HYPERPARATHYROIDISM AND HYPOPARATHYROIDISM

HYPERPARATHYROIDISM AND HYPOPARATHYROIDISM

Current diagnosis

Primary Hyperparathyroidism

• Third most common endocrine disorder and most common cause of hypercalcemia in the general population.

• Diagnosis based on confirmed hypercalcemia (total calcium [albumin corrected] or ionized calcium) associated with elevated or inappropriately normal serum parathyroid hormone level.

•   Genetic causes should be searched for in young patients.

Hypoparathyroidism

•   Rare disorder.

• Inadvertent removal or damage to the parathyroid gland during thyroid surgery and, much less frequently, autoimmune destruction are the most common causes.

• Diagnosis based on low serum calcium along with undetectable or inappropriately low serum parathyroid hormone level.

Current therapy

Primary Hyperparathyroidism

• Parathyroidectomy is the only definitive therapy.

• Surgery should be considered in all cases and recommended in symptomatic patients and in those who, albeit asymptomatic, meet the surgical criteria.

• Surveillance without surgery can be considered in asymptomatic patients who do not meet the surgical criteria.

• Patients followed without surgery should be replete with vitamin D and calcium intake should not be restricted.

• Medical treatment can be considered in selected cases: antiresorptive therapy to increase bone mineral density and cinacalcet (Sensipar) to lower serum calcium.

Hypoparathyroidism

• Severe hypocalcemia is a medical emergency and treatment with intravenous calcium should be promptly instituted and maintained for 24 to 48 hours; oral therapy with calcium and active vitamin D metabolites should be started as soon as practical.

• The goal of chronic treatment is to maintain serum calcium in the low-normal range, avoiding hypocalcemic symptoms and long-term complications.

• Chronic conventional therapy is based on adequate calcium intake (calcium supplement needed in most cases) and active vitamin D metabolites.

• Recombinant full-length parathyroid hormone 1-84 (Natpara) has been approved by the U.S. Food and Drug Administration for patients not controlled with conventional therapy.

• An individualized approach is necessary to optimize patient care. Lifelong monitoring is needed to decrease the risk of complications.

Primary Hyperparathyroidism

Primary hyperparathyroidism (PHPT) is currently the third most common endocrine disorder and the most frequent cause of hypercalcemia in the general population.

Epidemiology and Pathogenesis

The disease was considered rare until the early 1970s, when its incidence in the United States rose dramatically following the introduction of serum calcium in the multichannel autoanalyzer. The incidence varies according to geographic areas and assessment measures; recent data in the United States indicate an incidence of 79.6 per 100,000 person-years in women and 35.6 per 100,000 person-years in men of all races, with the highest rate among blacks. The incidence peaks in the sixth decade of life. The prevalence ranges between 1 and 7 cases per 1000 adults. Most cases occur in women (with a female-to- male ratio of 3:1), but there is no sex difference before the age of 45 years. PHPT is rare in children and adolescents.

PHPT mainly occurs as a solitary disease (90%) but may be part of hereditary syndromes (e.g., multiple endocrine neoplasia [MEN] types 1, 2A, and 4; hyperparathyroidism–jaw tumor syndrome [HPT-JT], and familial isolated hyperparathyroidism [FIPH]) (Table 1). A single, benign adenoma is found in 80% to 85% of cases, multigland involvement in 15% to 20%, and parathyroid carcinoma in less than 1%. Multigland involvement is more common in hereditary cases, particularly MEN1. In the absence of local infiltration or metastases, the diagnosis of parathyroid carcinoma may be difficult at histology.

Genetic studies (DCD73 gene mutations) and immunohistochemical studies (loss of parafibromin [the protein encoded by the CDC73 gene] expression) may help in equivocal cases. Predisposing factors are external neck irradiation in childhood and long-term lithium therapy.

Table 1

Hereditary Forms of PHPT and Related Involved Gene

Disorder                                                          Gene                                            Pattern of Inheritance
Multiple endocrine neoplasia type 1 MEN1 Autosomal dominant
Multiple endocrine neoplasia type 2A RET Autosomal dominant
Multiple endocrine neoplasia type 4 CDKN1B Autosomal dominant
Hyperparathyroidism–jaw  tumor syndrome CDC73 Autosomal dominant
Familial  isolated hyperparathyroidism MEN1, CDC73, CASR, CDKN1B Autosomal dominant
Familial hypocalciuric hypercalcemia type 1 CASR Autosomal dominant
Familial hypocalciuric hypercalcemia type 2 GNA11 Autosomal dominant
Familial hypocalciuric hypercalcemia type 3 AP2S1 Autosomal dominant
Neonatal  severe hyperparathyroidism CASR Autosomal recessive

Abbreviations: AP2S1 = Adaptor-related protein complex 2 sigma 1 subunit CASR = calcium- sensing receptor; CDC73 = cell division cycle 73; CDKN1B = cyclin-dependent   kinase inhibitor 1B; GNA11 = G protein subunit alpha 11; MEN1 = multiple endocrine neoplasia type 1; PHPT = primary hyperparathyroidism; RET = rearranged during  transfection.

