Pseudohypoparathyroidism & Hypocalcemia due to PTH Overwhelmed

Teena Luke

080201023

Pseudohypoparathyroidism (PHP)

Hereditary disorder characterized by symptoms & signs of hypoparathyroidism, typically in

association with distinctive skeletal and developmental defects

Classification of PHP

TypeHypocalcemia,

Hyperphosphatemia

Response of Urinary cAMP to

PTH

Serum PTH

GsαSubunit

DeficiencyAHO

PHP-Ia Yes ↓ ↑ Yes Yes

PHP-Ib Yes ↓ ↑ No No

PHP-II Yes Normal ↑ No No

PPHP No Normal Normal Yes Yes

PHP-Ia

• Hypocalcemia, hyperphosphatemia, ↓urinary cAMP, ↑ serum PTH, Gsa subunit deficiency

• Features of AHO:

– Short stature

– Round face

– Brachydactyly

– Heterotopic calcification

Inheritance and Genetic Patterns

PHP-1a becomes manifest only in patients who inherit the defective gene from an obligate female carrier (left). If the genetic defect is inherited from an

obligate male gene carrier, there is no biochemical abnormality; administration of PTH causes an appropriate increase in the urinary cyclic AMP and phosphate concentration. Both patterns of inheritance lead to

Albright's hereditary osteodystrophy (AHO)

GNAS-1 gene on chromosome 20q

PHP-1b

• Upstream deletions on maternal allele

• There is no Gsa in renal cortex but normal expression in other tissues

• Hypocalcemia, hyperphosphatemia, ↓ urinary cAMP, ↑ serum PTH

• May have excessive bone responsiveness

PHP-II

• Hypocalcemia, hyperphosphatemia, normal urinary cAMP, ↑ serum PTH

• Defect (in response to PTH) is at a locus distal to cyclic AMP production

Treatment of PHP

• Lower doses of Vitamin D & calcium are required than those required in true hypoparathyroidism

• Establish optimal regimen for each patient

• Maintain appropriate blood calcium level (8.5 – 10.5mg/dl) & urinary calcium excretion (100-250mg/24h)

PTH Overwhelmed

• Severe, Acute Hyperphosphatemia

– Tumor lysis

– Acute renal failure

– Rhabdomyolysis

• Osteitis Fibrosa after Parathyroidectomy

Severe, Acute Hyperphosphatemia

• release of phosphate from muscle & impaired phosphate excretion due to renal failure

• Hypocalcemia is reversed with tissue repair & renal function restoration may lead to mild hypercalcemia

• Other Causes: hypothermia, hepatic failure, & hematologic malignancies

Treatment

• Lower blood phosphate through phosphate-binding antacids or dialysis

• Calcium replacement is necessary in severe hypocalcemia

Osteitis Fibrosis after Parathyroidectomy

• Osteitis fibrosa cystica: rare manifestation of hyperparathyroidism

• Characterized by bone pain & bone fragility & brown tumor

• If severe, bone mineral deficits are large

• Hypocalcemia can persist for days after parathyroidectomy if calcium replacement is inadequate

Diagnosis

• Serum calcium level

• Serum Albumin (3.5-5.3g/dL)

• Serum Phosphorus (2.7-4.5mg/dL)

• Serum Magnesium (0.7-1.0mmol/L)

• Serum PTH: 10-65pg/ml

• PTH level is central to the evaluation of hypocalcemia

– A low PTH level → hypoparathyroidism

– Further history will often elicit the underlying cause

– An elevated PTH level → secondary hyperparathyroidism → vitamin D deficiency

– serum 25-hydroxyvitamin D levels (>20ng/ml)

Treatment• Acute, symptomatic hypocalcemia:

– calcium gluconate, 90 mg or 2.2 mmol IV, diluted in 50 mL of 5% dextrose or 0.9% sodium chloride, given IV over 5 min

• Continuing hypocalcemia : constant IV infusion (10 ampuls of ca or 900 mg of ca in 1 L of 5% dextrose or 0.9% sodium chloride administered over 24 h)

Treatment

• Hypomagnesemia: magnesium supplementation

• Chronic hypocalcemia due to hypoparathyroidism:

– calcium supplements (1000–1500 mg/d elemental calcium in divided doses) AND

– either vitamin D2 or D3 (25,000–100,000 U daily) OR calcitriol [1,25(OH)2D, 0.25–2 g/d]

Treatment

• Vitamin D deficiency - vitamin D supplementation

• Nutritional vitamin D deficiency:

– low doses of vitamin D (50,000 U, 2–3 times per week for several months)

• Vitamin D deficiency due to malabsorption:

– higher doses (100,000 U/d or more)

• Goal is to bring serum calcium into the low normal range and to avoid hypercalciuria, which may lead to nephrolithiasis