Alex P. Mowat

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.

Serum Concentrations of the Type I and III Procollagen Propeptides as Biochemical Markers of Growth Velocity in Healthy Infants and Children and in Children with Growth Disorders

ABSTRACT: The reproducibility and specificity of a new, rapid, simple RIA for measuring the concentration of the soluble carboxypropeptide of type I procollagen (PICP) in serum was confirmed. Serum PICP was determined in 442 healthy Caucasian subjects ranging in age from 3 wk to 18 y. Highest PICP values (mean ± SD: 2200 ± 350 μg/L) occurred in infants less than 3 mo of age, falling by 70% at 2 y and by an additional 10% at 4 y. There was no significant change in serum PICP between 4 and 16 y of age (330 ± 130 μg/L), but a decrease to adult levels of <160 μg/L, occurred by 18 y. In 76 children with growth disorders, serum PICP was related to linear growth velocity (p < 0.001), although there were no significant differences in PICP among the 38 children with growth hormone insufficiency, the 21 short children with no endocrinologic abnormality, or the 17 tall children. All 15 prepubertal children treated with growth hormone for 3 mo showed significant increases in both growth velocity and serum PICP, with a significant relationship (p < 0.01) between the degree of increases. The rise in serum PICP at 3 mo (but not baseline PICP values) predicted the increase in growth velocity after 1 y of treatment. Similar changes were observed in the concentration of the aminopropeptide of type III procollagen, except that serum aminopropeptide of type III procollagen showed a definite increase during puberty and a wider spread of values in growth disorders. We conclude that measuring serum PICP by the new, reproducible assay reflects height velocity in prepubertal children and may be a useful biochemical means of monitoring growth rates.

GENETICALLY DETERMINED LOW C4: A PREDISPOSING FACTOR TO AUTOIMMUNE CHRONIC ACTIVE HEPATITIS

Of 26 patients with autoimmune chronic active hepatitis (CAH) starting in childhood 18 (69%) had low C4 and 5 (19%) had low C3 serum levels. Impaired hepatic synthesis and immune-consumption were unlikely since transferrin levels were normal in all patients, albumin levels were persistently low in only 3, and only 3 had raised levels of activation fragment C3d. C4d was normal in all patients studied. In the families of 12 probands with low C4, 7 parents had low C4 and 2 had levels which were at the lower limit of normal. 5 of 10 siblings from 5 families had low C4. These results suggest that low C4 levels in CAH are genetically determined. C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls, indicating that defective expression of structural genes may contribute to the observed C4 deficiency.

Fulminant hepatic failure in childhood An analysis of 31 cases

To document the clinical features and complications of fulminant hepatic failure in childhood, 31 consecutive cases (of whom only 9 survived) were reviewed. Of 26 children with acute hepatitis (HbSAg-negative), liver function steadily deteriorated in all but 2, and encephalopathy occurred within 3 weeks of the onset of symptoms in all except 3 of them. Eight of these patients survived, as did one of 3 in which this deterioration was caused by paracetamol overdosage. Single cases due to Amanita phalloides and halothane died. Encephalopathy lasted from 2 to 16 days in the survivors, and from one to 20 days in the fatal cases. The severity fluctuated by more than one grade in 9 patients. The outcome was not related to the age or sex of patient, clinical or biochemical abnormalities at presentation, or to the duration of the encephalopathy. Prothrombin time was prolonged by more than 90 seconds in 10 fatal cases, but in none of the survivors. The outcome was related to the severity of the encephalopathy, only one (6%) of 19 children in grade 4 coma surviving, and to the occurrence of neurological complications—particularly brain stem dysfunction (9 cases), decerebrate posturing (12 cases), and convulsions (7 cases). Massive gastrointestinal bleeding (14 cases) and renal failure (10 cases) were confined to the fatal group. At necropsy 7 (54%) of 13 had cerebral oedema. Hypoglycaemia, septicaemia, respiratory tract infections, ascites, and haemopoietic complications occurred both in fatal cases and survivors. Although liver function tests and liver biopsy appearances remained abnormal in survivors for 24 and 30 months respectively, these children developed normally without evident disease during or after this period. Children with fulminant hepatic failure and severe encephalopathy develop major pathophysiological complications affecting almost every system. Such complications must be prevented or vigorously treated. The mortality is no lower than in adults. Effective treatment must be instituted before grade 4 coma is established.

α-Antitrypsin Deficiency and Neonatal Hepatitis

Five out of 28 infants investigated in a regional survey of neonatal hepatitis were found to have genetically-determined deficiency of α1-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 α1-antitrypsin deficiency may be commoner than previously realized and that Australia antigen acts as a trigger factor in these cases.

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, mothers 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.

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.

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.

Cirrhosis and its complications

This chapter discusses the classification, pathogenesis, clinical features, diagnosis, management, and treatment of cirrhosis. Cirrhosis is the irreversible end stage of many forms of liver injury. It is defined pathologically as a diffuse process affecting the whole liver in which normal architecture is replaced by structurally abnormal nodules surrounded by prominent fibrous tissue. Accumulation of fibrous connective tissue within the portal tracts and in septa extending between portal tracts interferes with hepatic blood flow and contributes to the development of portal hypertension. This is aggravated by the development of anastomotic channels within large fibrous septa that shunt blood from the hepatic artery to portal vein branches. In addition, sinusoidal blood flow is impeded by perisinusoidal fibrosis. In large fibrous septa linking portal tracts and central veins, anastomotic channels developing between hepatic artery branches and hepatic vein tributaries carry blood which completely bypasses the sinusoids. Such circulatory disturbances compromise many aspects of liver function and may lead to liver cell death, thereby perpetuating accumulation of connective tissue; thus a vicious circle is established. The main pathophysiological effects are impaired hepatic function and portal hypertension. Cirrhosis may be complicated by the development of hepatocellular carcinoma. The diagnosis of cirrhosis is a two-step process: (a) confirming the presence of cirrhosis, and (b) determining its cause.

Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia

Sixty-one children who have survived 2.5 years or more after corrective surgery for biliary atresia were prospectively followed by endoscopy. Esophageal varices were detected in 41 patients (67%), 17 of whom (28%) had experienced episodes of variceal hemorrhage. Control of variceal bleeding was achieved by endoscopic injection sclerotherapy in all but one child who died from hemorrhage before the completion of treatment. Complications of the technique comprised episodes of bleeding before variceal obliteration (7), esophageal ulceration (5), and stricture (3). These resolved with conservative management and without long-term sequelae. During a mean follow-up period of 2.8 years after variceal obliteration, rebleeding from recurrent esophageal varices developed in only one child and responded to further sclerotherapy. These results are better than those following surgical procedures for portal hypertension in biliary atresia, and therefore endoscopic sclerotherapy is recommended as the treatment of choice.