Louie Linarelli

Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis

Abstract Two siblings with impaired distal renal tubular acidification and nephrocalcinosis associated with vasopressin-resistant polyuria are described. They also exhibit decreased renal bicarbonate threshold and defective renal magnesium conservation with a concomitant hypomagnesemia. Evaluation of other family member revealed no such abnormalities. Parathyroid hormone (PTH) has been shown to affect the renal tubular handling of both bicarbonate and magnesium. The role of the hormone in the development of the observed abnormalities of excretion of these substances was evaluated in both siblings. Following initial determinations, which in the older child suggested increased PTH effect, studies were performed on the two siblings to assess levels of PTH secretion both by indirect methods and by direct immunoassay of their sera. The results indicated excessive PTH secretion in the older sibling, but not in the younger. It was concluded that increased PTH secretion was not responsible either for the abnormalities of bicarbonate excretion or for the excessive urinary magnesium losses demonstrated in the two siblings. Further, neither vitamin D resistance nor secondary hyperparathyroidism appears necessary for the development of nephrocalcinosis in such disorders. Finally, responses to therapy indicate that the acidosis in both siblings was corrected, as expected, by alkali administration, but the hypomagnesemia did not correct (due to increased urinary losses) with either oral on parenteral magnesium supplements.

Effect of phenobarbital on hyperlipemia in patients with intrahepatic and extrahepatic cholestasis

Four children with paucity of intrahepatic bile ducts and one with complete extrahepatic biliary atresia were treated with phenobarbital (final dose 6 to 12 mg. per kilogram per day). Clinical improvement occurred, as manifested by some relief of pruritus and decrease in size and number of xanthomata. An average of 50 per cent reduction in total serum lipids and total cholesterol occurred, and even greater reductions in free cholesterol and triglycerides. Serum bilirubin, transaminase, and alkaline phosphatase values were not significantly changed. There were significant improvements in lipoprotein electrophoretic patterns. The mechanism of the hypolipemic effect of phenobarbital was unclear. Phenobarbital is known to reduce the concentration of serum bile salts and to increase the hepatic excretion of the bile salts. The latter mechanism may be a partial explanation for some of the hypolipemic effects, especially in patients with paucity of intrahepatic bile ducts. These data suggest that phenobarbital is helpful in the management of hyperlipemia as well as of hyperbileacidemia and hyperbilirubinemia in cholestatic conditions.

Insulin-like Growth Factor 1 (IGF-1) and IGF Binding Protein-3 (IGFBP-3) Relationship To Height Velocity In Children With Idiopathic Short Stature 493

Serum IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratios were correlated with height velocity of children with idiopathic short stature (ISS). Thirty-one prepubertal male children ages 6.0 +/- 2.5 SD years whose height was below 2 standard deviations were studied. Stadiometer measurements were compared at baseline and at an interval of 1.17 +/- 0.99 yrs SD. Height standard deviation scores (SDS) were -2.2 +/- 0.7 SD, and height velocity was 5.5 +/- 2.0 SD cm/yr. Changes in IGF-1 and IGFBP-3 levels, and IGF-1/IGFBP-3 ratios were weakly correlated with height velocity (R =.29 P =.046, R = -.20 p =.140, R=.27 P =.071) and not statistically correlated with changes in height SDS (R=.15 P =.212, R = -.02 P =.448, R = -.05 P =.382). The actual serum levels were consistent with ISS and not growth hormone deficiency. In conclusion, in children with ISS, changes in IGF-1, IGFBP-3, and IGF-1/IGFBP-3 ratios measured between long-term periods do not significantly correlate with height velocity. These findings suggest that serial yearly measuremenents of IGF-1 and IGFBP-3 may not provide any additional information over observing height velocity in the management of children with ISS.

Self-Concept and Behavioral Characteristics in Hispanic Children and Adolescents with Acanthosis Nigricans 402

Self-Concept and Behavioral Characteristics in Hispanic Children and Adolescents with Acanthosis Nigricans 402

TRANSIENT NEONATAL DIABETES MELLITUS TREATED WITH INSULIN INFUSION PUMPS AND PANCREATIC BETA CELL FUNCTION FOLLOWED BY URINARY C-PEPTIDE EXCRETION

JM was a 1928 gram, 36-week small for gestation age male infant born to a Grav.-III, Para-0 mother. Hyperglycemia of 340 mg % was identified on arrival to the nursery. Conventional approach changing from regular to NPH insulin proved unsatisfactory. Thus regular S.C. insulin (U20) was administered every 3 hrs pre-formula feeding based on Glucometer blood heel stick glucose using a sliding scale insulin dosage of 0.1 to 0.5 units. Pen-Pump (U20 regular insulin) was utilized with manual administered pre-meal doses. Insulin syringes were refilled every 12 to 24 hrs and needle sites changed every 2 to 3 days. A trial on CPI Model 9100 ambulatory infusion pump was shown feasible with continuous insulin of 3 units/24 hr rate (U10 insulin). JM was discharged at 1 month of age on a Pen-Pump with home glucose monitoring pre-meals and sliding dose regular insulin. An infusion site staph aureus cellulitis resulted in rehospitalization. A new trial of NPH (U10) b.i.d. proved effective in management by six weeks of age in the range of 2.2 units b.i.d. As the NPH insulin dose decreased from 2.2 U b.i.d. to 0.3 U b.i.d. from 3 to 6 mos. of life, home glucose monitoring, hemoglobin A1C and urine C-peptide were helpful guidelines. Urine C-peptide proved an effective means of following residual pancreatic beta cell function with recovery of diabetes by 6 mos. of age. Timed measured urine samples every 2 weeks showed a rise from nil C-peptide to 4.0 ng/ml with return of pancreatic beta cell function.Urine C-Peptide measured by Immunex Tek-Pharma, Sorrento Valley,CA

