M. Michael Thaler

Vertical transmission of hepatitis C virus

There is evidence that hepatitis C virus (HCV) may be vertically transmitted from infected mothers to their children. To test this hypothesis, we prospectively studied 10 pregnant women at high risk from parenterally or sexually transmitted diseases with the polymerase chain reaction. HCV RNA was found in 8 newborn babies delivered by women who were anti-HCV seropositive, and persisted for 2-19 months of follow-up. Anti-HCV detected in 7 infants cleared by 9 months and remained undetectable thereafter. Serum alanine aminotransferase was raised in 3 infants. The findings provide evidence of vertical transmission of HCV and suggest that perinatal infection may initiate a silent disease process or chronic carrier state.

Metabolic Regulation of Heme Catabolism and Bilirubin Production. I. HORMONAL CONTROL OF HEPATIC HEME OXYGENASE ACTIVITY

Heme oxygenase (HO), the enzyme system catalyzing the conversion of heme to bilirubin, was studied in the liver and spleen of fed, fasted, and refed rats. Fasting up to 72 hr resulted in a threefold increase in hepatic HO activity, while starvation beyond this period led to a gradual decline in enzyme activity. Refeeding of rats fasted for 48 hr depressed hepatic HO activity to basal values within 24 hr. Splenic HO was unaffected by fasting and refeeding. Hypoglycemia induced by injections of insulin or mannose was a powerful stimulator of hepatic HO. Glucose given together with the insulin abolished the stimulatory effect of the latter. Parenteral treatment with glucagon led to a twofold, and with epinephrine to a fivefold, increase of hepatic HO activity; arginine, which releases endogenous glucagon, stimulated the enzyme fivefold. These stimulatory effects of glucagon and epinephrine could be duplicated by administration of cyclic adenosine monophosphate (AMP), while thyroxine and hydroxortisone were ineffective. Nicotinic acid, which inhibits lipolysis, failed to modify the stimulatory effect of epinephrine. None of these hormones altered HO activity in the spleen. These findings demonstrate that the enzymatic mechanism involved in the formation of bilirubin from heme in the liver is stimulated by fasting, hypoglycemia, epinephrine, glucagon, and cyclic AMP. They further suggest that the enzyme stimulation produced by fasting may be mediated by glucagon released in response to hypoglycemia. The possibility is considered that the enhanced HO activity in the liver may increase hepatic heme turnover and hence, bilirubin production, which may explain the rise of unconjugated serum bilirubin observed in fasting or hypoglycemic individuals.

The Effects of Phenobarbital on Bile Salts and Bilirubin in Patients with Intrahepatic and Extrahepatic Cholestasis

Abstract In two children with intrahepatic cholestasis treated with phenobarbital (10 mg per kilogram of body weight per day) for four days, serum bile salt concentration decreased from 100 to 400 to 1 to 10 μg per milliliter, and pruritus disappeared. The serum bilirubin concentrations were reduced to 20 to 50 per cent of pretreatment values, and the 131I-Rose Bengal fecal excretion increased during treatment. In contrast, phenobarbital had no effect on serum bile salts, bilirubin, 131I-Rose Bengal excretion and pruritus in a child with extrahepatic biliary obstruction. Decreased serum bile salt concentrations and concomitantly increased fecal excretion of Rose Bengal in phenobarbital-treated patients suggest that the barbiturate stimulates bile secretion and biliary excretion of bile salts. It may be helpful in the management of young patients with intrahepatic cholestasis.

Hepatitis B in Patients with HIV Infection: Relationship to AIDS and Patient Survival

Excerpt Hepatitis B virus (HBV) infection is common among persons with human immunodeficiency virus (HIV) infection (1-4). Hepatitis B virus DNA is found in lymphoid cells of patients co-infected w...

A synthetic tripeptide which increases survival of normal liver cells, and stimulates growth in hepatoma cells

Abstract A synthetic peptide with a structure analogous to a growth promoting human serum tripeptide was found to possess activities which, at nanomolar concentrations, increased the survival of normal hepatocytes from regenerating rat liver and which enhanced growth of a line of cultured hepatoma cells. The synthetic tripeptide (glycyl-histidyl-lysine) also stimulated the incorporation of labeled uridine and thymidine into trichloroacetic acid precipitable material.

GROWTH RETARDATION IN SICKLE-CELL DISEASE TREATED BY NUTRITIONAL SUPPORT

The effect of increased nutritional intake was evaluated in 5 growth-retarded children with sickle-cell disease. Growth on recommended daily calorie and protein intakes had been inadequate in all 5. Fat absorption and intestinal mucosal morphology were normal in all 5. 2 children were given nutritional supplementation by nasogastric intubation, 1 received nightly oral formula supplements, and 2 were supplemented with zinc, iron, folate, and vitamin E only. Nutritional supplementation by the nasogastric route produced a rapid sustained increase in growth rate, associated with striking reductions in pain crises and infections which had previously necessitated many hospital admissions. Oral supplementation improved the clinical course but had no effect on growth rate. Mineral and vitamin supplements influenced neither the growth rate nor the clinical course. The observations indicate that nasogastric nutritional supplementation may accelerate growth and reduce the incidence and severity of complications in growth-retarded children with sickle-cell disease.

