Hypoparathyroidism (HypoPT) is a rare disorder characterised by low serum calcium, elevated serum phosphorus, and inadequate secretion of parathyroid hormone (PTH), the main target tissues for which are kidney and bone. HypoPT is the cause of hypocalcaemia through the lack of an effective PTH secretion with consequent inadequate mobilisation of calcium from bone, reabsorption of calcium from the distal nephron and production of the active vitamin D metabolite, calcitriol, through renal 1-alpha-hydroxylase.1
The inappropriate low serum PTH concentrations, typical of HypoPT, cause an increased renal tubular reabsorption of phosphate, with resultant hypocalcaemia and hyperphosphataemia with hypocalcaemia being responsible for neuromuscular symptoms and hyperphosphataemia contributing to ectopic mineralisation of soft tissues (kidneys, brain, vessels, eyes).2
HypoPT can be characterised, as with the majority of endocrine disturbances, into primary (caused by intrinsic defects within the parathyroid glands and mostly genetic in nature) and the more common secondary, or acquired form, consequent to ablation, impairment or destruction of all the parathyroid tissue.3 The prevalence of HypoPT has been reported, and ranges from 22 to 37 per 100,000 person-years in different parts of the world.4–6 Post-surgical HypoPT accounts for approximately 75% of all cases of recognised HypoPT, with 1–5% of patients undergoing anterior neck surgery experiencing permanent HypoPT. Autoimmune destruction is the main reason for non-surgical HypoPT. Magnesium depletion or excess can cause hypocalcaemia by inducing functional HypoPT. Several genetic aetiologies can result in the loss of parathyroid function or actions causing isolated HypoPT, syndrome HypoPT or pseudoHypoPT.
The yearly costs of medical care for patients affected by HypoPT in the US has been estimated to be approximately three-times that of healthy people.7 However, because this study did not quantify the costs related to outpatient clinics, hospital, emergency departments and pharmacies, the estimates for care of hypoparathyroidism patients are likely to be much higher than the figures published.
Neuromuscular signs or symptoms due to hypocalcaemia are the main features of the disorder. Hyperphosphataemia contributes to several long-term complications, such as ectopic calcifications. The clinical presentation of HypoPT is variable, ranging from a mild (that is, only paresthesia) to a severe (that is, seizures), with the most severe cases resulting from surgical removal of the parathyroid glands (Figure 1). Chronic complications of HypoPT include: nephrocalcinosis and kidney failure in the long term, basal ganglia calcification, posterior subcapsular cataracts, reduced skeletal remodelling and impairment of quality of life (Figure1).8 Reduced quality of life is almost universal.
The personal and family history of the patient may help in recognising the cause of the hypocalcaemic condition. A family history of HypoPT suggests a genetic cause (Table 1). A history of neck surgery may indicate damage to and/or removal of the parathyroid glands during the surgical procedure. A history of autoimmune endocrine disorders (adrenal deficiency, candidiasis), immunodeficiencies or inborn anomalies (hearing loss or retardation) suggest the presence of congenital syndromic disorders (Autoimmune Polyendocrine Syndrome Type I or DiGeorge Syndrome) of which HypoPT is one typical component. A general bronzed skin colour, alongside liver insufficiency suggest haemochromatosis.
Patient examination should include testing the signs of Chvostek (twitching of facial muscles in response to tapping over the area of the facial nerve) and Trousseau (carpopedal spasm that results from ischaemia, such as that induced by pressure applied to the upper arm from an inflated sphygmomanometer cuff), useful in indicating the presence of neuromuscular irritability.
Laboratory tests should measure serum total and ionised calcium, proteins, phosphate, magnesium, creatinine, intact PTH and 25-hydroxy-vitamin D3 (25-OH D3) levels. The evaluation of calcium and phosphate levels in the 24-hour collection of urine enables the differential diagnosis of HypoPT, vitamin D deficiency and hypercalciuria/hypocalcaemia due to activating mutations of the calcium-sensing receptor.
The patient is usually referred to either a paediatric or adult endocrinologist.
Conventional treatment and clinical monitoring
The aims of HypoPT therapy are the control of symptoms and signs while reducing complications.
Because a normal concentration of ionised calcium is needed for many vital cell functions, acute hypocalcaemia in HypoPT can be a life-threatening emergency. When clinical circumstances require urgent treatment, intravenous (IV) calcium infusion is recommended, bearing in mind both the symptoms and the levels of calcium.9 Patients experience substantial relief of symptoms with IV therapy, but cardiac symptoms usually resolve slowly. In an emergency, the IV calcium infusions should be repeated at hourly intervals; this, however, cannot be used for chronic treatment.
