mimicking pseudohypoparathyroidism type 2 [PHP-II], which is a rare disorder.2 The diagnosis of PHP-II thus needs exclusion of vitamin D deficiency. We report ...
Case Report
Vitamin D Deficiency Masquerading as Pseudohypoparathyroidism Type 2 M Shriraam, A Bhansali, P Velayutham
Abstract A case of antiepileptic-induced vitamin D deficiency, who presented with hypocalcemia, hyperphosphatemia with increased tubular reabsorption of phosphate mimicking pseudohypoparathyroidism type 2, is reported. He showed remarkable improvement with calcium and vitamin D treatment with normalisation of serum calcium and phosphate with reestablishment of phosphaturic response.
itamin D deficiency is a relatively common disorder characterized biochemically by hypophosphatemia, hypocalcemia, increased alkaline phosphatase and increased parathormone (PTH). 1 Hypophosphatemia, the earliest biochemical abnormality is the result of decreased intestinal absorption of phosphate as well as exaggerated phosphaturic effect of PTH on renal tubular cells.1 However, occasionally, vitamin D deficiency may be associated with PTH resistance at renal tubular cells which may lead to hyperphosphatemia, mimicking pseudohypoparathyroidism type 2 [PHP-II], which is a rare disorder.2 The diagnosis of PHP-II thus needs exclusion of vitamin D deficiency. We report a case who presented with clinical and biochemical features of pseudohypoparathyroidism type 2 possibly related to antiepileptic drug-induced vitamin D deficiency.
and systemic examination was unremarkable. On investigation, he had hypocalcemia [mean serum calcium 5.3mg/dl (N- 9-11mg/dl)], hyperphosphatemia [mean serum phosphate 7.5mg/dl (N 3-5mg/dl)], mildly elevated alkaline phosphatase [mean-14.6 KAU (N 8-14KAU)] and normal magnesium levels [2.4mg/dl (N 1.5-3.0mg/dl) ]. His 24 hour urinary creatinine excretion was 800 mg, calcium 62.5 mg, phosphate 290mg ( N 600-1200mg) and tubular reabsorption of phosphate (TRP) was 95.6%. Maximum tubular absorption of phosphate to glomerular filtration rate ratio (TmPO4/GFR) could not be calculated from the nomogram because of very high serum phosphate levels. He had very low serum 25(OH) D3 [4.6ng/ml (N 9.1 - 41.3ng/ml)] and increased serum parathormone levels [92pg/ml (N 7-52pg/ml)] (Table 1). His ECG showed prolonged QTc interval of 52 milliseconds. Roentgenogram of the pelvis, scapula, wrist and hand did not show any changes of osteomalacia or signs of
CASE REPORT
Table 1 : Investigation profile of the patient
INTRODUCTION
V
A 23-year-old male presented with history of generalized seizures of five years duration for which he was initially on phenytoin. With this treatment, seizures were not well controlled and was switched to carbamazepine and presently he was seizure-free for last 3 years. He had proximal muscle weakness of the lower limbs for six months before presentation. There was no history of any other significant medical illness, malabsorption or steroid intake. Nutritional intake of dairy products and sunlight exposure were adequate. On examination, he had evidence of latent tetany in the form of Chvostek’s sign (grade 2/4) and lower limb muscle power of grade 4/5 and diminished deep tendon reflexes . He did not have Albrights Hereditary Osteodystrophy (AHO) phenotype Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh. Received : 20.12.2002; Revised : 15.4.2003; Accepted : 10.5.2003
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Serum biochemistry Calcium [mg/dl] Phosphate [mg/dl] Albumin [gm/dl] Alkaline phosphatase [KAU] Creatinine [mg/dl] Magnesium [mg/dl] 25(OH) D3 [ng/ml] PTH [pg/ml] 24 hour urinary profile Calcium [mg] Phosphate [mg] Creatinine [mg] Tubular reabsorption of phosphate [%] TRP [% change] TmPO4/GFR[mg/ml/min] QTc [milliseconds]
Pre -treatment 5.2 7.5 4.8 15 1.0 2.4 4.6 92
Post-treatment
5.1 7.5 5.1 14 0.8
5.6 7.5 4.9 15 1.0
8.2 4.0 5.1 18 1.0 2.6 23.7 32
8.4 4.0 5.0 15 1.0
60 290 800
270 780
65 290 800
51 780 800
52 750 750
95.2
96.4
95.2
75
— 52
—
75 -21.6 3 42
3
619
hyperparathyroidism in the form of subperiosteal resorption/ osteitis fibrosa cystica and osteopenia. Non-contrast CT scan of the head was normal. With this profile, diagnosis of pseudohypoparathyroidism type 2 like picture related to vitamin D deficiency was made. He was treated with calcium carbonate (500mg of elemental calcium thrice daily) and cholecalciferol (6 lacs units intramuscularly once followed by oral cholecalciferol 60,000 units fortnightly). At 12 weeks follow-up his proximal muscle weakness improved and biochemically serum calcium (mean 8.3mg/dl), phosphate (mean 4.03mg/dl), 25(OH) D3 (23.7 ng/ml) and PTH levels (32 pg/ml) were normalised. Importantly, there was restoration of phosphaturia from 290 to 780 mg/24hours and TRP (tubular reabsorption of phosphate) decreased from mean of 95.6% to 75% with TmPO4/GFR of 3.2mg/ml/min.
