Michael F. Bryson

Long-term administration of antiepileptic drugs and the development of rickets

Two young children developed rickets as a complication of anticonvulsant therapy and were subsequently cured by vitamin D therapy. They are the youngest patients thus far reported, and the first to be reported in the United States. On the basis of clinical studies, rickets and osteomalacia can be added to the list of toxic effects of anticonvulsant therapy. Although the exact mechanism of pathogenesis remains to be elucidated, it appears likely that these drugs alter the metabolism of vitamin D in certain patients. Special attention should be paid to the status of calcium and phosphorus metabolism in children who are receiving such drugs, and to their intake of vitamin D.

IMPAIRED CALCIUM HOMEOSTASIS IN THE INFANTILE HYPERCALCEMIC SYNDROME

The etiology of the “severe form” of the infantile hypercalcemic syndrome (a rare condition which includes supravalvular aortic stenosis, mental retardation, and an “elfin facies”) is not known, nor has the origin of the hypercalcemia been established. Current hypotheses include vitamin D hypersensitivity or excess, an abnormality of cholesterol metabolism, and delayed turnover or degradation of vitamin D. Although a review of the literature led Seelig (28) to conclude that these patients have an increased response to vitamin D, Fraser et al. (14) are of the opinion that none of these hypotheses have been proven. The hypercalcemia usually disappears during childhood but the other features remain. Although large oral doses of vitamin D will intensify the hypercalcemia in infants with this syndrome (28), modest doses do not alter serum calcium in older children (5, 13, 33). Barr & Forfar (6) and Dormandy & Begum (11) have reported that an oral calcium load resulted in higher and more sustained levels

Further observations on trypsinogen deficiency disease. Report of a second case.

A second infant with trypsinogen deficiency disease is described. The infant presented with severe hypoproteinemia, edema, anemia, and growth failure, and subsequently developed dyspigmentation of the hair. The clinical abnormalities and their dramatic response to protein hydrolysate diet are strikingly similar to those of the first patient described. The finding of a second case unrelated to the first in a single community suggests that trypsinogen deficiency disease is probably not a rare disease. Since it is a treatable disorder, it is important to consider it in the differential diagnosis of any infant with hypoproteinemia, edema, and failure to thrive.

Bilateral nephrectomy and splenectomy in renal failure

Abstract Sixty consecutive patients treated by bilateral nephrectomy and splenectomy as a preparation for renal transplantation are reviewed. Only 8 (13.3 per cent) of the patients were totally free of complications related to the procedure. The most frequent complications noted were atelectasis, pneumonia, hypotension, hyperkalemia, pulmonary effusion, hypertension, and gastrointestinal bleeding. There were 7 deaths in the group (11.7 per cent). As a result of this review bilateral nephrectomy in preparation for transplant is recommended to patients only with the following problems: uncontrolled hypertension of the high renin variety; infected, obstructed kidneys or the presence of vesicoureteral reflux; Goodpastures disease or certain cases of rapidly progressive glomerulonephritis, and some patients with polycystic kidney disease. The role of splenectomy is still controversial.

Metabolic Response to Growth Hormone Administration, with Particular Reference to the Occurrence of Hypercalcuria

