• Information
  1. Etiology
  2. Symptoms, Signs and Presentation
  3. Laboratory Evaluation
  4. Treatment
  5. Pseudohypoparathyroidism
• Resources

A. Etiology

1. Overall Classificiation
   1. Due to inappropriately low or absent levels of parathyroid hormone (PTH) - most common
   2. Defect in PTH-receptor
   3. Defect in signalling downstream of PTH-receptor
2. Surgical damage or removal of parathyroid glands - usually with thyroid surgery
3. Nonsurgical Damage to Parathyroid Glands
   1. Autoimmune
   2. Hemochromatosis
   3. Metastatic spread to glands
   4. Trauma
   5. Infarction
   6. Radioiodine therapy - uncommon
4. Associated with other Endocrine Failures
   1. These are the polyendocrine failure syndromes (PFS)
   2. PFS Type 1 is associated with increased monilia (candidal) infections
   3. Autoantigen of hypothyroidism Type 1 PFS is NALP5 (nacht leucine rich repeat protein 5) [5]
   4. PFS type 1 also called autoimmune polyendocrinopathy candidal ectodermal dystrophy (APECED)
5. Genetic Causes [4]
   1. Autosomal dominant hypocalcemia with hypocalciuria - defects in calcium sensor receptor
   2. Other PTH Deficiency: PTH gene mutations, abnormal transcription factors GCM2, GATA3
   3. Mitochondrial genome mutations - associated with PTH deficiency
   4. PTH-receptor gene mutations with impaired function
   5. Inactivating mutations in stimulatory G protein in pseudohypoparathyroidism
6. DiGeorge Syndrome
   1. Incomplete development of branchial arches
   2. Varying degrees of parathyroid and thyroid hypoplasia
   3. Cardiac defects
   4. Facial malformations
   5. Learning disabilities
   6. Closely related to velocardiofacial syndrome
   7. Apparently due to deletions of unknown gene(s) on chromosome 22p
7. Idiopathic failure
8. Pseudohypoparathyroidism (see below)
   1. Resistance of end organs to actions of PTH
   2. Normal or elevated levels of PTH
9. Hypomagnesemia - parathyroid cells require magnesium to secrete PTH

B. Symptoms, Signs and Presentation

1. Symptoms of Hypocalcemia
   1. Muscle Fatigue, Cramps
   2. Tetany - including laryngospasm (alkalosis is other metabolic cause of tetany)
   3. Paralytic Ileus
   4. Bradycardia, cardiomegaly, congestive heart failure
   5. Hypotension
   6. Central Nervous System: change in mental status, seizures, extrapyramidal features
   7. Cataracts - chronic, usually due to years of hypoparathyroidism
   8. Dry, scaly skin and eyebrows may be sparse
2. Clinical Signs
   1. Physical exam tests for low Ca2+ are rarely performed now with rapid serum Ca2+ levels
   2. Serum calcium (albumin) and PTH levels are sufficient to make the diagnosis
   3. In the past, Chvostek's and Trousseau's signs have been used
3. Chvostek's Sign
   1. tap over facial nerve in front of ear
   2. positive result is twitching over the facial muscles, especially upper lip
   3. 5-10% of normal population may have a positive test
4. Trousseau's Sign
   1. inflate blood pressure cuff over upper arm
   2. positive test with hand flexing at wrist and fingers flexed at metacarpophalangeal and extended at intercarpophalangeal joints
   3. this is a very painful test
5. Bone Changes
   1. Extremely dense bones
   2. Changes in the teeth including hypoplasia and aplasia
6. Central Nervous System
   1. Symmetrical, bilateral, punctate calcifications of the basal ganglia
   2. Increased intracranial pressure occasionally seen
   3. Seizures and death may occur with continued reduction in serum calcium

C. Laboratory Evaluation

1. Renal Function: BUN, creatinine, Ca2+, phosphate levels, urine electrolytes/calcium
2. Serum albumin, alkaline phosphatase (low)
3. Absence of calcium in urine strongly suggest hypoparathyroidism
4. ECG shows QTc prolongation ± bradycardia
5. Serum PTH level
   1. Gold standard test for primary hypoparathyroidism
   2. This is done mainly to rule out vitamin D deficiency (fairly common in sick patients)
6. Urine Calcium Level
   1. In true hypoparathyroidism, levels should be reduced considerably
   2. In familial hypercalciuric hypocalcemia, urine levels are very high

D. Treatment

1. Goal is normalization of serum calcium to prevent complications of hypocalcemia
2. Avoid hypercalciuria
3. Oral Calcium + Vitamin D to maintain serum calcium >7.5mg/dL
   1. Vitamin D analogs such as calcitriol may be more effective
   2. These metabolites have improved renal calcium sparing activities
4. Phosphate binders are rarely necessary
5. Parathyroid Hormone (PTH)
   1. Full length hormone (1-84 aminoacids) is not routinely available
   2. PTH 1-34 is more effective than calcium + calcitriol in reducing renal calcium loss [2]
   3. PTH is generally ineffective in pseudohypoparathyroidism
6. Monitor serum and urine calcium and phosphorus

E. Pseudohypoparathyroidism [1,3]

1. Two major types of pseudohypoparathyroidism
   1. Type I is also called Albright Hereditary Osteodystrophy
   2. Type I has deficient G-protein activity due to genetic loss of G(s)alpha
   3. Type II has normal G-protein activity and may have renal defect in PTH responses
   4. Type Ia caused by two Arg to His mutations (positions 231 and 385) in G(ß)alpha
   5. Type Ib is less severe with decreased function of G(ß)alpha proteins
2. Normal or elevated levels of PTH
3. Inability to respond to PTH
4. Developmental abnormalities
   1. Short fingers (brachydactyly), usually due to short metacarpal bone (metatarsals also)
   2. Faces tend to be quite round (>90% of cases)
   3. Statures are thickset and and short (>50%)
5. Calcification of soft tissues (~50%)
6. Mental Retardation (~75%)

Resources

Corrected Serum Calcium for Albumin

References

1. Mark SJ. 2000. NEJM. 343(25):1863
2. Winer KK, Yanovski JA, Cutler GB Jr. 1996. JAMA. 276(8):631
3. Farfel Z, Bourne HR, Iiri T. 1999. NEJM. 340(13):1012
4. Thakker RV. 2001. Lancet. 357(9261):974
5. Alimohammadi M, Bjorklund P, Hallgren A, et al. 2008. NEJM. 358(10):1018