Hepatitis C virus infection in infants whose mothers took street drugs intravenously

To assess the risk of transmission of hepatitis C virus from mother to infant during pregnancy or at delivery, we measured the antibody to hepatitis C virus (anti-HCV) by an enzyme-linked immunosorbent assay (ELISA) and a recombinant immunoblot assay (RIBA) in serum from 43 infants whose mothers took illicit drugs intravenously. Passively transmitted maternal anti-HCV was detected in 17 (40%) of the 43 infants tested with the ELISA during the first 4 postnatal months. Ten of these initially seropositive infants were followed to 15 months of age or beyond; anti-HCV cleared from nine infants and persisted in one. Among 24 initially seronegative infants, three (12.5%) showed persistent anti-HCV at 6, 11, and 18 months of age, respectively. The remaining two infants were initially tested with ELISA at 6 and 15 months of age; both were transiently seropositive, but anti-HCV disappeared by 12 and 24 months of age, respectively. Among the 17 infants with maternal antibody, nine with ELISA reactions greater than 2.5 optical density units were reactive by RIBA: the eight with weaker reactivity by ELISA were nonreactive by RIBA. When serum samples from the four infants who showed persistent reactivity by ELISA were tested with RIBA, one reacted to both antigens displayed by RIBA (C-100 and 5-1-1), one reacted to the 5-1-1 antigen only, and two were nonreactive. Serum transaminase values were elevated in three of these four infants; all four were also infected with human immunodeficiency virus. The results indicate that vertically transmitted hepatitis C virus may be a cause of hepatitis in infants, especially those coinfected with human immunodeficiency virus. Neonates at risk of hepatitis C virus infection should be monitored beyond 12 months of age. The interpretation of tests for anti-HCV antibody during infancy requires further investigation.

A Simple Liquid Chromatographic Method for Quantitative Extraction of Hydrophobic Compounds from Aqueous Solutions

Abstract We are reporting a rapid, high-capacity liquid chromatographic method for quantitative extraction and concentration of hydrophobic compounds from biological fluids and aqueous solutions. Samples are injected into commerically-available cartridges (Sep-Pak C18R) containing a microparticulate, reversed phase packing which retains hydrophobic compounds. Inorganic salts and organic hydrophilic contaminants are removed with a water wash. Hydrophobic compounds are eluted quantitatively with minimal volumes (∼5 ml) of organic solvents. As demonstrated with radiolabeled taurocholate, thin-layer chromatography, enzymatic fluorimetry and capillary gas chromatography, complete recovery of bile salts from large volumes of urine, serum, amniotic fluid and hydrolysis reaction mixtures was achieved at flow rates up to 20 ml/min. A single cartridge concentrated approximately 50 mg of either taurocholate or the more polar bile salt, taurolithocholate sulfate. The technique is simple and applicable to the isolatio...

Chronic fructose intoxication after infancy in children with hereditary fructose intolerance. A cause of growth retardation

In two unrelated boys, 5.3 and 3.8 years of age with hereditary fructose intolerance, apparently isolated growth retardation (-2.71 S.D. and -2.40 S.D.) occurred after infancy, even though acute symptomatic fructose intoxication was prevented by restriction of dietary fructose. When more stringent restriction of dietary fructose was instituted (approximately 40 mg per kilogram of body weight per day), growth velocity increased from the 25th to the 97th percentile in one child and from well below the 3d to above the 75th percentile in the other. When restriction of dietary fructose was experimentally relaxed (from 10 to 250 mg per kilogram per day), neither boy had symptoms, hypoglycemia, or evidence of hepatic or renal dysfunction, but both had sustained hyperuricemia and hyperuricosuria and increases in the plasma concentration and urinary excretion of magnesium. We conclude that in patients with hereditary fructose intolerance, clinically important chronic fructose intoxication can occur after infancy without causing symptoms of acute fructose intoxication and can be expressed as an apparently isolated, reversible retardation of somatic growth with a continuing disorder of adenine nucleotide metabolism, characterized in part by recurrently increased rates of degradation of adenine nucleotides.

REYE'S SYNDROME DUE TO A NOVEL PROTEIN-TOLERANT VARIANT OF ORNITHINE-TRANSCARBAMYLASE DEFICIENCY

Abstract A novel variant of ornithine-trans-carbamylase (O.T.C.) deficiency has been discovered in a patient with encephalopathy and fatty visceral degeneration (Reyes syndrome). Hepatic ornithine transcarbamylase activity was 20·7% of normal, with extremely low affinity of the enzyme for ornithine, and substrate inhibition by carbamyl phosphate and ornithine. The findings reveal a link between Reyes syndrome and heritable O.T.C. deficiency, and suggest that administration of ornithine or arginine may be specific therapy for this condition.