PHPT is characterized by excessive parathyroid hormone (PTH) secretion from one or more parathyroid glands, due to the loss of the homeostatic control of PTH synthesis and secretion. Extracellular ionized calcium (Ca2 +  ) is the main regulator of PTH secretion. Ca2 +interacts with the Ca2 +-sensing receptor (CaSR) present on the surface of parathyroid cells; there is an inverse sigmoidal relationship between Ca2 +concentration and PTH release. In adenomas hypercalcemia is due to the loss of normal sensitivity of the parathyroid cell to the inhibitory action of Ca2 + , whereas in parathyroid hyperplasia the increased number of parathyroid cells, which have a normal sensitivity to the inhibitory action of Ca2 + , causes hypercalcemia. Serum phosphate, 1,25-dihydroxyvitamin D (1,25(OH)2D), and fibroblast growth factor 23 (FGF23) are also involved in the control of PTH secretion.

Although major progress has been made in the last two decades, the molecular basis of PHPT is still unclear in the majority of cases. The clonality of most parathyroid tumors suggests a defect in the pathways that control parathyroid cell proliferation or the expression of PTH. The genes involved are listed in Table 1. Germline mutations are often found in hereditary forms. On the other hand, somatic mutations may occur in sporadic cases, even though germline mutations have also been described in apparently sporadic cases.

Clinical Presentation

In recent years the clinical presentation of PHPT in Western countries has changed from a symptomatic disease, characterized by hypercalcemia and renal (nephrolithiasis and nephrocalcinosis) and skeletal (osteitis fibrosa cystica, fragility fractures) manifestations, to one with subtle and nonspecific clinical manifestations (asymptomatic PHPT). Nephrolithiasis remains the most common classic clinical manifestation (15%–20%), and silent stones are frequently detected at ultrasound. Bone mineral density (BMD) is reduced particularly at sites rich in cortical bone (one-third distal radius). Studies using peripheral high-resolution quantitative computed tomography (CT) has shown involvement of both cortical and trabecular sites, the latter confirmed by the trabecular bone score (TBS) at the lumbar spine. An increased rate of vertebral and nonvertebral fractures has also been documented. Nonclassical manifestations, including subtle cardiovascular abnormalities and psychological and cognitive symptoms, have also been reported.

A new variant of PHPT (normocalcemic PHPT) has recently been identified, namely patients with increased serum PTH levels in the absence of hypercalcemia (also by measurement of ionized calcium) or other causes of secondary hyperparathyroidism. This condition, called normocalcemic PHPT, has been typically recognized in persons evaluated for low BMD, in whom PTH was measured even in the absence of hypercalcemia. In some cases this new phenotype may represent an early phase of classical hypercalcemic PHPT, when PTH elevation precedes the occurrence of hypercalcemia.

Evaluation and Diagnosis

The finding of hypercalcemia on routine blood testing or in postmenopausal women investigated for osteoporosis is typically the first clue to the diagnosis of PHPT. Hypercalcemia should be confirmed in repeated testing, preferably evaluating albumin- corrected total calcium (measured total calcium in mg/dL + [0.8 × (4.0 – serum albumin in g/dL)]) or ionized calcium. The next diagnostic step is the measurement of serum PTH. An elevated (or unexpectedly normal) serum PTH in the face of hypercalcemia is virtually diagnostic of PHPT. Serum phosphate is normal or in the low-normal range in mild PHPT and low in severe cases. A low or undetectable PTH level in a hypercalcemic patient rules out the diagnosis of PHPT. The most common cause of PTH-independent hypercalcemia is malignancy, where hypercalcemia is due to the secretion by the tumor of PTH-related peptide, a molecule that shares with PTH the amino- terminal active part but does not cross-react in the PTH assay, or osteolytic lytic bone metastases. Urinary calcium should also be measured. If hypercalciuria is greater than 400 mg per day, a more extended evaluation of the stone risk profile should be performed.

Urinary calcium measurement is also useful to exclude familial hypocalciuric hypercalcemia (FHH), which is suggested by the finding of the calcium-to-creatinine clearance ratio of less than 0.01.

A hereditary form of PHPT, accounting for 5% to 10% of cases, should be sought in patients younger than 30 years at diagnosis, with a family history of hypercalcemia and/or neuroendocrine tumors (see Table 1). In this setting serum calcium should be measured in first- degree relatives and genetic tests performed. Parathyroid cancer should be suspected in individuals, especially males, with marked hypercalcemia, a palpable neck mass, and serum PTH concentration 3 to 10 times the upper normal value.

Renal ultrasound should be performed in all patients, even in those with no history of nephrolithiasis, since recent studies have shown that silent kidney stones are common in patients with asymptomatic PHPT. Routine BMD testing by dual-energy x-ray absorptiometry (DXA) at the lumbar spine, hip, and distal forearm is also an essential component of the evaluation. BMD is typically low at the one-third distal radius, a site of enriched cortical bone, but a few patients may show predominant cancellous bone involvement, as documented by vertebral osteopenia or osteoporosis. The involvement of the trabecular compartment is also confirmed by the TBS at the lumbar spine. Vertebral imaging by x-ray or DXA (vertebral fracture assessment, VFA) should also be routinely performed to detect silent vertebral deformities since vertebral fracture risk is increased in asymptomatic patients.

