growth hormone, 23 with short stature and normal endocrinologic studies, 18 with tall stature) by means of a recently developed, simplified PIIINP radioimmunoassay. The PIIINP value appeared to be related to height velocity; in healthy children of each sex, the pattern of change with age mirrored the shape of the standard height velocity curve; in children with disorders of growth, there was a statistical correlation (p less than 0.001) between PIIINP concentration and height velocity. However, measurement of serum PIIINP alone had no diagnostic value because there was considerable overlap of PIIINP values in children with growth hormone insufficiency, short stature, normal stature, and tall stature. The most appropriate application of PIIINP may be in the monitoring of prepubertal children receiving exogenous growth hormone therapy; in these patients, increases in height velocity were reflected by increases in PIIINP, and early increases in PIIINP may have predictive value.

Different mechanisms responsible for in vitro cell-mediated cytotoxicity to autologous hepatocytes in children with autoimmune and HBsAg-positive chronic liver disease.

To investigate mechanisms of hepatocyte injury, lymphocytes from 41 children with chronic liver disease were incubated with autologous liver cells in a microcytotoxicity assay. Cytotoxicity was significantly increased in 18 of 25 patients with chronic hepatitis B virus (HBV) infection, in five of nine with "autoimmune" chronic active hepatitis (CAH), and in only one of seven with histologically inactive liver disorders. There was a good correlation between cytotoxicity and biochemical and histologic markers of disease activity in children with autoimmune CAH, whereas in HBsAg-positive disease a positive correlation was found only with serum alanine aminotransferase (SGPT). Children with autoimmune CAH receiving steroid treatment had normal cytotoxicity, whereas increased values were found in two of three HBsAg-positive patients receiving prednisolone. Fractionation studies revealed that non-T cells were cytotoxic in both autoimmune and HBcAg-positive chronic liver disease. T cell cytotoxicity was exclusively found in children with chronic HBV infection, particularly with HBc antigenemia. Blocking experiments showed that T-lymphocytes from HBsAg-positive children reacted with HBV core antigen on the hepatocyte surface. Non-T cells were directed against hepatocyte membrane antigens in both HBsAg-positive and HbsAg-negative children. These results suggest that different immune mechanisms of liver damage are involved in autoimmune and HBsAg-positive chronic liver disease.

Spontaneous bacterial peritonitis in children with chronic liver disease: clinical features and etiologic factors.

We analyzed the clinical and bacteriologic features of 12 episodes of spontaneous bacterial peritonitis (SBP) in 11 children (four boys, median age 5.5 years) with chronic liver disease. All patients had cirrhosis and ascites; four had hypersplenism, and one was asplenic. Symptoms included increasing abdominal distention, pyrexia, abdominal pain, gastrointestinal disturbance, and encephalopathy. Nine had rebound tenderness on abdominal palpation, and 12 had reduced bowel sounds. The most frequent organisms isolated from culture of ascitic fluid were Streptococcus pneumoniae (nine). Klebsiella (two), and Haemophilus influenzae (one); blood cultures grew identical organisms in nine. Seven patients died despite intensive antibiotic therapy. In the 3 months prior to onset of SBP, defective yeast opsonization and reduced serum concentration of C4 were found in all nine children tested; eight had reduced concentration of C3. Functional deficiency of all complement components was present in four tested within 1 to 5 months of the onset. In contrast, only eight of 59 cirrhotic children without SBP had low C3, and eight had defective yeast opsonization, although 35 had low C4 values. Four of the patients with SBP and low C3 and C4 concentrations had normal concentrations at the time of diagnosis of liver disease 2 to 5 years previously. Opsonization of type III pneumococci was reduced in sera from three patients who subsequently developed pneumococcal peritonitis. The incidence of SBP in children with chronic liver disease is similar to that in adults, as are the clinical features. Our observations suggest that complement deficiency induced by chronic liver disease may be important in the pathogenesis of SBP.

Cytotoxicity to isolated rabbit hepatocytes by lymphocytes from children with liver disease.

A test of lymphocyte cytotoxicity for isolated adult rabbit hepatocytes has been performed using lymphocytes from 40 children with acute or chronic liver disease. Positive cytotoxicity was not observed in 26 children without liver disease and rarely in 13 children with disease affecting primarily the biliary tract. Temporarily positive tests were found in those with acute hepatocellular disease, but tests remained positive in patients with chronic active hepatitis, while liver function tests remained abnormal. Persistently positive test occurred in those with liver disease associated with alpha-antitrypsin deficiency. Such altered immunoresponsiveness could be an important pathogenic mechanism leading to chronic liver disease in childhood.