DISORDERS OF CALCIUM HOMEOSTASIS

BYUNIT III

PROFESSOR :Dr. K.B.R.SASTRYASST PROF :Dr. P. ANURADHA

Dr. SUNEEL KUMAR PGs :Dr. MUJEEB AFZAL

Dr. P. PRIYADARSHINI Dr. ABDUL SAMAD

Dr. SURESH

Treatment of Hypercalcemia • Depends on severity of hypercalcemia .• Mild hypercalcemia (11-12mg/dl) Hydration

alone suffice.• Severe Hypercalcemia (13-15mg/dl) emergency

and requires aggressive therapy with combination of drugs.• Hypercalcemia of Malignancy bone resorptive

therapy • Vitamin D intoxication oral calcium restriction

Hydration and diuresis

• Hydration with normal saline upto 3-6 L of saline @ 250-500 ml/hr infusion, rapid action • Restoring a normal ECF volume increases urine

calcium excretion by 2.5–7.5 mmol/d (100–300 mg/d)• Adding Loop Diuretic Increasing urinary sodium

excretion to 400–500 mmol/d increases urinary calcium excretion even.• the serum calcium concentration usually falls 0.25–

0.75 mmol/L (1–3 mg/dL) within 24 h.

Bisphosphonates

• analogues of pyrophosphate, with high affinity for bone, especially in areas of increased bone turnover, where they are powerful inhibitors of bone resorption.• inhibit osteoclast action; the mechanism of action is

complex. Onset of action in 24 hrs• Zoledronic acid 4 mg IV over 15 min every 2-4 weeks • Pamidronate 30-90 mg IV over 2-24 h every 1-3 weeks • Caution- severe renal failure (glomerular filtrating rate ,

30 mL/ min). - jaw necrosis

Calcitonin

• Calcitonin acts within a few hours• receptors on osteoclasts, to block bone resorption• Tachyphylasis in 24hrs • Can be used in life threatening hypercalcemia with

saline hydration and diuresis therapy, till bisphosphonates start acting.• Usual doses of calcitonin are 2–8 U/kg of body

weight IV, SC, or IM every 6–12 h

Glucocorticoids

• increase urinary calcium excretion and decrease intestinal calcium absorption. Antagonism of vitamin D. • effective in treating hypercalcemia due to vitamin D

intoxication and sarcoidosis. • antitumor effects- Hodgkin’s lymphomas and

multiple myeloma.• dosage is 40–100 mg prednisone (or its equivalent)

daily in four divided doses

Dialysis

• the treatment of choice for severe hypercalcemia complicated by renal failure• Peritoneal dialysis with calcium-free dialysis fluid

can remove 5–12.5 mmol (200–500 mg) of calcium in 24–48 h and lower the serum calcium concentration by 0.7–3 mmol/L (3–12 mg/dL).• phosphate supplements should be added to the

diet or to dialysis fluids if necessary

Other therapies

• Denosumab, an antibody that blocks the RANK ligand (RANKL) antiresorptive, approved for osteoporosis.• Plicamycin and gallium nitrate rarely used • Phosphate therapy - Correcting hypophosphatemia

lowers the serum calcium concentration by several mechanisms but can be toxic with calcium phosphate precipitation in tissues • Rarely used in only in severely hypercalcemic patients

with cardiac or renal failure where dialysis, the preferable alternative, is not feasible or is unavailable

• Cinacalcet oral calcimimetic that binds to the calcium sensing receptor, making it markedlymore responsive to calcium activation. • 30-90 mg b.i.d.- q.i.d. PO Take with meals. Monitor

parathyroid hormone, Ca, and PO4 at least 12 h after dose.