Neck imaging (ultrasound and sestamibi scanning) has no value in the diagnosis of PHPT, but it is a useful tool for localizing the abnormal parathyroid gland in patients selected for parathyroidectomy (PTx). Sestamibi has the advantage of localizing the ectopic parathyroid gland outside the neck.

Treatment

The aim of treatment is to remove all hyperfunctioning parathyroid tissue, resolve biochemical abnormalities, improve BMD, and decrease the risk of nephrolithiasis and fractures.

Surgical Treatment

Parathyroid surgery represents the only definitive cure of PHPT. Successful PTx normalizes serum calcium and PTH, improves BMD, and decreases the risk of nephrolithiasis and fragility fractures.

Patients selected for surgery should be referred to an experienced parathyroid surgeon. A focused minimally invasive approach, guided by imaging studies associated with intraoperative monitoring of serum PTH, is the preferred surgical procedure in sporadic PHPT. In experienced hands the rate of surgical cure reaches 95% to 98% with a negligible rate of surgical complications. In hereditary cases the surgical approach (bilateral neck exploration by classical cervicotomy) may differ since multigland involvement is common. An “en bloc” resection of the parathyroid lesion together with the ipsilateral thyroid lobe with clear gross margins and the adjacent structures is recommended when parathyroid carcinoma is suspected. Particular attention should be paid to avoid seeding of neoplastic parathyroid cells. Surgery should be considered for any patient with a confirmed diagnosis of PHPT and recommended in those with symptomatic disease.

Patients with mild hypercalcemia (serum calcium < 12 mg/dL [3 mmol/L]) can proceed directly to surgery. When serum calcium is higher, preoperative treatment with saline infusion eventually followed by loop diuretics, intravenous bisphosphonates, denosumab, or cinacalcet (Sensipar) may be considered to reduce serum calcium levels and decrease the risk of complications, particularly cardiac arrhythmias, which are associated with more severe hypercalcemia.

Surgery is also a reasonable option for patients with asymptomatic PHPT. International guidelines provide guidance to select patients who should be referred for surgery or followed without surgery. The most recent revised (2013) guidelines for surgery or monitoring are reported in Table 2. These guidelines are largely consistent with the previous ones and recommend PTx for all patients with symptomatic PHPT and asymptomatic patients who meet one or more of the indicated criteria. The new indications for surgery in asymptomatic patients include (1) the presence of silent vertebral fractures detected by x-ray, CT, magnetic resonance imaging (MRI), or vertebral fracture assessment (VFA) by DXA, and (2) a 24-hour urinary calcium excretion greater than 400 mg/dL, increased stone risk (evaluated by urinary stone risk profile), and subclinical kidney stone or nephrocalcinosis detected by x-ray, ultrasound, and CT. According to the guidelines, about 60% of patients with asymptomatic PHPT meet the criteria for surgery. As mentioned before, patients with mild PHPT may have subtle cardiovascular abnormalities and complain of psychological and cognitive symptoms. It is unclear whether and to what extent these abnormalities are reversible after successful PTx; for the time being they are not considered indications for surgery.

Nonetheless, surgery could be considered in a middle-aged patient in whom asymptomatic PHPT is associated with increased cardiovascular risk (metabolic syndrome, hypertension, ischemic heart disease) if the surgical risk is low.

Table 2

Guidelines for Surgery for Patients With Asymptomatic PHPT and Monitoring for Those Followed Without Surgery

 

Modified from Bilezikian et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab 99:3561, 2014.

Abbreviations: BMD = bone mineral density; CT = computed tomography; DXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging; PHPT = primary hyperparathyroidism; VFA = vertebral fracture assessment.

Randomized clinical trials have also shown that patients with sporadic asymptomatic PHPT who do not met the surgical criteria may benefit from surgery, not only because it normalizes serum calcium and PTH but also because it improves BMD and quality of life (QoL). On the other hand, surgery could be postponed in hereditary cases with mild hypercalcemia, because multigland disease, occasionally with asynchronous involvement of the various parathyroid glands, is not uncommon and carries an increased risk of surgical complications and recurrence/persistence of PHPT.

Therefore, individual counseling addressing the benefits and risks of PTx is mandatory, and the preference of the patients should be taken into account. It is well known that parathyroid surgery, when performed by skilled neck surgeons, is safe, cost-effective, and associated with low perioperative morbidity. On the other hand, it is important to recognize that PTx, particularly if performed by inexperienced surgeons, may be associated with complications that could be invalidating and not acceptable for a patient with mild disease and a good QoL. In this regard, the choice of surgery may be reconsidered in a patient with asymptomatic PHPT in whom parathyroid surgery was initially advised or selected by the patient when preoperative imaging studies are negative. Indeed, in this setting the patient may feel uncomfortable undergoing a blind neck exploration, a surgical procedure more extensive than the minimally invasive approach and carrying the greatest risk of complications.

Nonsurgical Management

As mentioned before, many patients with PHPT do not meet the criteria for surgery. These patients, as well as those who decline surgery or have contraindications to surgery, need to be monitored.