Extract: The effect of human growth hormone (GH) administration (5 mg daily) was studied in 12 children with short stature, in an attempt to elucidate the cause of the hypercalcuria which so commonly occurs at the initiation of GH therapy. Complete metabolic balances were determined for Ca, P, N, Na, K, and Cl; and urine was analyzed for hydroxyproline, stable Sr, Pb, Mg, 137Cs, F, and creatinine. Some subjects had determinations of basal metabolic rate (BMR) and of ultrafiltrable serum Ca. In keeping with the reports of others, levels of N, P, K, Na, and Cl in urine all declined, as did that of 137Cs; Mg excretion fell slightly.Ten of the 12 children with short stature (6 of whom had subnormal plasma GH responses to a variety of stimuli) had hypercalcuria; 3 of these had an increase in urine Ca in the face of a low Ca diet (170 mg/24 hr). Fecal Ca declined in some subjects and rose in others. Ultrafiltrable serum Ca did not change.A majority of the subjects showed an increase in the urinary excretion of F, Sr, Pb, and hydroxyproline.The effect of the hormone was also studied in three patients with idiopathic hypo-parathyroidism; two of these responded with an increase in urine Ca.The magnitude of the rise in urine Ca could not be correlated with changes in BMR, changes in creatinine clearance, or changes in Na excretion; it was positively correlated with the increases in Sr and Pb in urine.Speculation: We have evidence that the hypercalcuria accompanying GH administration is not due to increased gastrointestinal absorption, alterations in serum Ca, or changes in metabolic rate or renal function; nor is it mediated via parathyroid activity. These considations, plus the fact that the hypercalcuria is accompanied by hydroxyprolinuria and an increase in the urinary excreation of three “bone seekers” (Sr, Pb, and F), lead us to postulate that the hormone enhances bone resorpation, either per se or via “sulfation factor.”

Metabolic risk factors for cardiovascular disease in a working population: A retrospective cohort study

Risk factors for cardiovascular disease (CVD) appear to cluster in individuals, possibly because of a single, underlying metabolic disorder. We describe the prevalence of metabolic risk factors for CVD in a young working population and the tendency for individuals with some risk factors to acquire additional factors. This was a retrospective three-year follow-up study of baseline CVD risk factors assessing (1) incidence of risk factors and (2) fatal CVD. The study group consisted of 9,747 Eastman Kodak employees, who participated in a worksite-based cardiovascular screening program in Rochester, New York, which included a medical history, physical examination, and laboratory evaluation. Abnormal metabolic risk factors were defined as (1) an abnormal glucose value (fasting blood sugar greater than 115 mg/dl); (2) abnormal lipids (high-density lipoprotein cholesterol under 35 mg/dl in men or under 45 mg/dl in women; or low-density lipoproteins of 160 or greater; or triglycerides greater than 250 mg/dl), and (3) hypertension (blood pressure systolic above 160 mmHg; or diastolic above 90 mmHg). Subjects were classified as having none, one, two, or all three risk factors. Prevalence of single risk factors were: hypertension 9.8%, abnormal lipids 22.6%, and abnormal glucose 1.5%. Combinations of two risk factors were greater than expected by chance (p < 0.01). Individuals who started with one or more abnormal values tended to have an increased risk of developing others. The highest relative risk (RR) was for those with hypertension and a later diagnosis of abnormal glucose (RR 2.0; 95% CI = 0.87, 4.58). Seven employees of 4,263 with at least one risk factor died of CVD, compared with one of 5,484 employees with no factors (RR 9.0, 95% CI = 1.1, 73.2). In conclusion, this study suggests that young working individuals with CVD risk factors may continue to acquire additional factors. This clustering could be an indication of an underlying metabolic disorder and identify individuals at risk for negative CVD sequelae.

Hereditary hemorrhagic telangiectasia of bladder in a child

Abstract A female child with gross painless hematuria and cutaneous telangiectasia was found to have 3 telangiectasic areas in the bladder. This represents a case of Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia), a rare occurrence in a child or in the urinary bladder.

