Paul V. Fennessey

Diagnostic Importance of an Increased Serum Anion Gap

Abstract Fifty-seven hospitalized patients with increased serum anion gaps, defined as [Na] − ([Cl] + [HCO3]), were studied to explore the biochemical basis and the diagnostic importance of the anion gap. We found that an anion gap greater than 30 meq per liter was usually due to an identifiable organic acidosis (lactic acidosis or ketoacidosis). However, 10 of 35 patients (29 per cent) with anion gaps of 20 to 29 meq per liter did not have lactic acidosis or ketoacidosis. In 22 patients, the composition of the anion gap was studied in detail. Lactate and ketoanions accounted for 62 per cent of the increments in anion gaps, and changes in the equivalents of total proteins, phosphorus, potassium, and calcium accounted for 15 per cent. However, nine patients had an increment in anion gap of 5.5 meq per liter or more (average, 8.7 meq per liter) that was not explained by any of the factors measured here. The possibility of unidentified anions or unrecognized changes in the ionic equivalents of normal plasma ...

Steady state maternal-fetal leucine enrichments in normal and intrauterine growth-restricted pregnancies.

The aim of this study was to compare the fetal/maternal (F/M) leucine-enrichment ratio in normal (AGA) and intrauterine growth-restricted (IUGR) pregnancies at the time of fetal blood sampling (FBS). A maternal primed-constant infusion of L-[1-13C]-leucine was given in six AGA and 14 IUGR pregnancies, divided into three groups according to the pulsatility index (PI) of the umbilical artery and to fetal heart rate (FHR): group 1 (normal FHR and PI, four cases); group 2 (normal FHR and abnormal PI, five cases); and group 3 (abnormal FHR and PI, five cases). Maternal arterialized samples were taken at time zero and every 20 min for 125 ± 7 min. Umbilical venous samples were obtained after 114 ± 42 min of infusion. Under steady state conditions, there was a significant linear relationship between maternal leucine disposal rate and maternal leucine concentration. The comparison of fetal to maternal leucine enrichment showed a progressive dilution of the fetal enrichment relative to the mother between AGA and IUGR of group 1 (0.89 versus 0.78, p < 0.02), group 2 (0.71, p < 0.001), and group 3 (0.62, p < 0.001), and also among the three IUGR groups. The F/M leucine molar percent enrichment (MPE) ratio showed a positive correlation with the umbilical venous oxygen content and an inverse correlation with fetal lactate concentration. We conclude that the dilution in the fetal/maternal leucine-enrichment ratio correlates with the severity of growth restriction and reflects decreased transplacental leucine flux and/or increased protein breakdown within the fetoplacental compartments.

Human β-mannosidase deficiency

LYSOSOMAL disorders in humans due to deficiencies of lysosomal enzymes or effector proteins (activator or protector proteins) have been described for most steps in the catabolism of glycoproteins, ...

Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Aciduria Type II) with Transient Hypersarcosinemia and Sarcosinuria; Possible Inherited Deficiency of an Electron Transfer Flavoprotein

Summary: When amino acids were infused at a rate of 4 g/kg/day, an infant with hypoglycemia, metabolic acidemia and chronic regurgitation showed hypersarcosinemia and excreted abnormal amounts of sarcosine, isovalerylglycine, isobutyrylglycine, α-methylbutyrylglycine, and β-hydroxyisovaleric, glutaric, α-hydroxyglutaric, methylsuccinic, and α-hydroxyisobutyric acids in urine. On all other occasions, when protein intake was lower and lipid intake higher, urine organic acids were dominated by methylsuccinic, ethylmalonic, and α-hydroxyglutaric acids, and hypersarcosinemia was absent. Autopsy showed severe fatty changes in liver, kidneys, and skeletal muscle. A previous female sibling had died with similar autopsy findings at 4 days of age. While activity of glutaryl-CoA dehydrogenase was completely deficient in liver and almost completely so in kidney, it was normal in cultured fibroblasts in the presence of flavin adenine dinucleotide (FAD) and only marginally low in its absence. Incorporation of d-(2-14C) riboflavin into flavin mononucleotides (FMN) and FAD by kidney tissue was normal.The authors conclude that this disorder is not due to generalized deficiency of glutaryl-CoA dehydrogenase or to a defect in FAD synthesis. The amino and organic acid abnormalities noted are most consistent with a defect in the flavoprotein which transfers electrons from the FAD of sarcosine and acyl-CoA dehydrogenases into the respiratory chain, although a defect in intercompartmental transfer of C4-5 acyl CoA esters across cell membranes is not excluded.The variability of the organic aciduria, which possibly reflects changes in protein and fat intake, suggests that a previous name for this disorder, i.e., glutaric aciduria type II, is inappropriate and should be replaced, perhaps by “multiple acyl-CoA dehydrogenase deficiency.”Speculation: What appears to be simultaneous deficiency of several acyl-CoA dehydrogenases may be caused by a number of different primary gene defects; the presence of hypersarcosinemia and/or sarcosinuria may delineate a subtype due to deficiency of an electron carrier flavoprotein. Further, the presence of organic aciduria may define a form of hypersarcosinemia more likely to be associated with phenotypic abnormalities than isolated deficiency of the sarcosine dehydrogenase apoenzyme.