Monitoring

Randomized clinical studies have shown stability over a short period of observation (up to 2 years) in patients with asymptomatic PHPT followed without surgery and benefits in those who underwent PTx even if they did not meet the criteria for surgery. The extension up to 5 years of one of these randomized studies has shown a more frequent occurrence of vertebral fracture in patients belonging to the observation group than in those cured by PTx. Long-term observational studies indicate that the disease remains stable in the majority for up to 8 to 9 years, but more than one third of patients show a progression of the disease.

Calcium intake should not be restricted, and an intake appropriate for age and sex as in the general population (preferably with food) should be recommended (Table 3). Vitamin D–depleted patients should be supplemented with daily doses of 800 to 1000 IU of vitamin D; weekly or monthly doses calculated on this daily dose can also be used. A serum level of 25(OH)D greater than 20 ng/mL should be reached, and the attainment of a higher target (> 30 ng/mL) is suggested by some guidelines.

Table 3

Classification of Hypoparathyroidism*

Abbreviations: AIRE = autoimmune regulatory; CASR = calcium-sensing   receptor; FAM111A = family with sequence similarity 111 member A; GATA3 = GATA-binding protein 3; GCM2 = glial cell missing homolog 2; GCMB = glial cell missing gene; GNA11 = G protein subunit alpha 11; GNAS = GNAS complex locus; PTH = parathyroid  hormone; STX16 = syntaxin 16; TBCE = tubulin folding cofactor E; TBX1 = T-Box1; UPD = uniparental disomy.

*  Mutated genes are indicated in parentheses.

General principles for monitoring are reported in Table 2. Serum calcium and creatinine (estimated glomerular filtration rate [eGFR]) should be measured annually and BMD at the lumbar spine, total hip, and distal forearm measured every 1 to 2 years. Vertebral morphometry (by x-ray or VFA) should be performed when clinically indicated (back pain, height loss). Finally, 24-hour urinary collection for biochemical stone risk profile and renal imaging (x-ray, ultrasound, or CT) should be performed if there is a suspicion of renal stones.

Parathyroid surgery should be recommended in patients who are followed without surgery in the following instances: (1) serum calcium concentration greater than 1 mg/dL above the upper normal limit; (2) creatinine clearance less than 60 cc/min; (3) detection of nephrocalcinosis or kidney stones; (4) BMD T-score at any site less than –2.5 or the finding of a significant (greater than the least significant change as defined by the International Society for Clinical Densitometry) decrease of BMD, even if the T-score is not less than – 2.5; and (5) clinical fractures or morphometric vertebral fractures, even if asymptomatic.

Medical Treatment

No medical treatment is currently available to cure PHPT. Therefore, when PTx is indicated and there are no contraindications for surgery, medical treatment should not be considered a valuable alternative option. Medical treatment may be considered for patients who have contraindications to surgery or are unwilling to undergo PTx, as well as for those who have failed surgery. Treatment should be guided by the aim of therapy.

Calcimimetics

If the aim of treatment is to reduce serum calcium, the calcimimetic cinacalcet can be effective. The serum calcium typically declines over a few weeks and may normalize in most patients with moderate hypercalcemia. In addition, cinacalcet increases serum phosphate and only slightly reduces PTH concentration, but has no effect on BMD. The beneficial effects are sustained over time as long as the drug is used. Adverse events are dose related: modest and transient when low doses of cinacalcet are used (up to 30 mg twice daily), but rather frequent, particularly gastrointestinal, symptoms, occasionally severe enough to require treatment withdrawal, when higher doses are employed. The use of cinacalcet has been approved by the US Food and Drug administration (FDA) for the treatment of severe hypercalcemia in patients with PHPT who are unable to undergo PTx, and by the European Medical Agency (EMA) for the reduction of hypercalcemia in patients with PHPT, for whom PTx would be indicated on the basis of serum calcium levels (as defined by relevant guidelines), but in whom surgery is not clinically appropriate or contraindicated. As clearly stated, the EMA indications leave more room for the use of cinacalcet.

Cinacalcet should not be used as an initial treatment or in patients who do not meet the approved criteria for its prescription. The long- term safety of cinacalcet has not been established. Moreover, the rather high cost is another important limit for its long-term use.

Bisphosphonates

If the aim is to increase BMD, antiresorptive therapy can be considered. Alendronate (Fosamax) is the bisphosphonate that has been more extensively used and shown to be effective in reducing bone turnover markers and increasing BMD. Over a short period of time, its effectiveness in increasing BMD is comparable to that observed after successful PTx. No effect has been shown on serum calcium and PTH levels.

Combined Therapy With Cinacalcet and Bisphosphonates

As mentioned before, cinacalcet is effective in the control of hypercalcemia but has no effect on BMD. Conversely, bisphosphonates increase BMD, with no effect on serum calcium. Limited data indicate that combination therapy is associated with both the calcium-lowering effect of cinacalcet and the skeletal advantage of bisphosphonates. Therefore, if a patient has a low BMD and serum calcium concentration appropriate for the use of cinacalcet, combined therapy could be of benefit.

