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Hypoparathyroidism is the result of reduced secretion or impaired action of parathyroid hormone (PTH).
PTH is secreted by the 4 parathyroid glands, located in the neck behind the thyroid gland. It regulates serum calcium and phosphorus levels and also plays a part in bone metabolism. Low levels of PTH cause serum calcium levels to fall and serum phosphate levels to rise.
Calcium and phosphate homeostasis
- Maintenance of normal serum calcium levels involves the regulation of the flux of calcium between the intestinal tract, kidneys and bone.
- Calcium itself, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 all play a role in calcium regulation.
- 1,25-dihydroxyvitamin D3 facilitates intestinal calcium absorption, whilst both 1,25-dihydroxyvitamin D3 and PTH stimulate calcium release from bone.
- PTH also stimulates the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 enabling distal renal tubular calcium reabsorption.
- High concentrations of serum calcium inhibit PTH secretion while low concentrations stimulate it.
- Phosphate reabsorption from the kidney is reduced by PTH. Thus if PTH levels are low, serum phosphate will rise (more will be reabsorbed).
- This is a rare disorder.
- Found equally in males and females.
- Age of onset depends on the aetiology.
Hypoparathyroidism may be transient, congenital/genetically inherited or acquired.
Transient hypoparathyroidism in the neonatal period
- Prematurity at birth: up to 50% of very low birthweight infants do not have a normal parathyroid hormone (PTH) surge postnatally, thus resulting in hypocalcaemia.
- Infants of diabetic mothers: hypomagnesaemia due to maternal magnesuria impairs PTH release and action.
- Delay in PTH surge postnatally: this can occur in otherwise healthy neonates.
- Maternal hyperparathyroidism: this results in hypercalcaemia which can cause prolonged PTH suppression in the neonate.
Congenital or genetically inherited hypoparathyroidism
- Defects in parathyroid gland development:
- DiGeorge's syndrome: there is abnormal development of the parathyroid glands from the third and fourth pharyngeal pouches. The thymus gland, aortic arch and parts of the lips and ears also develop from these pouches.There is hypoparathyroidism, T-cell immune deficiency, abnormal facies such as cleft palate, and cardiac anomalies.
- Defects in the PTH gene
- Defects in the calcium-sensing receptor gene:
- Presents as hypocalcaemia, inappropriately normal levels of PTH and raised phosphate levels
- This is not true hypoparathyroidism but its presentation mimics it
- Can present from birth to adulthood
- Defects in PTH action (pseudohypoparathyroidism):
This is when the somatic features of pseudohypoparathyroidism are present in patients with normal serum calcium and phosphate levels. PTH is either normal or raised. The patient may fluctuate between hypocalcaemia and normocalcaemia and may develop cataracts.
- A rare inherited disorder where there is failure of target cells to respond to PTH, ie there is PTH resistance.
- PTH levels are not low but are appropriate for the degree of hypocalcaemia.
- There is an association with:
- As part of an autoimmune process:
- Autoimmune polyglandular syndrome type 1 (APS-1): autosomal recessive inheritance. Features include hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis. Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Presents in childhood.
- Autoimmune polyglandular syndrome type 2 (APS-2): features include adrenal insufficiency, insulin-dependent diabetes mellitus and thyroid disease. Presents in adulthood. Autosomal dominant inheritance.
- Isolated hypoparathyroidism with a possible autoimmune cause can also be inherited.
- Genetic syndromes, including:
- Hypoparathyroidism, deafness and renal (HDR) dysplasia syndrome.
- Hypoparathyroidism, retardation and dysmorphism (HRD) syndrome.
- Neck surgery (thyroid, parathyroid, laryngeal or oesophageal surgery) is the most common cause and includes:
- Accidental damage to, or accidental removal of, the parathyroid glands. Most likely during thyroid surgery. May be transient or permanent. Surgeon-dependent.
- Removal of parathyroid glands because of potential malignancy.
- After surgery for hyperparathyroidism. Transient hypoparathyroidism may occur whilst the body returns to a normal response to PTH.
- Radiation or drugs:
- Infiltration of the parathyroid glands:
- Magnesium deficiency, which can occur in:
- Magnesium excess, eg when magnesium is used for the treatment of preterm labour or pre-eclampsia.
- Autoimmune process: sporadic forms of APS-1 can occur as described above.
- Isolated idiopathic hypoparathyroidism:
- Parathyroid hormone (PTH) deficiency is present but no other associated endocrine or developmental disorders.
- Usually sporadic but can be familial.
- May possibly be a form of autoimmune hypoparathyroidism.