Biochemical and Clinical Aspects of the Human Flavin-Containing Monooxygenase Form 3 (FMO3) Related to Trimethylaminuria

Trimethylaminuria is a rare metabolic disorder that is associated with abnormal amounts of the dietary-derived trimethylamine. Excess unmetabolized trimethylamine in the urine, sweat and other body secretions confers a strong, foul body odor that can affect the individuals ability to work or engage in social activities. This review summarizes the biochemical aspects of the condition and the classification of the disorder into: 1) primary genetic form, 2) acquired form, 3) childhood forms, 4) transient form associated with menstruation, 5) precursor overload and 6) disease states. The genetic variability of the flavin-containing monooxygenase (form 3) that is responsible for detoxication and deodoration of trimethylamine is discussed and put in context with other variant forms of the flavin-containing monooxygenase (forms 1-5). The temporal-selective expression of flavin-containing monooxygenase forms 1 and 3 is discussed in terms of an explanation for childhood trimethylaminuria. Information as to whether variants of the flavin-containing monooxygenase form 3 contributes to hypertension and/or other diseases are presented. Discussion is provided outlining recent bioanalytical approaches to quantify urinary trimethylamine and trimethylamine N-oxide and plasma choline as well as data on self-reporting individuals tested for trimethylaminuria. Finally, trimethylaminuria treatment strategies and nutritional support are described including dietary sources of trimethylamine, vitamin supplementation and drug treatment and issues related to trimethylaminuria in pregnancy and lactation are discussed. The remarkable progress in the biochemical, genetic, clinical basis for understanding the trimethylaminuria condition is summarized and points to needs in the treatment of individuals suffering from trimethylaminuria.

In Vivo Placental Transport of Glycine and Leucine in Human Pregnancies

ABSTRACT: L-[1-13C]Glycine and L-[l-13C]leucine were infused as a bolus into 12 pregnant patients carrying normal fetuses before fetal blood sampling at gestational ages ranging from 20 to 37 wk. Maternal venous samples were obtained every 2-3 min for 15 min after the bolus infusion. Fetal samples were obtained from the umbilical vein within 15 min of the bolus. Amino acid plasma enrichments (molar percent enrichment) were determined by gas chromatography-mass spectroscopy and their concentrations by ion exchange chromatography. The ratios of glycine and leucine transfer were assessed from fetal/maternal enrichment ratios for each amino acid. We now report that over the gestational age range of 20-37 wk, under relatively undisturbed fetomaternal conditions (fetal blood sampling), human placental glycine transfer is limited, with a glycine/leucine ratio = 0.16 ± 0.02. We hypothesize that, in human pregnancies, the relative rates of in vivo transplancental transport of amino acids can be assessed indirectly utilizing fetal blood sampling and stable isotope methodology. The application of this approach to leucine and glycine demonstrates that the transfer of leucine is rapid (demonstrable in seconds), whereas that of glycine is more limited.

