Craig B. Langman

Latent Hypoparathyroidism in Children With Conotruncal Cardiac Defects

BACKGROUND DiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell-mediated deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11. METHODS AND RESULTS Blood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions. CONCLUSIONS A significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.

Role of Fetal 1,25-Dihydroxyvitamin D Production in Intrauterine Phosphorus and Calcium Homeostasis

ABSTRACT: During intrauterine life, fetal mineral accretion depends on active transfer from mother to fetus by the placenta. To evaluate the role of fetal production of 1,25-dihydroxyvitamin D in regulation of fetal phosphorus, calcium, and parathyroid homeostasis, studies were performed in ewes and their fetal lambs. Fetal nephrectomy caused a rise in fetal serum phosphorus and a fall in total calcium 5 days after nephrectomy. Fetal blood ionized calcium also fell and serum parathyroid hormone rose. In sham-nephrectomized fetuses, all four measurements were unchanged compared to control values. Simultaneous maternal values of ionized calcium were normal in control and nephrectomized fetuses. Fetal ureteral severance and drainage of urine into the fetal peritoneal cavity produced none of the effects of fetal nephrectomy. Daily intravenous injection of 1,25-dihydroxyvitamin D into fetuses after nephrectomy prevented the rise in serum phosphate, and serum calcium did not fall. The results suggest that fetal 1,25-dihydroxy vitamin D regulates fetal phosphate homeostasis, perhaps by the placenta, which in turn regulates blood-ionized calcium concentration.

Vitamin D metabolism and osteomalacia in cystic fibrosis

A 25-yr-old black man with cystic fibrosis and cirrhosis developed symptoms of osteomalacia and hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and low circulating 25-hydroxyvitamin D (25-OHD). Serum 1,25-dihydroxyvitamin D (1,25-[OH]2D) was within the normal range. Iliac crest bone biopsy confirmed the diagnosis of osteomalacia. Oral administration of 50,000 IU of vitamin D2 failed to relieve symptoms or raise serum 25-OHD levels to normal. Intramuscular vitamin D2, 10,000 IU every 8-12 week, improved symptoms, raised serum 25-OHD to normal, and increased circulating 1,25-[OH]2D to values five times normal. Over the next 10 mo circulating 1,25-[OH]2D remained elevated despite normalization of serum calcium, phosphorus, and parathyroid hormone. Repeat bone biopsy 1 yr after parenteral vitamin D showed healing of the osteomalacia. Malabsorption of vitamin D appears secondary to profound steatorrhea due to pancreatic insufficiency and secondary biliary cirrhosis. Although extensive hepatocellular disease was present, hepatic conversion of vitamin D to 25-OHD was intact. Both high and low circulating 1,25-[OH]2D levels during active osteomalacia have been reported; initially, the level was in the normal range and higher values in this patient occurred with repletion of 25-OHD substrate. This study shows that symptomatic osteomalacia may be a major manifestation of cystic fibrosis in those patients surviving into adulthood. Measurements of serum 25-OHD in cystic fibrosis patients may identify those who should receive supplemental vitamin D.

Intestinal Calcium Transport In Utero. Clinical Implications for the Newborn Infant

Calcium requirements for growth and for skeletal mineralization during fetal life and in early postnatal development are substantial. During fetal life, significant active transfer of calcium occurs from mother to fetus via the placenta.1 At birth, the connection between mother, placenta, and infant is severed and the intestinal tract becomes the major organ of calcium acquisition for the infant. Early studies in newborn animals demonstrated increased rates of intestinal calcium absorption compared to adult animals.2 However, recent studies of vitamin D deficient and vitamin D-replete rat pups showed that intestinal calcium transport during the first two weeks of life is not meditated by 1,25-dihydroxyvitamin D as is true for adult animals.3 In these studies, a vitamin D-sensitive intestinal calcium transport system developed late in the suckling and in the early weanling period. In light of developmental changes taking place in the intestinal tract and the apparent lack of absolute dependence on vitamin D mediated intestinal calcium transport in the immediate postnatal period, we began studies on the ontogeny of intestinal calcium transport in utero. This paper reports the results of preliminary experiments carried out in fetal lambs.