Is essentially with the symptoms of hypocalcaemia. May present acutely, requiring immediate treatment. Some patients are even symptomatic within the normal calcium reference range; that is, they have their own narrow individual range within the normal range. Symptoms vary between individuals and include:
- Muscle pains
- Abdominal pain
- Paraesthesiae (tingling, vibrating, burning and numbness) of the face, fingers and toes
- Facial twitching
- Carpopedal spasm
- Convulsions (usually grand mal)
- Emotional lability, anxiety and depression, confusion
- Memory impairment
- Brittle nails
- Dry hair and skin
- Painful menstruation
Important points to elicit in the history include:
- History of previous neck surgery
- Family history of any hypoparathyroid disorders
- Chvostek's sign: detects latent tetany. Tapping of the fifth facial nerve in front of the ear with the patient's mouth slightly open causes contraction of the facial muscles. 25% of the normal population have a positive response.
- Trousseau's sign: occlude the arterial circulation of the forearm using a blood pressure cuff inflated to the systolic blood pressure for 3 minutes. Carpopedal spasm is induced.
- Raised intracranial pressure with papilloedema.
- Dental abnormalities and enamel dysplasia.
- Brittle nails with transverse grooves.
- Dry, rough skin.
Other symptoms and signs depend on the aetiology:
- DiGeorge's syndrome:
- Recurrent infections due to T-cell immunodeficiency
- Congenital heart disease and its related symptoms, heart murmur
- Speech delay
- Abnormal facies: cleft palate, micrognathia, ear abnormalities
- Familial autoimmune polyglandular syndrome type I (APS-I):
- Genetic syndromes:
- Sensorineural deafness
- Renal dysplasia
- Mental retardation
Hypocalcaemia and hyperphosphataemia can also be caused by:
- Blood tests (to exclude other causes of hypocalcaemia):
- Calcium, phosphate, parathyroid hormone (PTH) and alkaline phosphatase
Typical blood test results in hypoparathyroidism
- Low serum calcium
- High serum phosphate
- Low PTH
- Normal alkaline phosphatase
- Low serum calcium
- High or normal PTH
- Serum magnesium: may be low
- Urea and electrolytes: to exclude chronic renal failure
- 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3: to exclude vitamin D deficiency as a cause of hypocalcaemia. 25-hydroxyvitamin D3 is normal in hypoparathyroidism and pseudohypoparathyroidism but 1,25-dihydroxyvitamin D3 is low because PTH is not available for its activation
- Calcium, phosphate, parathyroid hormone (PTH) and alkaline phosphatase
- Additional blood tests:
If an autoimmune process is suspected, look for coinciding thyroid and adrenal insufficiency:
- Thyroid stimulating hormone (TSH), thyroxine and thyroid autoantibodies
- Adrenocorticotrophic hormone (ACTH) and adrenal antibodies
- Urine tests: 24-hour urinary calcium is usually low
- Other possible investigations:
- ECG: prolonged QT interval which may progress to ventricular fibrillation or heart block
- Echocardiogram: cardiac abnormalities (in DiGeorge's syndrome)
- Renal ultrasound: looking for renal calculi
- Hand radiography: looking for shortened metacarpals
- Brain MRI scan: basal ganglia calcification (sign of a longstanding hypocalcaemic state)
- Genetic studies: as appropriate
Parathyroid hormone (PTH)
- As yet, PTH is not commercially available to treat hypoparathyroidism.
- A randomised controlled study, published in 2003, compared synthetic human PTH therapy to conventional therapy with calcitriol and calcium over a three-year period. It showed that normal serum calcium levels could be achieved over this time without hypercalciuria in the group taking synthetic PTH.
Calcium and vitamin D3
- The basis of treatment is with calcium and vitamin D.
- The doses are tailored to the individual's needs and regular monitoring is needed.
- In some people, once adequate doses of vitamin D are achieved, they can absorb all the calcium that they need through the diet. However, in others, calcium levels remain permanently unstable and maintenance doses of calcium and vitamin D will need to be regularly monitored and adjusted.
- Usual doses of calcium supplements: 1-1.5 g daily
- Vitamin D is best given in its active form of 1,25-dihydroxyvitamin D3 as calcitriol: 0.5-1 micrograms is usual daily dose.
- Treatment is lifelong.
- There is no restriction on activities but patients should wear a bracelet to identify themselves as suffering from hypoparathyroidism.
- If severe hypocalcaemia symptoms are present, such as tetany, urgent IV calcium gluconate should be given.
