Daniel Alagille

Autoimmune Hepatitis Associated with Anti-actin Antibodies in Children and Adolescents

Summary The clinical, biochemical, morphological, and evolutive features of autoimmune hepatitis associated with serum smooth muscle antibodies of anti-actin specificity were retrospectively analyzed in 31 children and adolescents. Cirrhosis was present at diagnosis in all but six patients, including nine of the 12 diagnosed within 6 months from the onset. In 15 children, one or more associated diseases of an immune-mediated mechanism were present, including chronic arthritis, sclerosing cholangitis, inflammatory bowel disease, and cutaneous vasculitis. All patients were treated with prednisone and azathioprine with normalization or improvement of liver function tests: 28 children are currently alive after a mean follow-up of 4 years, 10 months. Treatment was inter rupted in four patients only. Two patients died of liver failure in spite of immunosuppressive therapy before the era of liver transplantation. In spite of prolonged therapy, five other patients ultimately required liver transplantation during adolescence or early adulthood. These results (a) further define a group of autoimmune hepatitis in children characterized by the presence of serum anti-actin antibodies; (b) indicate that immunosuppressive therapy improves liver function, although in most cases it must be continued for a long period to maintain remission; and (c) suggest that progressive liver failure may occur in early adulthood and may require liver transplantation.

Interstitial deletion of the short arm of chromosome 20 in arteriohepatic dysplasia (Alagille syndrome)

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.

Long-term neuropsychological outcome in children undergoing portal-systemic shunts for portal vein obstruction without liver disease

Forty-two children with portal vein obstruction (cavernoma) and without liver disease had a portosystemic surgical shunt performed at different ages. All of them had severe gastrointestinal hemorrhage prior to surgery. To evaluate the long-term neurological and psychological effects of shunt procedures in children with normal liver function, they were studied up to 24 years postoperatively with psychometric testing. A comparison with two control groups as to the impact of surgery, family situation, and neonatal events was considered. Twenty-four children with portal vein obstruction who were not operated on and 19 children splenectomized for hematological reasons acted as the control groups. No differences were observed in schooling and employment. Psychometric tests were almost identical in shunted patients and in the control groups. Minimal portal systemic encephalopathy appeared to be undetectable clinically either by electroencephalogram or by venous ammonia levels. The results of psychometric tests appear to show no loss of intellectual and psychological capacity in patients operated on for portal obstruction. Only visual memory and spatiotemporal tests showed slightly worse results in those children who underwent this procedure. Further longitudinal studies are required to substantiate these findings.

Pharmacokinetics and safety of a new solution of vitamin K1(20) in children with cholestasis.

In cholestatic diseases, the absorption of fat-soluble compounds, including vitamin K1(20), is low and periodic administration of vitamin K1(20) is often necessary. Due to the low absorption of vitamin K1(20) from the Konakion formulation, late hemorrhagic disease of the newborn also occurs especially after oral vitamin K1(20) prophylaxis with Konakion. We investigated the pharmacokinetics and the safety of a new formulation of vitamin K1(20) in a mixed micelles (MM) solution. Compared to the old formulation (Konakion) using Cremophor EL as a solubilizer, the higher vitamin K1(20) levels (as measured by HPLC) in serum obtained after oral administration of the MM formulation clearly demonstrate a superiority of this new formulation. Additionally, the elimination of Cremophor EL as well as of propylene glycol from the formulation avoids possible adverse effects associated with intravenous or intramuscular administration. Furthermore, in most cases, the discomfort of parenteral injections can be overcome by simple oral administration even in children with severe cholestasis.

Plasma vitamin E levels in children with cholestasis.

Plasma vitamin levels were assayed in 58 children presenting with chronic cholestasis. In the infants who developed cholestasis during the first weeks of life, vitamin E levels dropped below normal values after the age of 4 months. In the older children, vitamin E levels were not correlated with the etiology of cholestasis but with the degree of cholestasis, as expressed by serum bilirubin, serum bile acids, and fat absorption coefficient. We did not find any relationship between vitamin E levels and other biological parameters such as alkaline phosphatases, triglycerides, phospholipids, and cholesterol. These results further support the importance of vitamin E deficiency in chronic cholestasis of infants and children.

Detection of anti-endoplasmic reticulum antibody-positive autoimmune hepatitis in children, using an ELISA technique.

Anti-endoplasmic reticulum antibody positive autoimmune hepatitis in children is characterized by the recognition of a single 50,000 MW protein of the endoplasmic reticulum in liver microsomal fractions by their sera. We have developed an enzyme-linked immunosorbent assay technique with rat liver microsomal preparations as the antigen to be used for detection of this disease. Titers obtained may be useful in following the course of the disease and as an aid in determining when therapy can be discontinued. The technique is rapid, sensitive, reproducible, and simple to perform and is easier to manipulate than immunofluorescence or radioimmunoassay techniques.

Effects of Vitamin E Treatment in Cholestatic Children

Several years ago, it has been shown1,2 that there was a relationship between vitamin E (Vit. E) deficiency and the neurological disorders observ ed in patients with chronic cholestasis and lipid malabsorption. We report here our clinical experience of eight years of Vit. E treatment (10 mg/kg of DL-α-tocoρherol acetate, IM, every two weeks) in these patients.