Lawrence M. Gartner

Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome.

The cerebro-hepato-renal syndrome is a rare familial malady with cerebral, renal, and skeletal abnormalities, severe hypotonia, cirrhosis, iron and lipid storage, and death within 6 months. Correlated electron microscopic, histochemical, and biochemical studies demonstrate defects in two oxidative organelles. Peroxisomes cannot be found in hepatocytes and renal proximal tubules. In hepatocytes and cortical astrocytes, mitochondria are distorted in their appearance and glycogen stores are increased. Oxygen consumnption of brain and liver mitochondrial preparations with succinate and with substrates reducing nicotinamide adenine dinucleotide is markedly diminished, but the consumption is normal with ascorbate and tetramethylphenylenediamine, which suggests a defect in electron transport prior to the cytochromes. Histochemical studies of mitochondrial oxidation point to a defect between the succinate dehydrogenase flavoprotein and coenzyme Q, possibly in the region of nonheme iron protein.

Prolonged Neonatal Unconjugated Hyperbilirubinemia Associated with Breast Feeding and a Steroid, Pregnane-3 (Alpha), 20 (Beta)-Diol, in Maternal Milk That Inhibits Glucuronide Formation In Vitro*

The effect of mothers milk from the mothers of 7 jaundiced children was compared with milk from control mothers and from pregnant and postpartum cows on glucuronyl transferase activity in vitro. This infant jaundice a syndrome of severe and prolonged unconjugated hyperbilirubinemia occurred in association with breast feeding in 7 unrelated full-term infants. In vitro the breast milk obtained from the mothers of the 7 infants consistently inhibited glucuronyl transferase activity when compared with 99 milk specimens from 71 women whose infants did not have this syndrome. In vitro isolation of steroid products in the 2 milk pools (i.e. jaundiced infant vs. nonjaundiced) located a steroid pregnane-3(alpha)20(beta)-diol that was consistently present in the mothers milk from the jaundiced infant group but never present in control mothers milk. In vitro this steroid inhibited competitively glucuronyl transferase activity. The precursor of the isolated steroid pregnane-3(alpha)20(beta)-diol is unknown as are its mechanisms of action. The steroid metabolite is unknown in human tissues but is a major progesterone metabolite in guinea pigs and cattle. The same mothers whose breast milk inhibited glucuronyl transferase in vitro had serum samples tested similarly and the sera was no more inhibitory than that of normal mothers.

The narcotic-dependent mother: fetal and neonatal consequences.

During the years 1971--1974, 230 infants born to drug-dependent women and 33 infants born to ex-addicts were studied. Heroin abuse declined while methadone usage increased during those years. Compared to heroin abuse, methadone maintenance treatment during pregnancy was associated with more consistent prenatal care, more normal fetal growth and reduced fetal mortality. Meconium staining of amniotic fluid was increased in the heroin and heroin-methadone groups; this was not associated, however, with an increase in meconium aspiration or a reduction in Apgar scores. Of special note was the equally severe intrauterine growth retardation of infants of former heroin addicts who were free of narcotic use during pregnancy. Neonatal withdrawal from methadone appeared to be more severe than from heroin, as judged by amount of medication required to control symptoms and duration of treatment. In all groups, central nervous system signs were the most common manifestations of withdrawal. Severity of withdrawal did not correlate with late pregnancy maternal methadone dosage. Neonatal seizures occurred in 1.5% of the heroin group and 10% of the methadone group. Discharge of an infant to a parent rather than to an alternate care-taker was more likely if the mother was enrolled in a methadone treatment program. Methadone maintenance programs appear to offer significant therapeutic benefits, balancing the untoward effects of the drug on the newborn infant.

Development of bilirubin transport and metabolismin the newborn rhesus monkey

Hepatic transport and metabolism of bilirubin have been examined in term, premature, and postmature newborn Macaca mulatta (rhesus) monkeys with and without prior phenobarbital treatment of pregnant mother and neonate. In untreated neonates a biphasic pattern of physiologic unconjugated hyperbilirubinemia has been observed. Phase I was characterized by a rapid increase in serum bilirubin concentration to 4.5 mg/dl by 19 hours and an equally rapid decline to 1.0 mg/dl by 48 hours of age. Phase II was characterized by a stable elevation at 1.0 mg/dl (four times greater than in the adult) from 48 to 96 hourse of age, followed by a decline to normal adult concentrations thereafter. An identical pattern was observed in 29 normal, term human neonates, but the duration of each phase was approximately three times as long as that in the monkey. Phase I hyperbilirubinemia appears to result from a sixfold increase in bilirubin load presented to the liver in the neonatal period, combined with marked deficieny in hepatic bilirubin conjugation, the rate-limiting step during Phase I. Hepatic uptake of bilirubin is not rate limiting during Phase I but may contribute to Phase II hyperbilirubinemia. An increased bilirubin load persists throughout the first 19 days of life in the monkey. Phase I physiologic jaundice in the monkey neonate was completely eliminated by prenatal maternal and neonatal administration of phenobarbital. A threefold enhancement of hepatic conjugation of bilirubin (glucuronyl transferase activity) during Phase I entirely accounted for the prevention of hyperbilirubinemia. The bilirubin load was unaffected by administration of phenobarbital. Whereas in control neonates the bilirubin load slightly exceeded hepatic bilirubin conjugating capacity and resulted in retention of bilirubin, in phenobarbital-treated neonates, hepatic conjugating capacity slightly exceeded that required for the bilirubin load. Administration of phenobarbital failed to alter Phase II hyperbilirubinemia and did not enhance either maximal hepatic uptake or excretion of bilirubin. Hepatic glucuronly transferase activity was increased threefold during Phase II and during the remainder of the neonatal period. Premature birth retarded maturation of hepatic glucuronyl transferase activity. In one phenobarbital-treated premature monkey neonate, there was no apparent response to treatment. Accelerated maturation of bilirubin uptake, conjugation, and excretion of bilirubin was observed in one postmature monkey neonate.