Parathyroid autotransplantation and allotransplantation
- If a patient has a thyroidectomy, one of the parathyroids can be 'autotransplanted' into either the neck or the forearm to give a continuing supply of PTH.
- Allotransplantation of cultivated parathyroid tissue is also a possibility.
- A diet rich in dairy products containing calcium and vitamin D is recommended.
Potential treatment problems
- Pregnancy, diuretics, antacids, anticonvulsants, intercurrent illness, ammonium chloride and acetazolamide may alter the requirements for vitamin D.
- Close monitoring of calcium levels is needed.
- There has been one case report of hypoparathyroidism refractory to vitamin-D therapy, treated with multipulse teriparatide.
Mostly due to hypocalcaemia:
- Laryngospasm can cause stridor and airway obstruction.
- Neuromuscular irritability can lead to muscle cramps, tetany and seizures.
- QT interval changes can cause syncope, arrhythmias and death.
- Calcium can be deposited in the kidneys causing calculi.
- Stunted growth, malformed teeth and mental impairment can develop if untreated in childhood.
- Over-treatment with vitamin D can cause hypercalcaemia and renal impairment.
- The regular monitoring required to ensure appropriate calcium levels mean that the prognosis is challenging for many people. This may improve if synthetic parathyroid hormone (PTH) becomes widely available.
- Regular review and blood monitoring programmes within the GP setting are likely to be beneficial.
Close monitoring of patients undergoing thyroid or neck surgery, radiotherapy to the neck or chest and chemotherapy treatment for symptoms and signs of hypocalcaemia.
Further reading & references
- Bushinsky DA, Monk RD; Electrolyte quintet: Calcium.; Lancet. 1998 Jul 25;352(9124):306-11.
- Pitukcheewanont P, Pediatric Hypoparathyroidism, Medscape, Jul 2010
- Ahonen P; Autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin Genet. 1985 Jun;27(6):535-42.
- Ahonen P, Myllarniemi S, Sipila I, et al; Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990 Jun 28;322(26):1829-36.
- Sciume C, Geraci G, Pisello F, et al; Complications in thyroid surgery: symptomatic post-operative hypoparathyroidism incidence, surgical technique, and treatment. Ann Ital Chir. 2006 Mar-Apr;77(2):115-22.
- Osmolski A, Frenkiel Z, Osmolski R; Complications in surgical treatment of thyroid diseases, Otolaryngol Pol. 2006;60(2):165-70.
- Manfredini R, Bariani L, Bagni B, et al; Hypoparathyroidism in chronic alcohol intoxication: a preliminary report. Riv Eur Sci Med Farmacol. 1992 Sep-Oct;14(5):293-6.
- Understanding the causes of Hypoparathyroidism, Hypoparathyroidism UK. Information obtained from website in October 2007
- Shoback D; Clinical practice. Hypoparathyroidism. N Engl J Med. 2008 Jul 24;359(4):391-403.
- Winer KK, Ko CW, Reynolds JC, et al; Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003 Sep;88(9):4214-20.
- Walker Harris V, Jan De Beur S; Postoperative hypoparathyroidism: medical and surgical therapeutic options. Thyroid. 2009 Sep;19(9):967-73.
- Lo CY; Parathyroid autotransplantation during thyroidectomy. ANZ J Surg. 2002 Dec;72(12):902-7.
- Testini M, Rosato L, Avenia N, et al; The impact of single parathyroid gland autotransplantation during thyroid surgery on postoperative hypoparathyroidism: a multicenter study. Transplant Proc. 2007 Jan-Feb;39(1):225-30.
- Nawrot I, Wozniewicz B, Tolloczko T, et al; Allotransplantation of cultured parathyroid progenitor cells without immunosuppression: clinical results. Transplantation. 2007 Mar 27;83(6):734-40.
- McIlroy J, Dryburgh F, Hinnie J, et al; Oestrogen and calcium homeostasis in women with hypoparathyroidism. BMJ. 1999 Nov 6;319(7219):1252-3.
- Kanis JA, Disorders of calcium metabolism, Hypoparathyroidism. Chapter 7.5.2. Concise Oxford Textbook of Medicine First edition - April 2000
- Puig-Domingo M, Diaz G, Nicolau J, et al; Successful treatment of vitamin D unresponsive hypoparathyroidism with multipulse Eur J Endocrinol. 2008 Nov;159(5):653-7. Epub 2008 Aug 14.
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|Original Author: Dr Michelle Wright||Current Version: Dr Hayley Willacy||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 20/02/2012||Document ID: 2299 Version: 25||© EMIS|