Arnold Silverman

Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy

OBJECTIVE To determine the outcome, in index patients followed at an American Center, of syndromic paucity of interlobular bile ducts (sPILBD; Alagille syndrome), with onset of cholestasis in infancy. DESIGN Cohort. SETTING Regional referral center for infants and children with liver disease. RESULTS During the past 10 years, 26 unrelated children with sPILBD were identified. Fifteen (58%) are alive without liver transplantation at a median age of 12.1 years. Three (11%) died, all before 2 years of age. Eight patients (31%) underwent liver transplantation at a median age of 6.5 years; all eight are alive a median 5.4 years after transplantation. The most common factors contributing to the decision for transplantation were bone fractures, pruritus, and severe xanthoma. The predicted probability of reaching 19 years of age without transplantation is about 50%; however, with transplantation, the predicted probability of long-term survival is 87%. Of 26 patients 4 (15%) have had significant central nervous system disease, and two of them have died of intracranial hemorrhage. Of the four patients who underwent cholecystoportostomy or portoenterostomy, three required liver transplantation. CONCLUSIONS Children with sPILBD identified in infancy because of cholestasis have a 50% probability of long-term survival without liver transplantation, a worse prognosis than other follow-up studies have reported. In selected patients, liver transplantation provides the opportunity for long-term survival with improved quality of life. Patients with sPILBD are at risk of having intracranial hemorrhage.

Improved neurologic function after long-term correction of vitamin E deficiency in children with chronic cholestasis

We studied the effect of long-term correction of vitamin E deficiency on neurologic function in 14 children with chronic cholestasis. Vitamin E repletion was achieved in all, either by large oral doses (up to 120 IU per kilogram of body weight per day) or by intramuscular administration of dl-alpha-tocopherol (0.8 to 2.0 IU per kilogram per day). With early institution of therapy, neurologic function remained normal in two asymptomatic children below the age of three years after 15 and 18 months of therapy. Neurologic function became normal in three symptomatic children below age three after 18 to 32 months of therapy. Restitution of neurologic function was more limited in nine symptomatic children 5 to 17 1/2 years old after 18 to 48 months of therapy. We conclude that vitamin E repletion therapy should be initiated at an early age in children with chronic cholestasis complicated by vitamin E deficiency, to prevent irreversible neurologic injury.

Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis.

Infection with reovirus 3 (Reo-3) has been suggested as the cause of extrahepatic biliary atresia and idiopathic neonatal hepatitis, but confirmation has been lacking. Therefore we have searched for a specific anti-Reo-3 antibody response in the sera of patients with biliary atresia or neonatal hepatitis and for Reo-3 antigens in their hepatobiliary tissues. Sera from 23 infants with extrahepatic biliary atresia, 12 with neonatal hepatitis, 30 age-matched control patients with other liver diseases, and 55 control patients without liver disease were tested by an enzyme-linked immunosorbent assay for total (IgA, IgG, and IgM) anti-Reo-3 antibodies; sera of infants younger than 6 months of age were tested also for IgM anti-Reo-3 antibodies alone. There was no difference between either total or IgM anti-Reo-3 antibody levels in infants with extrahepatic biliary atresia or neonatal hepatitis and levels in control infants. Reo-3 antigens were not detected in the hepatobiliary tissues of 19 infants (18 with biliary atresia, one with neonatal hepatitis) by an immunoperoxidase method that readily demonstrated Reo-3 in control infected HEp-G2 cells. Our data do not support a relationship between neonatal liver diseases and infection with Reo-3.

Treatment of vitamin E deficiency during chronic childhood cholestasis with oral d-α-tocopheryl polyethylene glycol-1000 succinate

Treatment of vitamin E deficiency during chronic childhood cholestasis is hampered by the poor intestinal absorption of available oral preparations of vitamin E when bile flow is severely impaired; thus parenteral vitamin E has been the only effective therapy for many children with this problem. We studied the intestinal absorption, efficacy, and safety of a water-soluble oral form of vitamin E, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), in 22 children (7 mo to 19 yr old) with severe cholestasis and vitamin E deficiency who were unresponsive to massive oral doses (100-200 IU/kg.day) of dl-alpha-tocopherol. The results of oral vitamin E tolerance tests showed that TPGS was well absorbed in virtually all study subjects, that TPGS intestinal absorption was superior to that of dl-alpha-tocopherol, and that TPGS absorption in teenage children with chronic cholestasis was similar to that of normal adults. In addition, 1.7% +/- 1.6% (mean +/- SD) of the administered polyethylene glycol 1000 contained in the TPGS was absorbed and excreted in the urine of the 13 subjects analyzed, compared with 3.0% +/- 1.3% in 4 normal adults. A chronic oral dose of 15-25 IU/kg.day of TPGS corrected the biochemical vitamin E deficiency state over 1-19 mo (mean, 10.6 mo) of TPGS therapy. No clinical or biochemical evidence of gastrointestinal, renal, hepatic, or hematologic toxicity was demonstrated. This study suggests that TPGS administered orally in a dose of 15-25 IU/kg.day may be a safe and effective form of vitamin E for prevention and correction of vitamin E deficiency during severe childhood cholestasis.

