Hypoparathyroidism a case based approach

Hypothyroidism case based approach

1. Hypoparathyroidism Dr. Deepak Yadav MBBS, MD

2. Definition Inadequately low PTH in the presence of low calcium levels and high phosphate levels

3. Calcium Turnover

4. Calcium Regulators

5. Calcium sensing Receptor (CaSR)

6. Calcium sensing Receptor (CaSR)

7. PTH Synthesis

8. PTH Hormone

9. PTH Receptors PTH 1 receptor Expressed predominantly in bone and Kidney Also present in other tissues, autocrine/paracrine function G-protein coupled receptor Works via cAMP, IP3-DAG pathway PTH 2 Receptor Function not know Receptor distribution wider than PTH 1

10. PTH Function Direct Increased reabsorption of calcium from kidney and bone Increased excretion of phosphate from kidney Indirect Increased absorption of calcium and phosphate from GI tract Mediated via increase in calcitriol Increased expression and activity of 1-alpha hydroxylase

11. Magnesium in hypocalcemia Magnesium is needed for the secretion of PTH by the parathyroid glands and its depletion or excess may cause hypoparathyroidism and subsequent hypocalcemia Lack or excess magnesium plays a role in defective cyclic AMP generation in the parathyroid glands interfering with PTH synthesis and secretion

12. Approach to Hypocalcemia

13. Approach to Hypocalcemia

14. Hypocalcemia approach

15. Prevalence studies estimate the incidence of hypoparathyroidism in the U.S. to 24–37/100,000 person-years, with an estimate of 60,000–80,000 affected individuals 75% of cases are female and 25% male About 75% of patients are aged 45 years older, 75% of cases are due to neck surgery 25% are reported to be due to non-surgical causes. 38% are due to total thyroidectomy, 21% parathyroidectomy, 9% partial thyroidectomy, and 5% other neck surgeries

16. Symptoms

17. Peripheral nervous system Myoclonic jerks, twitching, new-onset seizures, or worsening of seizures are neurologic manifestations CNS calcification at basal ganglia, grey and white matter, the cerebellar parenchym Chvostek sign (ipsilateral twitching of facial muscles when tapping on the area of the facial nerve) and the Trousseau sign (muscular contraction of the hand when inflating a blood pressure cuff on the arm above systolic blood pressure for 3 minutes)84.

18. Cardiovascular system prolongation of QT interval along with prominent U wave and T wave abnormalities92 Hypocalcaemia­associated dilated cardio­ myopathy, cardiac arrhythmias Renal system nephrocalcinosis and kidney stones Bones :> higher bone density due to low bone turnover

19. Treatments

20. Emerging Treatments Teriparatide (PTH 1-34)  Recombinant Human Parathyroid Hormone (rhPTH) 1-84

21. Familial Isolated Hypoparathyroidism (FIH) Rare heterogeneous group of metabolic disorders characterized by abnormal calcium metabolism due to deficient secretion of parathormone (PTH), without other endocrine disorders or developmental defects. can occur at any age Hypocalcemia, myopathy, muscular weakness, cramps, tetany, lenticular cataracts, teeth anomalies and short stature. Diagnosis is made when hypocalcemia, hyperphosphoremia , and low or undetectable PTH levels are observed

22. FIH

23. Genetic causes of Hypoparathyroidism DiGeorge syndrome DiGeorge syndrome has been reported in ~60% of children. Presents with hypoparathyroidism, cardiac outflow tract malformations, facial dysmorphia, psychiatric illness, palatal dysfunction and thymic hypoplasia Microdeletion of chromosome 22q11.2 Abnormalities in the function of TBX1 explain all the main phenotypical features of DiGeorge syndrome type

24. Pseudohypoparathyroidism Disorder associated with parathyroid hormone (PTH) resistance. Hypocalcaemia and hyperphosphataemia with increased circulating PTH concentrations Primary causes of pseudo­hypoparathyroidism are genetic or epigenetic mutations in GNAS Type 1a exhibit features of Albright hereditary osteodystrophy (AHO), including short stature, obesity, round facies, subcutaneous calcifications and brachydactyly

25. Albright Hereditary Osteodystrophy

26. Autoimmune polyendocrine syndrome type 1 AKA Autoimmune polyendocrinopathy – candidiasis–ectodermal dystrophy syndrome Autosomal recessive disorder characterized by immune deficiency and autoimmune destruction of endocrine organs, such as the parathyroid glands, adrenal cortex and ovaries. Mutations in auto­ immune regulator ( AIRE ). Presence of at least two components of a triad of mucocutaneous candidiasis infection of the skin, mucous membranes or nails, hypoparathyroidism and adrenal insufficiency

27. Hypoparathyroidism, sensorineural deafness and renal disease syndrome HDR syn­drome is an autosomal dominant disorder in which patients often have hypocalcamia and undetectable, low or inappropriately normal serum PTH concen­trations HDR syndrome is caused by germline heterozygous mutations in GATA­ binding factor 3 ( GATA3 )

28. Mitochondrial disorders associated with hypopara­thyroidism Kearns–Sayre syndrome characterized by progressive external ophthalmoplegia (paralysis of the eye muscles) and pigmentary retino­pathy occurring at <20 years of age Mito­chondrial encephalomyopathy with lactic acidosis and stroke­ like episodes (MELAS) syndrome, Mito­chondrial trifunctional protein (MTP) deficiency syn­drome

29. Autosomal dominant hypocalcamia type 1 and type 2 are geneti­cally distinct disorders that were found to be associated with germline gain ­of ­function mutations of CaSR and G11 α proteins Type 1, most common type associated with hypocalcemia and PTH levels ranging from undetectable to normal and elevated fractional excretion of calcium, which can lead to frank hypercalciuria even in the setting of low serum calcium concentrations Ectopic calcifi­cations of the kidneys or basal ganglia affect ~35%

30. Summary Hypoparathyroidism though rare are important cause of childhood hypocalcemia Hypoparathyroidism is a heterogenous group of disorder Familial forms of hypoparathyroidism do occur Hypocalcemic seizure may be a presenting symptom Once identified serum calcium can be maintained by use of calcium supplements and Calcitriol administration

31. Thank You