Pregnancy and Lactation

PHPT may be diagnosed during pregnancy by the finding of hypercalcemia on routine blood testing. There are some distinctive features that should be considered in the evaluation and management:

(1) pregnancy is associated with hemodilution and occasionally hypoalbuminemia, and therefore it would be preferable to measure ionized calcium; (2) the hereditary form should be sought because of the young age of pregnant women; and (3) women with mild elevation of calcium should be managed conservatively, mostly by hydration—in the case of worsening of hypercalcemia PTx in the second trimester and cinacalcet1  may be considered.

Secondary Hyperparathyroidism

Secondary hyperparathyroidism (SHPT) defines any condition in which the increased PTH secretion occurs as a normal physiologic response, often mediated by a decrease of serum calcium. Vitamin D deficiency, as a result of inadequate nutritional intake/sun exposure, malabsorption, liver diseases, or chronic renal failure, is the most common cause. Other less common causes include vitamin D resistance (Fanconi syndrome, vitamin D receptor defects), PTH resistance (pseudohypoparathyroidism, hypomagnesemia), drugs (calcium chelators, inhibitors of bone resorption, and drugs that interfere with vitamin D metabolism [phenytoin and ketoconazole]), acute pancreatitis, and osteoblastic metastases (prostate and breast cancer).

SHPT should always be considered and ruled out before making the diagnosis of normocalcemic PHPT. At variance with PHPT, SHPT is characterized by low or, more often, low-normal serum calcium and decreased urinary calcium excretion. An elevation of serum phosphate levels can be a clue to pseudohypoparathyroidism.

A prolonged stimulation of PTH synthesis and secretion, as may occur in end-stage renal failure and severe gastrointestinal diseases, may lead to the emergence of an autonomous clone of parathyroid cells into a single gland, leading to hypercalcemia (tertiary hyperparathyroidism).

Hypoparathyrodism

Hypoparathyroidism (HypoPT) is the clinical spectrum caused by insufficient production of PTH by the parathyroid glands. The major distinguishing feature is hypocalcemia, resulting from inadequate mobilization of calcium from bone and reabsorption of calcium at the distal tubule, and decreased activity of renal 1α-hydroxylase and, therefore, generation of calcitriol; as a consequence, the intestinal calcium absorption will be reduced.

Epidemiology and Pathogenesis

HypoPT is a rare condition designated in both the United States and Europe as an orphan disease. The estimated prevalence is 37 and 24 per 100,000 inhabitants in the Unites States and Europe, respectively. HypoPT can be congenital or acquired (Table 3).

Congenital HypoPT is usually hereditary and may be isolated or combined with organ defects. The autoimmune is the most common form and may be either isolated or part of the autoimmune polyglandular syndrome type 1 (APS1). The other forms are much more rare.

Acquired HypoPT is much more common than the congenital counterpart. Bilateral neck surgery for thyroid or parathyroid disorders is the most common cause. Postoperative HypoPT can be transient (caused by reversible parathyroid ischemia and resolving within a few weeks) or chronic/permanent (caused by irreversible parathyroid damage, such ischemia, electric scalpel damage, or, rarely, inadvertent removal of parathyroid glands). Its rate largely depends on the experience of the surgeon and the extent of the neck surgery.

Clinical Presentation

The clinical manifestations of HypoPT are largely related to the level of serum calcium and the speed of its fall and may range from asymptomatic cases, when hypocalcemia is mild (corrected calcium ≥ 7.0 mg/dL [1.75 mmol/L]), to a severe life-threating condition that requires hospital admission and intensive treatment. In mild cases signs related to neuromuscular irritability, namely the Chvostek sign (twitching and/or contracture of the facial muscles produced by tapping on the facial nerve just anterior to the ear and just below the zygomatic bone) and Trousseau sign (carpal spasm evoked by inflating a sphygmomanometer cuff above systolic blood pressure for several minutes), may be present at physical examination. Moderate to severe hypocalcemia (corrected calcium < 7.0 mg/dL [1.75 mmol/L]) is usually symptomatic, even though there is no strict relationship between the severity of symptoms and the degree of hypocalcemia. In patients with postoperative HypoPT, symptoms usually appear on the first postoperative day, but in some cases hypocalcemia may become clinically manifest even after 3 to 4 days. Classical manifestations include paresthesias, carpopedal spasm, tetany, seizures, positive Chvostek and Trousseau signs, and prolongation of the QT interval on electrocardiography. Papilledema and subcapsular cataract can be present. Pseudohypoparathyroidism is a group of genetic disorders caused by end-organ resistance to the action of PTH. Patients with the type 1a variant have a typical phenotype (Albright hereditary osteodystrophy), characterized by short stature, shortened fourth and fifth metacarpals, rounded face, and mild intellectual deficiency.

Other endocrine glands, including the thyroid and the gonads, may be dysfunctional. This clinical and endocrine phenotype is also typical of patients with type 1c. Patients with type 1b have PTH resistance and in some cases partial resistance to thyroid-stimulating hormone (TSH) and mild brachydactyly. Patients with the type 2 variant have PTH resistance in the absence of the aforementioned clinical phenotype.