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PARATHYROIDECTOMY

• Symptomatic hypercalcemia• Ca 1 mg/dL above upper normal limit• BMD T score any side <-2.5• Reduction CrCl < 30 %• Urine Ca > 400 mg/day• Age < 50 years

Hypocalcemia

• Hypocalcaemia Total calcium <8.5 mg/dL, if serum protein is normal OR Ionized calcium < 4.5mg/dL

• corrected for hypoalbuminemia by the addition of 0.8 mg/dL to the serum calcium level for every 1.0 g/dL that the albumin level is below 4.0 g/dL.• Corrected Ca (mg/dL) = serum Ca (mg/dL) + 0.8(4.0 -

measured albumin (g/dL)

CLINICAL FEATURES

Onset1. Acute hypocalcemia

i. Critically ill patients, respiratory alkalosisii. Drugs: Citrates, ACEI’s

2. Transient hypocalcemiai. Sepsis, Burns, Acute renal failure, transfusionsii. Drugs: Protamine, Heparin, Glucagon

3. Chronic hypocalcemia

CLINICAL FEATURES

• The hallmark sign of acute hypocalcemia is tetany. - neuromuscular irritability• Mild tetany: perioral numbness, acral paresthesias,

and muscle cramps.• Severe tetany: carpopedal spasms, laryngospasm,

and focal or generalized seizures.• Latent tetany: Trousseau’s and Chvostek’s signs

Symptoms of hypocalcemia• Cardiovascular symptoms: arrhythmias,

bradycardia, and hypotension• Central nervous system symptoms: irritability,

paranoia, depression, psychosis, organic brain syndrome, and seizures; “cerebral tetany,” which is not a true seizure ; subnormal intelligence.• Chronic symptoms: papilledema, basal ganglia

calcifications, cataracts, dry skin, coarse hair, and brittle nails

Causes

Hypocalcemia

Parathyroid hormone deficient

Parathyroid hormone

ineffective

Parathyroid hormone

overwhelmed

Parathyroid hormone low

Secondary HyperParathyroidism

Parathyroid hormone cannot compensate

Parathyroid hormone deficient

Hereditary hypoparathyroidism Acquired hypoparathyroidism

Hypomagnesemia

HERIDITARY HYPOPARATHYROIDISM

Isolated

Autosomal Dominant Hypocalcemic Hypercalciuria

Barrter Syndrome type V

With associated features

With associated features

Autosomal dominant Autosomal recessive Mitochondrial Autoimmune

DiGeorge Syndrome

HDR Syndrome

Kenney-Caffey syndrome

Sanjad-Sakatisyndrome

MELAS

Kearns-Sayresyndrome

PolyglandularAutoimmune

Type Ideficiency

Aplasia/Hypoplasia of Parathyroid Glands

• DiGeorge/velocardiofacial syndrome (1/4000)• In 90% of patients, the condition is caused by a

deletion of chromosome 22q11.2.• Approximately 25% of these patients inherit the

chromosomal abnormality from a parent.

• Neonatal hypocalcemia occurs in 60% of affected patients, but it is transitory in the majority; hypocalcemia can recur or can have its onset later in life.

• Associated abnormalities of the 3rd and 4th pharyngeal pouches are common;

Conotruncal defects of the heart in 25%,Velopharyngeal insufficiency in 32%, Cleft palate in 9%, Renal anomalies in 35%, and Aplasia of the thymus with severe immunodeficiency in

1%.

HDR Syndrome

• Hypoparathyroidism, • sensorineural Deafness, and • Renal anomaly• The GATA3 gene is located at chromosome 10p14.

ACQUIRED HYPOPARATHYROIDISM• Inadvertent surgical removal• Even if parathyroids retained, Hypoparathyroidism

sometimes resulted• Surgery for hyperparathyroidism

• Radiation induced• Haemochromatosis

Autoimmune Hypoparathyroidism• Parathyroid antibodies• Autoimmune polyglandular disease type I

autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APCED).• Autosomal recessive• AIRE gene (autoimmune regulator); chromosome

21q22• One third of patients with this syndrome have all 3

components; 66% have only 2 of 3 conditions.