Noninfectious colitis associated with short gut syndrome in infants.

We describe noninfectious bloody diarrhea in 13 of 16 infants referred for management of short bowel syndrome and parenteral nutrition during a 33-month period. The condition was characterized by bloody, watery stools associated with carbohydrate malabsorption. Colitis occurred at a mean age of 4.2 months during periods of advancing enteral feedings of a hydrolyzed protein- or amino acid-containing formula. Sigmoidoscopy performed in nine patients revealed edema, patchy erythema, loss of normal vascular pattern, and mucosal friability without ulcerations or pseudomembranes. Colonic biopsy specimens demonstrated edema and mixed hypercellularity of the lamina propria, with prominent eosinophilia. Rectal bleeding ceased if formula feedings were decreased or withheld. Of multiple medications administered, sulfasalazine seemed to improve rectal bleeding most effectively in our patients and allowed for more rapid reintroduction of enteral feedings.

Vitamin E deficiency and neurologic disease in childrenwith cholestasis: A prospective study

CHILDREN WITH CHRONIC CHOLESTASIS may develop a characteristic progressive and disabling neurologic disease related to vitamin E deficiency, ~4 but neither the earliest signs nor the time required for its development is known. Therefore we thought it important to ascertain the incidence and severity of vitamin E deficiency in children with cholestasis. In this prospective clinical study we determined serum vitamin E concentration and performed systematic and sequential neurologic examinations in 48 children with previously identified cholestasis and in 23 others with either noncholestatic malabsorption or progressive ataxia.

Homotransplantation of the liver in a patient with hepatoma and hereditary tyrosinemia

A girl with hereditary tyrosinemia, diagnosed at 6 months of age, was treated with a diet restricted in phenylalanine and tyrosine. At 9 1/2 years of age she developed an acutely enlarged liver and spleen, and the diagnosis of hepatocarcinoma was made. The patient received a liver transplant and tyrosine metabolites became normal while she was receiving a regular diet. Three months later, an infected thrombosis of the portal vein caused her death. Liver transplant appears to be an effective method of enzyme replacement in tyrosinemia and should be considered for prevention of hepatoma.

Clearance of chronic hepatitis B virus infection in young children after alpha interferon treatment

Nine children aged 18 months to 17 years (mean 5.7 years) with chronic hepatitis b virus infection and chronic active hepatitis were treated with 5 to 6 million units/m2 of body surface area of interferon -alpha 2b administered subcutaneously three times per week for 4 months (n = 1) or 6 months (n = 8). At 12 months after the start of therapy, six children less than 3 years of age responded to the treatment (three completely and three partially), whereas only one of three children older than 7 years of age responded. We conclude that IFN treatment may be effective in children with chronic HBV infection, especially when administered while they are young.

Tocopheryl polyethylene glycol 1000succinate therapy for vitamin E deficiency during chronic childhood cholestasis: Neurologic outcome

Treatment of the vitamin E deficiency neurologic syndrome in children with chronic cholestasis is hampered by the very poor intestinal absorption of available forms of vitamin E, thus requiring prolonged treatment with intramuscular injections of vitamin E in many patients. D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble investigational form of vitamin E that is well absorbed during cholestasis. We studied the effect of TPGS therapy on the neurologic function in 12 children with vitamin E deficiency (aged 9 months to 6 years) with prolonged forms of neonatal cholestasis. Each child had failed to respond to up to 100 to 200 IU/kg/d of standard oral preparations of vitamin E. Treatment with 15 to 25 IU/kg/d TPGS for a mean of 19.3 months normalized the biochemical indices of vitamin E status and was well tolerated by all patients. Neurologic function, assessed by serial neurologic examinations, remained normal during therapy in the two children with no neurologic symptoms younger than age 3 years at onset of therapy. Neurologic function, which had deteriorated before this study, improved in six of seven patients with symptoms who were younger than 3 years and in all three with symptoms older than 3 years. TPGS appears to be a safe and effective form of orally administered vitamin E for use in children with chronic cholestasis who are unresponsive to available oral preparations of vitamin E.

Glutaric, 3-hydroxypropionic, and lactic aciduria with metabolic acidemia, following extensive small bowel resection

Abstract A patient with extensive small bowel resection as a neonate excretes glutaric, 3-hydroxypropionic, and lactic acids in a manner atypical for any recognized genetic metabolic disease. The organic aciduria varies with dietary intake: lactic acid predominates when he takes a high-carbohydrate, low-protein diet, and glutaric acid and products of aromatic amino acid catabolism dominate when protein intake increases. The association of 3-hydroxypropionic acid excretion with dietary intake is less clear. The available evidence is consistent with the hypothesis that the organic aciduria results from rapid transit and decreased absorption of ingested nutrients in his shortened small intestine, followed by bacterial metabolism of these substances in the colon, absorption of the metabolic products, and urinary excretion of those bacterial products which do not serve as intermediates in human metabolism.