Evaluation and Diagnosis

The finding of low albumin-corrected serum calcium, high serum phosphate, and inappropriately low or undetectable serum PTH confirms the diagnosis of HypoPT. A recent neck surgery strongly suggests the postoperative form. A family history of hypocalcemia suggests a genetic cause. Coexistence of other autoimmune endocrinopathies (i.e., adrenal insufficiency) or candidiasis prompts consideration of APS1. Immunodeficiency and the presence of other congenital organ defects point to DiGeorge syndrome. Genetic testing may be warranted to confirm the diagnosis of this and other genetic forms. Magnesium should also be measured because magnesium deficiency impairs the secretion of PTH and its action in target tissues. Urinary calcium is usually low, because of the low filtered calcium.

The 24-hour calcium-to-creatinine clearance ratio is increased in patients with the activating mutation of CaSR. A biochemical profile of low serum calcium and high phosphate levels, together with high serum PTH, in the absence of vitamin D deficiency, reflects the PTH- resistant state, and suggests a case of pseudohypoparathyroidism.

Treatment

The goal is to control symptoms of hypocalcemia and improve QoL while avoiding side effects and complications. The target serum calcium concentration is in the lower part of the normal range.

Treatment relies on the administration of calcium (oral [dietary or supplements] or intravenous), active vitamin D metabolites, magnesium, and, where available, recombinant human PTH1 -84 (Natpara). Thiazide diuretics may help to reduce hypercalciuria; a low-phosphate diet and phosphate binders may help to control hypophosphatemia and lower the calcium–phosphate product.

Acute Hypoparathyroidism

Acute hypocalcemia typically follows neck surgery and may be favored by a low vitamin D status and magnesium deficiency that, when present, should be corrected before surgery. In patients with high risk (total thyroidectomy, repeated thyroid surgery), perioperative administration of calcitriol (Rocaltrol) decreases the incidence of postoperative hypocalcemia and shortens the hospital stay.

Mild Hypocalcemia

In mild hypocalcemia (corrected calcium ≥ 7.0 mg/dL [1.75 mmol/L]), oral calcium supplements (usually calcium carbonate, 1–3 grams daily in divided doses) alone or combined with active vitamin D metabolites should be administered. Calcitriol is typically initiated at an initial dose of 0.5 to 1.0 µg twice daily; equivalent doses of 1α- calcifediol2 (1.0–2.0 µg) may also be used (see later [Chronic Hypoparathyroidism, Conventional Therapy] for more details on calcium and active vitamin D therapy) (Table 4). Serum calcium is checked weekly until optimal levels are reached.

Table 4

Calcium Preparation and Vitamin D Metabolites in the Management of Hypocalcemia

 

Modified from Shoback D: Clinical practice. Hypoparathyroidism. N Engl J Med 2008;359:391–403, 2008.

*  Not available in the United States.

†  This compound is rapidly activated in the liver to 25(OH)  dihydrotachysterol.

‡ These compounds could be used in a setting where active vitamin D metabolites are not available and/or are too expensive.

Moderate to Severe Hypocalcemia

Patients with moderate to severe hypocalcemia (corrected calcium < 7.0 mg/dL [1.75 mmol/L]) are usually admitted to the hospital and treated with IV calcium until an oral regimen can be started. One to two ampules of 10% calcium gluconate diluted in 50 to 100 mL of 5% dextrose should be infused over a period of 10 to 20 minutes with electrocardiographic and clinical monitoring. The calcium infusion will raise the serum calcium concentration for no more than 2 to 4 hours; thus this initial treatment should be followed by a continuous infusion (50–100 mL/h) of a solution containing 1 mg/mL of elemental calcium (11 ampules of 10% calcium gluconate added to 5% dextrose in a final volume of 1 liter). The rate should be adjusted according to corrected serum calcium level, which should be measured initially every 1 to 2 hours and subsequently every 4 to 6 hours, and maintained at the lower limit of the normal range, while the patient is asymptomatic. This calcium infusion protocol maintained for 8 to 10 hours will raise serum calcium by approximately 2 mg/dL. Oral administration of active vitamin D metabolites and calcium should be started as soon as practical. Calcitriol is typically initiated at a dose of 0.5 to 1.0 µg twice daily; oral calcium (1–3 g daily in divided doses) is also added.

If hypocalcemia is due to magnesium deficiency, the previous protocol should be applied while magnesium is being replaced by administering IV magnesium sulfate (initial dose 2 g as a 10% solution over 10–20 minutes, followed by 1 g/h in 100 mL) until a normal serum level of magnesium is reached. The only administration of magnesium will be unable to correct hypocalcemia because hypomagnesemia inhibits the secretion of PTH, and consequently the renal activation of 25OHD and induces a peripheral resistance to the action of PTH.

The rate of calcium infusion should be increased if symptoms of hypocalcemia recur. The IV infusion should be slowly tapered and discontinued when an effective regimen of oral calcium and active vitamin D is reached (up to 24–48 hours or longer) and stable desired serum calcium levels are obtained.