Studies of prolonged neonatal jaundice in the breast-fed infant†

The clinical course of 20 breast-fed infants with prolonged unconjugated hyperbilirubinemia is described. Severe jaundice began during the latter part of the first or beginning of the second week of life and maximum concentrations of unconjugated bilirubin in the serum ranged from 9.0 to 26.0 mg. per 100 ml. Milk from the mothers of the jaundiced infants markedly inhibited hepatic glucuronyl transferase activity in vitro. Pregnane-3(α),20(β)-diol was isolated from milk obtained from 4 mothers of infants with prolonged jaundice, but has not been isolated from normal human milk. The relationship between intensity and duration of inhibition by milk and intensity and duration of hyperbilirubinemia in the infants is illustrated. Two thirds of the breast-fed siblings of the infants studied had a history of prolonged jaundice, whereas none of the artificially fed siblings had a history of prolonged jaundice.

The use of medium-chain triglycerides in the management of biliary atresia

This study demonstrates reduction in fecal fat losses, improvement in bowel patterns,or enhanced growth in 11 children with biliary atresia who were offered medium-chain triglyceride (MCT) diets. In 3 children the start of the MCT diet allowed for catch-up growth, and initiation of this formula during very early infancy in 3 other patients permitted a normal growth pattern. Careful clinical and laboratory appraisal of these patients failed to demonstrate any untoward effects.

Fluorescent dye method for determination of the bilirubin-binding capacity of serum albumin

A simple, rapid microfluorometric method utilizing a fluorescent dye, Direct Yellow 7, for quantitative measurement of serum albumin-binding capacity for bilirubin has been developed. The dye binds exclusively to serum albumin with enhancement of fluorescence. The dye shares bilirubin-binding sites on albumin with up to 2 mols of bilirubin per mol of albumin with differing affinities to the first and second sites. Lowered pH reduces albumin-binding capacity and exposure to light increases binding capacity of icteric sera. The binding capacity of adult human sera is greater than that of human cord sera or purified human serum albumin compared on albumin molar basis.

Solitary neonatal hepatic abscess

A solitary hepatic abscess was found at postmortem examination in a neonate who died at 25 days of age. Elevation of the right diaphragm was noted radiologically from the first day of life, suggesting congenital presence of the abscess. Recognition of the previously unsuspected association between hepatic abscess and congenital diaphragmatic elevation might have led to surgical intervention and have increased the infants chance of survival.

Hypocalcemia and the patent ductus arteriosus

THIS REPORT presents the findings of a controlled retrospective analysis undertaken to investigate the association of early neonatal hypocalcemia with persistent patency of the ductus arteriosus in low-birth-weight infants. METHODS The charts of all infants admitted to the Neonatal Intensive Care Unit of the Bronx Municipal Hospital Center (Kennedy Center Clinical Research Unit) between January 1, 1976, and April 30, 1978, with the diagnosis of PDA were reviewed. The diagnosis was based upon clinical evaluation by a senior neonatologist or a pediatric cardiologist, or both. The babies with PDA were subdivided into two groups: Subgroup A-infants managed successfully with fluid restriction, with or without administration of furosemide and digitalis, and Subgroup Bmore severely affected infants who, in addition to the above therapy, required indomethacin in an attempt to close their PDA. The criterion for the use of indomethacin was either the lack of improvement in concUrrent respiratory distress or the persistence of congest!ve heart failure after conservative medical managemen t . No infant in either group required surgical closure of the PDA. A control group of infants, without PDA, treated concurrently in the same unit, was matched by computer with the PDA group fo r gestationa! age, birth weight, and pattern of early respiratory distress. Both the control and the PDA groups were selected from the pool of neonates who survived the first two weeks of life, so that persistent patency of the ductus could be ascertained, and were either born in BMHC or transferred into the intensive care unit within the first 12 hours of life. All the infants were treated either in radiant warmers or incubators. Management of respiratory distress syndrome in both groups was similar. Those who required respiratory assistance were supported by a Bourns LS 104-150 volume ventilator (Bourns, IncorPorated, Life Systems, Riverside, Calif.). The babies were fed human milk when available, or PM 60/40 (24 calories/ounce) formula.

Diminished Enhancement of Hepatic UDP Glucuronyl Transferase (Bilirubin) by Phenobarbital during Pregnancy in the Rat

UDP glucuronyl transferase (bilirubin) (UDPGT) was studied in liver homogenates of pregnant and nonpregnant adult female rats. No change in maternal liver UDPGT activity was observed during pregnancy.