A METABOLIC BASIS FOR SEVERE INTRACTABLE ASTHMA

We have previously reported that severe asthmatics after receiving catecholamines have decreased urinary cyclic AMP as compared to normals. To better define this abnormality, which suggests B-adrenergic blockade, 15 severe asthmatic children were studied prospectively. Whereas, normals had a mean 3.2±0.4 Nm/min/1.73M2 increment in 2 hour urinary cyclic AMP, asthmatics had a mean 1.6±0.3 Nm/min/1.73M2 increment after 6 μg/Kg of epinephrine. After 12 μg/Kg epinephrine the asthmatics had a mean 2.2±0.4 Nm/min/1.73M2 increment in 2 hour urinary cyclic AMP: individually, 7 asthmatics had no increased urinary cyclic AMP excretion with double the epinephrine; whereas, 8 patients had 1.0 to 5.2 Nm/min/1.73M2 increment after 12 μg/Kg epinephrine. Clinical evaluation the past 18 months demonstrated that 6 of 7 asthmatics who had no increase in urinary cyclic AMP to 12 μg/Kg epinephrine persisted with severe intractable asthma. However, 5 of 8 asthmatics who demonstrated with the dose response test an increase in urinary cyclic AMP had clinical improvement: their asthma is intermittent and less severe. These data support the hypothesis that severe asthmatic patients have a defect in formation of cyclic AMP after B-adrenergic stimulation. Also, lack of a dose response to epinephrine has delineated a unique group of asthmatics.

METABOLIC RESPONSE TO I.V. GLUCAGON IN CHILDREN WITH CHRONIC LIVER DISEASE

Studies were performed to evaluate glucose homeostasis in children with intrahepatic biliary hypoplasia (IBH) with chronic cholestatic syndrome and growth retardation. Eight I.V. glucagon tolerance tests (30 μg/kg) on five IBH patients (4-12 yrs of age) were compared to 8 controls. Fasting (14-16 hr) glucose was lower in IBH (67 ± 4 mg% vs 80.8 ± 3.67; p < 0.025), and peak rise was significantly less (107 ± 10.6 vs 147 ± 7.9; p < 0.01). Baseline urinary cyclic AMP levels in IBH vs controls (5.8 ± 2 M ± S.E.M. nmoles/mg creatinine vs 4.5 ± 0.4) and 2 hour excretion response to glucagon (31.1 ± 3 vs 28.6 ± 5.2) were not significantly different. Insulin response to glucagon were similar in IBH vs control. Glucagon has previously been shown to lower plasma gluconeogenic amino acids as a indication of hepatic uptake and gluconeogenesis. Fasting plasma alanine was not significantly different in IBH vs control (210 ± 38 umoles/L vs 245 ± 40). Controls had a significant delta decline at 30 minutes post - glucagon of 100 umoles/L for alanine, 66 for glycine and 39 for glutamine plus asparagine. IBH patients failed to elicit a consistent reduction in gluconeogenic amino acids. These studies suggest that hepatic gluconeogenesis and glycogen storage are impaired in chronic liver disease. The noted cyclic AMP response may reflect adequate adenyl cyclase activity in spite of hepatocellular damage.

PUBERTAL RICKETS WITH FAILURE OF RENAL PHOSPHATE AND CYCLIC AMP RESPONSE TO PARATHORMONE; AN EXPLANATION FOR PSEUDO HYPOHYPER-PARATHYROIDISM

An 11 y o girl had unilateral ankle bowing during the pre-menarchial growth spurt while on normal dietary vitamin D. Generalized rickets on x-ray, slight decrease in serum Ca (8.8 - 9.7) and increase in P (5.4 - 6.3 mg%) and alk.phos. (8.4 BLU) were associated with failure to increase phosphate clearance with parathormone (pth). Malabsorption was excluded by appropriate studies. Rickets healed completely and 47 calcium absorption was normal during 2 years on vit D2 50,000 IU/day, yet laminas dura were absent and remained so after adult height was reached. Restudy at age 15 years showed failure of increase in phosphate clearance, and CAMP (Δ 2.2 nanomoles/mg creat; vs 36 ± 0.7 SEM controls) with I.V. pth. Basal pth 640 pg/ml (normal 135 - 350) was elevated and decreased to normal 211 following Ca infusion, ruling out primary hyperparathyroidism.We suggest that renal unresponsiveness to pth and failure to lower renal tubular cell P interfered with conversion of 25-OH-D2 → 1,25-OH-D2 with resulting hypocalcemia, rickets, and hyperparathyroldism during the stress of pubertal growth. This represents a novel explanation of pubertal onset rickets with hyperparathyroidism in absence of renal disease and is probably the basis of so called pseudo hypo-hyperparathyroidism.