Chronic Hypoparathyroidism

The goal of therapy is to maintain serum calcium in the low-normal range, avoid hypocalcemic symptoms and long-term complications, and improve QoL. An individualized approach is necessary to optimize patient care. Guidelines for the management of chronic HypoPT have only recently been developed by the European Society of Endocrinology, the American Association of Clinical Endocrinologists, the American College of Endocrinology, and a panel of international experts.

Conventional Therapy

An adequate calcium intake from dietary sources (mainly dairy products) should be recommended, but calcium supplements (1–3 g daily in divided doses) are needed in almost all patients. Calcium carbonate is generally preferred because fewer pills per day are needed. Calcium carbonate requires an acidic gastric environment to be absorbed and should be taken with meals. Its bioavailability decreases in patients with atrophic gastritis or taking proton pump inhibitors. In these circumstances, calcium citrate, which is well absorbed independent of meal and acid environments, should be preferred. Calcium citrate might also be a preferred option for patients who complain of gastrointestinal side effects using calcium carbonate or who prefer to take calcium supplements outside mealtimes.

Calcium carbonate and calcium citrate interfere with levothyroxine absorption; therefore thyroidectomized patients should be advised to take levothyroxine well apart from calcium supplements.

Prior to the availability of synthetic active vitamin D metabolites, supraphysiologic doses (25,000–200,000 IU daily) of either cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) were used. Nowadays, active 1α-hydroxylated vitamin D metabolites are preferred because patients with HypoPT have impaired renal activation of 25-hydroxivitamin D. Calcitriol (Rocaltrol) and alfacalcidol (One-Alpha)2 have a similar time of onset, but the latter has a longer time of offset (5–7 vs. 2–3 days). Calcitriol is more potent (about 50%) than alfacalcidol when compared in terms of the calcemic effect. The daily dose of calcitriol ranges between 0.25 and 2.0 µg, equal to 0.5 to 4 µg of alfacalcidol. Another active vitamin D analog, dihydrotachysterol,2 is also available in some countries. Where active vitamin D metabolites are not available or too expensive, large doses of parent vitamin D can still be used, but attention should be paid to the risk of vitamin D toxicity.

A low vitamin D status is not uncommon in patients with HypoPT, and vitamin D–deficient patients treated with active vitamin D metabolites should be supplemented with vitamin D2 or D3, because active vitamin D metabolites do not correct hypovitaminosis D.

Active vitamin D metabolites stimulate intestinal absorption of phosphate, which may cause hyperphosphatemia and an increased calcium–phosphate product, with the risk of soft tissue calcification. In this setting the intake of phosphate-rich foods should be reduced and the daily dose of calcium supplements increased, since calcium binds phosphate.

Hypercalciuria (≥ 250 mg [6.25 mmol] in women or ≥ 300 mg [7.5 mmol] in men or > 4 mg [0.1 mmol]/kg body weight in both sexes) is a common feature in patients with chronic HypoPT, because of the lack of PTH-dependent renal tubular reabsorption of calcium. In such instances a low-sodium diet should be advised either alone or combined with the administration of a thiazide diuretic that decreases renal calcium excretion. The combination of thiazide with amiloride1 may further lower urinary calcium excretion and decrease the risk of hypokalemia. Thiazide diuretics are not advised in autosomal dominant hypocalcemia, a condition due to mutations of the CaSR. Magnesium deficiency, when present, should also be corrected.

Lifelong monitoring is needed in patients with chronic HypoPTH. No study has evaluated how to best monitor these patients. The target serum calcium concentration is within the low-normal range, with no symptoms of hypocalcemia. In some patients a higher serum calcium level is needed to be symptom-free. A baseline renal imaging should be obtained. The recently published guidelines of the European Society of Endocrinology suggest measuring ionized or albumin- corrected total calcium, magnesium, and creatinine (eGFR) and 24-hour urinary calcium excretion every 3 to 6 months and performing renal imaging when patients have symptoms of nephrolithiasis or increasing serum levels of creatinine. Biochemical monitoring should be performed weekly or every other week when changing the daily dose of calcium or active vitamin D metabolites or introducing a new drug. It is important to note that serum calcium may fluctuate once the therapeutic regimen has been stabilized. Several comorbidities (e.g., gastrointestinal disease, diarrhea, immobilization) and drugs (loop and thiazide diuretics, systemic glucocorticoids, proton pump inhibitors, antiresorptive drugs, cardiac glycosides, and chemotherapeutics) may interfere with calcium homeostasis, and therefore patients should be periodically asked about their occurrence or use.

Conventional therapy only partially restores calcium homeostasis, and patients with chronic HypoPT have a reduced QoL and an increased risk of comorbidities, which include nephrocalcinosis, nephrolithiasis, impaired renal function, neuropsychiatric diseases, muscle stiffness and pain, infections, and seizures. An increased rate of intracerebral calcifications and cataracts has been documented in nonsurgical HypoPT. Bone mineral content is increased in patients with chronic HypoPT, but cancellous bone microarchitecture is abnormal.