• The candidiasis almost always precedes the other disorders (70% of cases occur in children <5 yr of age);• The hypoparathyroidism (90% after 3 yr of age)

usually occurs before Addison disease (90% after 6 yr of age).• Alopecia areata or totalis, malabsorption disorder,

pernicious anemia, gonadal failure, chronic active hepatitis, vitiligo, and insulin dependent diabetes

Hypomagnesimia

• Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L) is associated with hypocalcemia• impaired PTH secretion and reduced responsiveness to

PTH. PTH levels are undetectable or inappropriately low • Serum phosphate levels are often not elevated• The effects of magnesium on PTH secretion are similar to

those of calcium; hypermagnesemia suppresses and hypomagnesemia stimulates PTH secretion• Alcoholism and chronic PPI therapy common causes for

deficiency• Treatment – Magnesium Repletion.

Chronic hypomagnesaemia

Intracellular magnesium deficiency

Interferes with secretion and peripheral response to PTH

Mechanism: Effects on adenylate cyclase proposed

Parathyroid hormone ineffective

Pseudohypoparathyroidismchronic kidney disease

vitamin D deficiencyvitamin D defective Metabolism

Pseudohypoparathyroidism(Albright Hereditary Osteodystrophy)

Hereditary disorder characterized by symptoms & signs of hypoparathyroidism, typically in association with distinctive skeletal and developmental defects

Pseudohypoparathyroidism PHP-Ia• Hypocalcemia, hyperphosphatemia, ↓urinary

cAMP, ↑ serum PTH, Gsα subunit deficiency • Genetic defect of the α subunit of the stimulatory

guanine nucleotide-binding protein (Gsα). • Features of Albright Hereditary Osteodystrophy

(AHO) :• Short stature• Round face• Brachydactyly• Heterotopic calcification

Inheritance and Genetic Patterns

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

Classification of PHP

Type Hypocalcemia, Hyperphosphatemia

Response of Urinary cAMP to

PTHSerum PTH

Gsα Subunit

DeficiencyAHO

PHP-Ia Yes ↓ ↑ Yes Yes

PHP-Ib Yes ↓ ↑ No No

PHP-II Yes Normal ↑ No No

PPHP No Normal Normal Yes Yes

Chronic kidney disease

• 1,25(OH)D is now thought to be the principal factor causes calcium deficiency, secondary hyperparathyroidism, and bone disease• Low levels of 1,25(OH) D due to increased FGF23 production

in bone• The uremic state also causes impairment of intestinal

absorption. • lower intestinal phosphate absorption early during the

course of kidney disease and to thereby lower FGF23 levels• adequate calcium intake by mouth, usually 1–2 g/d; and

supplementation with 0.25–1 μg/d calcitriol or other activated forms of vitamin D

Impaired production of 1,25(OH)2*D

HypocalcemiaSecondary Hyperparathyroidism

Hyperphosphtemia (later stages)

FGF-23 increases

Chronic kidney disease

VITAMIN D DEFICIENCY

• Inadequate diet and/or exposure to sunlight• Investigations my show: ↓ vitamin D metabolites,

↓ calcium, ↑ PTH, ↑phosphate• Hypocalcaemia itself causes steatorrhoea

• Treatment: Various metabolites can be given depending on the disorder

DEFECTIVE VITAMIN D METABOLISM1. Anticonvulsant therapy: Enzyme induction2. Vitamin D-dependant rickets type 1:

a) Autosomal recessiveb) Mutations in genes coding 25-(OH)D-1α-hydroxylasec) Hypocalcemia, hyperphosphatemia,

Hyperparathyroidism, osteomalacia, ↑ ALPd) Reversible on calcitriol supplementation

3. Vitamin D-dependant rickets type 2: a) End organ resistance to active metaboliteb) Mutations in Vitamin D receptorc) More severe, associated partial or total alopecia.d) Plasma 1,25(OH)2*D are elevated

Treatment: Regular calcium infusions

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

Approach to Hypocalcemia

• Confirm hypocalcemia• Transient in severe critical illness• duration of the illness, Adolescence onset, signs or

symptoms of associated disorders, and the presence of features that suggest a hereditary abnormality• nutritional history vitamin D def• history of excessive alcohol intake magnesium deficiency• Neck surgery, even long past • Rickets and a variety of neuromuscular syndromes and

deformities ineffective vitamin D action• Chronic renal failure

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

Thanks