The management of chronic hypocalcaemia in HypoPT is guided by certain treatment goals: preventing signs of hypocalcaemia; maintaining the serum calcium concentrations slightly below the normal or in the low normal range; maintaining the serum calcium–phosphate product below 55mg2/dl2; to avoid hypercalciuria; to avoid hypercalcaemia; and to avoid soft tissue calcification.10 In long-term treatment, active vitamin D metabolites have to be administered because the lack of PTH prevents the renal conversion of 25-OH D3 into 1,25-dihydroxy vitamin D3 (calcitriol), the active hormone. Usually, the initial calcitriol dose administered is 0.25–0.5µg twice daily. The maintenance of the calcitriol effect can last approximately 24 hours. Other vitamin D formulations that undergo activation in the liver are 1-hydroxy vitamin D3 (alfacalcidol) and dihydrotachysterol.
Calcium salts (typically calcium carbonate and calcium citrate) are required to maintain normal serum calcium concentrations in HypoPT. Amorphous calcium was recently stabilised, showing an increased fractional absorption compared with crystallised calcium.11
Patients are also supplemented with parenteral vitamin D when circulating levels of calcifediol are low; this is because other tissues, except kidney, are able to activate calcifediol into calcitriol.
Other drugs that can help to adjust mineral metabolism in HypoPT are thiazide diuretics that promote renal tubular calcium retention. Their use is recommended in hypoparathyroid patients who are hypercalciuric. Phosphate binders can also be used in situations where hyperphosphataemia is not correctable. Magnesium should also be administered when hypomagnesaemia is present.
The monitoring of the patients depends on the level of control of calcium/phosphate homeostasis in HypoPT. Patients well controlled could be monitored every 6–12 months. More frequent monitoring is indicated when therapy is initially adjusted, with several controls in a week. Renal function (that is, 24-hour urinary calcium, creatinine clearance) is monitored yearly, with renal imaging being recommended every five years. At baseline, central nervous system calcifications, eye examination and bone mineral density measurements are also recommended.
Advances in the therapy of HypoPT
Although the conventional treatment of HypoPT with calcium and active vitamin D metabolites can offer a control of the affected patients, the required doses can be very high and sometimes the conditions can be defined as brittle.The complications that follow an insufficient control of HypoPT are severe and encompass symptoms and signs that severely affect the quality of life and the survival of the patients. The explanation for this is the fact that calcium and vitamin D active metabolites do not represent a real substitutive therapy because the actions of PTH on bone and kdneys are not restored (Figure 2).
To develop a more physiological alternative to conventional therapy of HypoPT, studies aimed at PTH replacement were first based on the use of synthetic human PTH(1-34) (teriparatide, approved for the treatment of osteoporosis in the elderly population).12 Studies with this peptide are limited. Today this therapy is used mainly for patients affected by HypoPT caused by activating mutations of the CaSR gene, and doses are often higher than those recommended for osteoporosis. Long-term safety of these dosages is not known.
For this reason the full PTH molecule, PTH(1-84), appeared to be more attractive than teriparatide as a replacement hormonal therapy in HypoPT.
A double-blind, multinational, randomised controlled clinical trial with PTH (1-84) (REPLACE) was conducted in 134 patients.13 When PTH(1-84) was initiated at 50µg daily, active vitamin D metabolites and/or calcium supplements were reduced by approximately 50%. The US Food and Drug Administration approved rhPTH(1-84) in 2015 as an adjunct to calcium and vitamin D for the treatment of adults with HypoPT who cannot be well-controlled on conventional therapy. In 2017, the European Medicines Agency granted conditional marketing authorisation for rhPTH(1-84) in Europe. This is the first and only approved hormone therapy indicated as adjunctive treatment for adult patients with chronic HypoPT who cannot be adequately controlled with standard therapy alone.
- Hypoparathyroidism (HypoPT) is a rare disorder.
- Diagnosis is often delayed because symptoms are initially subtle.
- Therapy of HypoPT is unsatisfactory under the conventional route (calcium and active vitamin D compounds).
- Therapy with parathyroid hormone will potentially change the clinical history of HypoPT patients.
- The need for a strong engagement of all the stakeholders in the management of this disorder is crucial.
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Mannstadt M et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomized, phase 3 study. LancetDiabetes