DISCUSSION Pseudohypoparathyroidism [PHP] is a heterogenous group of disorders of PTH resistance characterised by hypocalcemia, hyperphosphatemia, increased PTH levels and decreased urinary cyclic AMP and phosphaturic response to exogenous PTH.1 However, in PHP II there is normal urinary cyclic AMP response but decreased phosphaturic response to exogenously administered PTH differentiating this from other variants of PHPI. Parathormone resistance in PHP at renal tubular cells is invariably present, however there are varying reports of PTH resistance at the osseous tissues.6,8 Hypocalcemia, hyperphosphatemia, high serum PTH levels, decreased urinary phosphate excretion [TRP 95.6%] relative to the degree of secondary hyperparathyroidism in our patient bespeak PTH reistance at renal tubular cells. However, presence of low calcium and lack osteitis fibrosa cystica possibly suggests PTH resistance at bone tissues as well in our patient. Hypophosphatemia is the cardinal feature of vitamin D deficiency while hyperphosphatemia with it is distinctly unusual. Low phosphate excretion in a setting of high PTH state implies defective action of PTH at renal tubular cells. Magnesium depletion may also present as hypocalcemia and hyperphosphatemia with increased tubular reabsorption of phosphate mimicking PHP-II.2 Our patient neither had any other cause of hyperphosphatemia like renal failure, tumoral calcinosis, heparin or bisphosphonate therapy nor magnesium depletion. Therefore, the most likely diagnosis for the above clinical and biochemical profile (short of urinary cyclic AMP) in our patient was PHP-II. It is well documented that vitamin D deficiency can impair phosphaturic response to PTH and exclusion of the same is necessary before diagnosing PHP II.2 Restoration of phosphaturic response with normalisation of serum 25 (OH) D3 and calcium after vitamin D supplementation in our case suggests vitamin D deficiency-induced PTH resistance. The exact pathogenesis of the disorder remains unclear. However, normal urinary cyclic AMP response but decreased phosphaturic response to exogenous PTH suggests defect distal to cyclic AMP. This is due to impaired permeability to 620
PTH-mediated calcium influx into the renal tubular cells which hampers calcium-activated intracellular events distal to cyclic AMP generation including phosphaturic response.6 In some studies, phosphaturic response in patients with vitamin D deficiency has been restored after calcium infusion.3 However, other studies suggest that the defect may be due to deficiency of the action of calcidiol [25(OH) D3] /calcitriol [1,25(OH)2 D3] or its metabolites.2 Basal levels of calcitriol has been found to be low in PHP implying resistance at the level of 1-alpha hydroxylase also, which is an important PTH dependent enzyme. The calcitriol level does not rise even after the administration of the exogenous PTH.7 The cause of vitamin D deficiency in our patient was likely to be chronic ingestion of anticonvulsant medications.5 Phenytoin and phenobarbitone are well known to cause vitamin D deficiency by decreasing intestinal absorption and increasing metabolism of 25 (OH) D3 in liver. Carbamazepine also interferes with 25 (OH) D3 metabolism in the liver and long term therapy with it results in vitamin D deficiency as occurred in our patient. A case of PHP-II like picture in anticonvulsant related vitamin D deficiency has also been reported previously.5 In conclusion, vitamin D deficiency can mimic PHP-II and therefore before considering this rare diagnosis vitamin D deficiency must be excluded.
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Rao S, Perfitt AM, Kleerekoper M, Pumo S, Frame B. Dissociation between the effects of endogenous parathormone on Adenosine3', 5' Monophosphate generation and phosphate reabsorption in hypocalcemia due to vitamin D depletion: An acquired disorder resembling pseudohypoparathyroidism type 2. J Clin Endocrinol Metab1985; 61:285.
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Rodriguez JH, Villarrea lH, Klahr S, Slatopolsky E. Pseudohypoparathyroidism Type 2 : Restoration of normal renal responsiveness to parathyroid hormone by calcium administration. J Clin Endocrinol Metab 1974;39:693. StogmannW,Fischer J A. Disssappearance of the resistance to parathyroid extract during treatment with vitamin D. Am J Med 1975;59:140. Matsuda I, Takekoshi Y, Ynaka M, Matsura N, Nagai B, Sein Y. Pseudohypoparathyroidism type II and anticonvulsant rickets. Eur J Pediatr 1979;132:303.
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Lambert POW, Hollis BW, Bell NH, Epstein S. Demonstration of a lack of change in serum 1,25 (OH)2 Vitamin D in response to parathyroid extract in PHP. J Clin Invest 1980;66:782 Breslau NA, Moses AM, Pak CYC. Evidence for bone remodelling but lack of calcium mobilisation response to parathyroid hormone in pseudohypoparathyroidism. J Clin Endocrinol Metab 1983; 57:638
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