1223 HIGH EXTRACELLULAR PHOSPHATE (Pi) IN VITRO REVERSES THE INHIBITION OF 1,25(OH) 2 D 3 (1,25D) SYNTHESIS IN CHRONIC METABOLIC ACIDOSIS (CMA)

Low calcium diet (LCD) and low Pi, in vitro, stimulate 1,25D synthesis by proximal tubules (PT). CMA inhibits the rise in serum 1,25D during LCD, but the effect on synthesis is unknown. To investigate in vitro synthesis of 1,25D during CMA, Sherman rats were fed LCD±1.5% NH4Cl for 10d. to produce CMA (pH=7.34±.03, LCD vs. 7.23±.03, LCD±NH4Cl, p<.05). PT in suspension were incubated for 20 min. in Krebs-Henseleit bicarbonate (KHB) media, pH 7.4, in KHB low in Pi (0.2mM Pi, KHB-Pi), high in Pi (4.6mM Pi, KHB+Pi), low in Ca (0.2mM Ca, KHB-Ca), or low in both (KHB-CaPi), and then for 5 min. at 37°C with 16.6uM 25OHD3 to measure 1,25D synthesis. PT from rats fed LCD produced 10±1 pmol l,25D/mg protein in KHB; 20±2 in KHB-Pi and 21±3 in KHB-CaPi (p<.005 vs. KHB for each); 8±1 in KHB+Pi and 11±1 in KHB-Ca (p=NS vs. KHB for each). PT from rats fed LCD+NH4Cl produced 5±1 pmol l,25D/mg protein in KHB (p<.001 vs. LCD, KHB);8±1 in KHB+Pi(p<.05 vs. KHB);4±2 in KHB-Pi, 4±2 in KHB-Ca, and 4±1 in KHB-CaPi (p=NS vs.KHB). Pt cAMP from rats fed LCD±1.5% NH4Cl were similar (p=NS), and were not altered by media Ca or Pi.Conclusions: normalization of pH in vitro did not restore diminished 1,25D synthesis in Pt from rats with CMA. CMA blocks cAMP dependent 1,25D synthesis distal to cAMP generation, and also blocks cAMP independent (low Pi) 1,25D synthesis. High medium Pi, in vitro, reverses the inhibition of cAMP dependent 1,25D synthesis in CMA. CMA may be a state of critical PT Pi depletion.

Metabolic Bone Disease in Low Birth Weight Neonates

The marked advances in neonatal care over the last decade have allowed survival of the small premature infant less than 1500 gms. Unfortunately, the advances in survivorship have been accompanied by a multitude of new problems, including the presence of bone disease which may result in short term morbidity and also affect future growth potential.

The Oliquric Neonate

Recent improvements in medical and nursing care of the newborn infant have resulted in a significant decrease in infant morbidity as well as mortality. In the main, these improvements have been technological with development of sophisticated monitoring devices and expansion of nursing care to that of clinician/practitioner with independent but supervised diagnostic and treatment skills. The latter has greatly enhanced successful implementation of improved monitoring technology. Despite technological advances, high-level care of the newborn infant requires continued use of traditional data gathering skills by history taking and physical assessment. Evaluation of the neonate with apparent oliguria is a classic example of the need to merge traditional techniques with current technology.

Highlights: Renal Concentrating Capacity in the Newborn. Development, clinical Disorders, Evaluation, and Management.

Polyuria, the excretion of an excessive volume of dilute urine, is a potentially lethal disorder in the neonate. Since body water accounts for roughly 60-70 percent of lean body mass in the newborn, loss of body water without adequate replacement may lead to circulatory collapse and death of the infant. The capacity of the kidneys to elaborate urine hypertonic to plasma or the concentrating capacity, involves many physiologic processes. These include countercurrent multiplication, recycling of filtered urea, antidiuretic hormone (ADH), solute delivery to the distal nephron, and the adenylate cylase (cyclic AMP) system. Although urine elaborated by the kidney in utero is normally hypotonic to plasma, development of the capacity to excrete a concentrated urine begins early in fetal life.