Parathyroid Hormone

Until recently, HypoPT was the only major hormonal insufficiency state not treated with the missing hormone. The development of the recombinant human N-terminal 1-34 fragment (rhPTH1 -34) and the full-length 1-84 (rhPTH1 -84) molecule has stimulated several studies on its use as replacement therapy, which led to the approval by the Food and Drug Administration of rhPTH1 -84 (Natpara) for the management of chronic HypoPT.

The official recommendation is to consider rhPTH1 -84 therapy “only in patients who cannot be well-controlled on calcium and active forms of vitamin D and for whom the potential benefits are considered to outweigh the potential risk.” Treatment should be started with subcutaneous administration in the thigh of 50 µg once daily, while reducing by 50% the daily dose of active vitamin D if serum calcium is greater than 7.5 mg/dL (1.875 mmol/L). Serum calcium should be monitored every 3 to 7 days and the daily dose of rhPTH1 -84 titrated every 4 weeks, aiming to reduce the daily calcium supplements to 500 mg and discontinue active vitamin D therapy while maintaining the serum calcium in the low-normal range. Afterward, serum calcium should be monitored every 3 to 6 months. Hypercalcemia has been reported in some cases, but a careful adjustment of the daily dose may decrease this risk. A “black box” in the official recommendation highlights the potential risk of osteosarcoma (studies in rats have shown that both rhPTH1 -34 and rhPTH1 -84 can cause osteosarcoma). However, there is no evidence that individuals treated with either PTH molecules are at increased risk for osteosarcoma. The safety and efficacy of rhPTH1 -84 in pediatric patients have not been established.

The FDA approval for using rhPTH1 -84 in patients with HypoPT not “well controlled” with conventional therapy leaves room for decision making in individual cases. The guidelines recently elaborated by a panel of international experts suggest considering the use of rhPTH1 -84 therapy, where available, in any patient with chronic HypoPT of any etiology, except in patients with autosomal dominant hypocalcemia.

At the time of writing this chapter, the use of rhPTH1 -84 therapy is under evaluation by the European Medicine Agency.

Pregnancy and Lactation

There are limited data to inform treatment strategies in chronic HypoPT in pregnancy and lactation. The guidelines of the European Society of Endocrinology suggest the use of active vitamin D metabolites and oral calcium as in nonpregnant women. Frequent monitoring (every 2–3 weeks) of serum calcium, possibly ionized calcium, is recommended. No studies have addressed the use of rhPTH1 -84  therapy in pregnant women. The FDA suggests that it should be used “only if the potential benefit justifies the potential risk to the fetus.”

References

1.     Arnold A., Levine A. Molecular basis of primary hyperparathyroidism. In: Bilezikan J.P., et al., eds. The Parathyroids, Basic and Clincial Concept. London: Academic Press; 2015:279–296.

2.    Bilezikian J.P., Khan A., Potts Jr. J.T., et al. Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res. 2011;26:2317–2337.

3.     Bilezikian J.P., Brandi M.L., Eastell R., et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab. 2014;99:3561–3569.

4.    Bilezikian J.P., Cusano N.E., Khan A.A., et al. Primary hyperparathyroidism. Nat Rev Dis Primers. 2016;2:1–16.

5.     Bollerslev J., Rejnmark L., Marcocci C., et al. European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173:G1– G20.

6.      Brandi M.L., Bilezikian J.P., Shoback D., et al. Management of hypoparathyroidism: Summary statement and guidelines. J Clin Endocrinol Metab. 2016;101:2273–2283.

7.    Cetani F., Marcocci C. Parathyroid carcinoma. In: Bilezikian J.P., ed. The Parathyroids. Basic and Clincial Concepts. London: Academic Press; 2015:409–422.

8.    Cusano N.E., Silverberg S.J., Bilezikian J.P. Normocalcemic primary hyperparathyroidism. J Clin Densitom. 2013;16:33–39.

9.       Mannstadt M., Clarke B.L., Vokes T., et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): A double-blind, placebo- controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013;1:275–283.

10.       Marcocci C., Bollerslev J., Khan A.A., Shoback D.M. Medical management of primary hyperparathyroidism: Proceedings of the fourth international workshop on the management of asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab. 2014;99:3607–3618.

11.    Marcocci C., Cetani F. Clinical practice. Primary hyperparathyroidism. N Engl J Med. 2011;365:2389–2397.

12.       NATPARA. Shire-NPS Pharmaceuticals, Inc. [package insert]. In: 2015. http://www.fda.gov/Drugs/. Rubin M.R., Bilezikian J.P., McMahon D.J., et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab. 2008;93:3462–3470.

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14.    Shoback D.M., Bilezikian J.P., Costa A.G., et al. Presentation of hypoparathyroidism: Etiologies and clinical features. J Clin Endocrinol Metab. 2016;101:2300–2312.

15.    Udelsman R., Akerstrom G., Biagini C., et al. The surgical management of asymptomatic primary hyperparathyroidism: Proceedings of the fourth international workshop. J Clin Endocrinol Metab. 2014;99:3595–3606.

16.    Vignali E., Viccica G., Diacinti D., et al. Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2009;94:2306– 2312.

1  Not FDA approved for this  indication.

2  Not available in the United  States.

2  Not available in the United  States.

1  Not FDA approved for this  indication.

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