Effect of growth hormone on fluoride balance

Fluoride balances were determined in nine children, aged 4 to 18 years, undergoing treatment with human growth hormone. Urinary F was increased in 6 of the 9 subjects during the period of initial treatment. The hyperfluoruria occurred in the face of a preexisting negative F balance. Fecal F did not change, and since the magnitude of the hyperfluoruria could not be correlated with changes in renal function it is likely that it, together with the increases in Ca and hydroxyproline excretion, represents a direct effect of the hormone (or possibly “sulfation factor”) on bone resorption. During the control periods, the F balance data reveal that 10–90% of dietary F (all of which came from food) appeared in the feces; these values are generally higher than those reported for subjects whose intake was primarily from water.RésuméDes bilans de fluor ont été réalisés chez neuf enfants, âgés 4 à 18 ans, soumis à un traitement à l’hormone de croissance humaine. Le F urinaire est augmenté chez 6 des 9 sujets pendant la période de traitement initial. L’hyperfluorurie s’observe au cours de la phase de bilan négatif en F. Le F fécal ne change pas et, étant donné que l’amplitude de l’hyperfluorurie ne parait pas liée à des modifications de la fonction rénale, il est vraisemblable qu’il s’agisse d’un effet direct de l’hormone (ou peut-être «du facteur de sulfatation») sur la résorption osseuse, ainsi que des augmentations en excrétions en Ca et en hydroxyleproline. Pendant les périodes de contrôle, les résultats de bilans en F montrent que 10–90% du F alimentaire apparait dans les fèces: ces valeurs sont généralement plus élevées que celles relevées chez des sujets où l’apport provient surtout de l’eau.ZusammenfassungBei 9 Kindern zwischen 4 und 18 Jahren, welche menschliches Wachstumshormon erhielten, wurden die Fluoridbilanzen bestimmt. Das Fluorid im Urin war zu Beginn der Behandlung bei 6 von den 9 Kindern erhöht. Die Hyperfluorurie fand sich auch bei einer vorherigen negativen Fluorid-Bilanz. Der fäkale Fluoridgehalt veränderte sich nicht, und da die Höhe der Hyperfluorurie nicht mit Veränderungen der Nierenfunktion in Zusammenhang gebracht werden konnte, scheint es wahrscheinlich, daß die Hyperfluorurie, zusammen mit der erhöhten Calcium- und Hydroxyprolinausscheidung, eine direkte Wirkung des Hormons (oder möglicherweise des „Sulfation-Faktors”) auf die Knochenresorption darstellt. Die Fluorid-Bilanzdaten während der Kontrollperioden zeigen, daß 10–90% des eingenommenen Fluorids (ausschließlich aus der Nahrung stammend) in den Faeces erschienen; diese Werte sind allgemein höher als diejenigen von Personen, welche das Fluorid hauptsächlich in Wasser erhielten.

Sony-W sharing of cadaver kidneys for transplantation

Abstract A regional network composed of 12 major medical centers has been organized in southern Ontario, Canada, and upstate New York. During the first four years of experience over 85 cadaver kidneys have been transported to the institution of the waiting recipient. The majority of kidneys were judged to be functioning at thirty days. Simple flushing of the kidney with 500 ml. of Ursol (University of Rochester Solution) is effective in preserving the kidney for fifteen hours.

ARGININOSUCCINIC ACIDURIA: A SURVIVOR OF THE NEONATAL VARIANT

The neonatal form of argininosuccinic aciduria (ASA) is usually fulminating and lethal. J.V. presented at two days of age with this variant and is developnentally normal at four months.At two days of age, following milk feedings, J.V. became hypothermic and lethargic. He had respiratory alkalosis (ph=7.57), hyperammonemia (771 μg/dl) and ASA. EEG was diffusely abnormal. Family history was negative. Therapy included mechanical ventilation, peritoneal dialysis and gut sterilization. An initial protein free formula was followed by a 1.6 gm protein/kg/d formula at 16 days of age, after his blood ammonia had fallen below 200 μg/dl. Urine quantitation had 328 mg/d of ASA (normal = trace). Skin culture assay for argininosuccinase activity showed J.V. had 0.006/<moles urea/ mg protein/hr, his parents 0.044 and 0.049, with the control of 0.073.At four months J.V. has normal blood ammonia (38 μg/dl) on a 1.6 gm protein/kg/d diet. Growth parameters are all at the third percentlie. Denver Developmental, neurological, and EEG are all currently normal. ASA should be considered in neonates presenting with signs of sepsis because even the “ fulminant ” form of the disease may be amenable to aggressive medical therapy.