The use of stable isotope techniques to assess zinc metabolism

The refinement of techniques that can accurately measure small changes in zinc stable isotope ratios in biological samples provides new opportunities for advancing our understanding of human zinc metabolism. The feasibility of utilizing more than one zinc stable isotope label simultaneously is invaluable for more complex kinetic studies. These techniques are especially valuable for investigations of the regulation of Zn homeostasis in infants and in women during the reproductive cycle in whom problems with zinc nutriture may be relatively frequent and of concern for preand postnatal growth and development. Initially, these techniques have been applied to studying the role of the intestine in the maintenance of zinc homeostasis and have served to emphasize the importance of the modulation of fecal excretion of endogenous zinc. Application of stable isotope techniques to explore zinc metabolism beyond the intestinal tract is still limited but has considerable potential for advancing our understanding of zinc metabolism in health and disease.

An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies

The presence of fetal glucogenesis was evaluated in nine patients with pregnancies complicated by intrauterine growth retardation (IUGR) at the time of fetal blood sampling (FBS) between 29 and 35 weeks of pregnancy. Eight were singleton pregnancies and one was a twin pregnancy in which blood samples were obtained from both twins. A maternal primed-constant infusion of D(U-13C]glucose was performed, and the presence of fetal glucogenesis was assessed by a comparison of steady-state maternal and fetal glucose enrichments. No significant difference was present between maternal and fetal molar percent excess ([MPE] P = .97), and the mean fetal to maternal (F/M) MPE ratio (0.99 +/- 0.01) was not significantly different from 1 (P = .76). F/M MPE ratio was independent of the time of FBS and umbilical venous glucose and lactate concentrations. Thus fetal glucogenesis is not demonstrable in a group of fairly severe growth-retarded fetuses after an overnight fast with this relatively noninvasive approach.

Metabolism and Transport of Maternal Serine by the Ovine Placenta: Glycine Production and Absence of Serine Transport into the Fetus

ABSTRACT: The present study compares the transplacen-tal transport of L-[l-13C]serine and L-[l-13C]leucine in sheep. An in vivo preparation using twin gestations was set up such that the arterial circulation to one uterine horn, including its placenta and fetus, was infused with tracer serine and leucine while the umbilical circulations of both fetuses were sampled. Uterine and umbilical blood flows were measured in each horn. Plasma serine enrichments were 14.6 ± 2.7% and 4.3 ± 1.6% in the uterine veins draining the experimental and control horns, respectively. Fetal plasma leucine enrichments in the umbilical veins were 50 and 55% of the uterine venous enrichments in the control and experimental fetuses, respectively. By contrast, during 280 min of infusion, there was no detectable serine enrichment in either fetal circulation. However, significant plasma glycine enrichment was present in the fetal circulation of the experimental horn and venous glycine enrichments in the experimental horn were significantly greater than arterial glycine enrichments for both the umbilical (p < 0.02) and uterine (p < 0.001) circulations. We conclude that under conditions in which leucine transport is easily demonstrable there is no significant transplacental transport of maternal serine and that maternal plasma serine is used within the uteroplacental tissues for producing glycine, some of which is delivered into the fetal circulation.

Comparison of leucine, serine and glycine transport across the ovine placenta

To estimate the transport rate of maternal glycine across the placenta [1-13C]glycine and L-[1-13]serine were infused intravenously in pregnant sheep using both continuous and bolus infusions. Each tracer was infused together with L-[1-13C]leucine, to enable a comparison with the placental transport of an essential amino acid. At steady state, fetal plasma leucine enrichment was 40 per cent of maternal enrichment, indicating that approximately 60 per cent of the entry rate of leucine into fetal plasma is derived from protein breakdown in the placenta and fetus. Fetal plasma glycine enrichment was 11 per cent of maternal and there was no detectable fetal serine enrichment. The direct flux of maternal leucine into the fetal circulation was approximately 3.0 (bolus experiments) to 3.6 (continuous infusion experiments) mumol/min (kg fetus) and greater than the estimated 1.4 mumol/min (kg fetus) direct flux of maternal glycine, despite the fact that the net umbilical uptake of glycine exceeds that of leucine. This supports the conclusion that placental glycine production is a quantitatively important contribution to fetal glycine uptake via the umbilical circulation. The fetal glycine supply from the placenta is provided by a relatively small direct maternal glycine transplacental flux and a larger contribution derived from serine utilization within the placenta for glycine production.