Robert M. Kliegman MD, in Nelson Textbook of Pediatrics, 2020 The termidiopathic hypoparathyroidism should be reserved for the small residuum of children with
hypoparathyroidism for whom no causative mechanism can be defined. Most children in whom onset of hypoparathyroidism occurs after the 1st few years of life have anautoimmune condition. Autoantibodies to the extracellular domain of the calcium-sensing receptor have been identified in some patients with acquired hypoparathyroidism. One should always consider incomplete forms of DiGeorge syndrome or an activating calcium-sensing receptor mutation in the differential diagnosis. There is a spectrum of parathyroid deficiencies with clinical manifestations varying from no symptoms to those of complete and long-standing deficiency. Mild deficiency may be revealed only by appropriate laboratory studies. Muscular pain and cramps are early manifestations; they progress to numbness, stiffness, and tingling of the hands and feet. There may be only a positive
Chvostek or Trousseau sign or laryngeal and carpopedal spasms. Convulsions with or without loss of consciousness can occur at intervals of days, weeks, or months. These episodes can begin with abdominal pain, followed by tonic rigidity, retraction of the head, and cyanosis. Hypoparathyroidism is often mistaken for epilepsy. Headache, vomiting, increased intracranial pressure, and papilledema may be associated with convulsions and might suggest a brain tumor. In patients with long-standing hypocalcemia, the teeth erupt late and irregularly. Enamel formation is irregular, and the teeth may be unusually soft. The skin may be dry and scaly, and the nails might have horizontal lines. Mucocutaneous candidiasis, when present, antedates the development of hypoparathyroidism; the candidal infection most often involves the nails, the oral mucosa, the angles of the mouth, and less often, the skin; it is difficult to treat. Cataracts in patients with long-standing untreated disease are a direct consequence of hypoparathyroidism; other autoimmune ocular disorders such as keratoconjunctivitis can also occur. Manifestations of Addison disease, lymphocytic thyroiditis, pernicious anemia, alopecia areata or totalis, hepatitis, and primary gonadal insufficiency may also be associated with those of hypoparathyroidism. Permanent physical and
mental deterioration occurs if initiation of treatment is long delayed. The serum calcium level is low (5-7 mg/dL), and the phosphorus level is elevated (7-12 mg/dL). Blood levels of ionized calcium (usually approximately 45% of the total) more nearly reflect physiologic adequacy but also are low. The serum level of alkaline phosphatase is normal or low, and the level of
1,25(OH)2D3 is usually low, but high levels have been found in some children with severe hypocalcemia. The level of magnesium is normal but should always be checked in hypocalcemic patients. Levels of PTH are low when measured by immunometric assay. Radiographs of the bones occasionally reveal an increased density limited to the metaphyses, suggesting heavy metal poisoning, or an increased density of the lamina dura. Radiographs or CT scans of the skull can reveal
calcifications in the basal ganglia. There is a prolongation of the QT interval on the electrocardiogram, which disappears when the hypocalcemia is corrected. The electroencephalogram usually reveals widespread slow activity; the tracing returns to normal after the serum calcium concentration has been within the normal range for a few weeks, unless irreversible brain damage has occurred or unless the parathyroid insufficiency is associated with epilepsy. When hypoparathyroidism occurs
concurrently with Addison disease, the serum level of calcium may be normal, but hypocalcemia appears after effective treatment of the adrenal insufficiency.Hypoparathyroidism
Idiopathic Hypoparathyroidism
Clinical Manifestations
Laboratory Findings
Autoimmune Hypoparathyroidism
Michael P. Whyte, in The Parathyroids (Third Edition), 2015
Treatment
Disease targeted therapy is currently not available, and treatment relies principally on hormone replacement and managing clinical symptoms.96 Immunosuppressive therapy has been used only for potentially fatal complications such as hepatitis, nephritis, or severe malabsorption. In 2013, O’Gorman and colleagues149 reported the dramatic response of a young girl with APS1 to immunosuppression with mycophenolate mofetil. Immunomodulatory treatment of Aire knock-out mice, targeting both T and B cells,150,151 lends hope for strategies that could be useful for patients. More recently, a monoclonal antibody against B cells, Rituximab, has been successfully used to treat pulmonary disease in APS1 patients.152
Clinicians must understand that children with hypoparathyroidism or Addison’s disease may develop full-blown APS1. Here, the Addison’s disease can “conceal” coexisting hypoparathyroidism105 by its effects on circulating calcium levels, and therefore glucocorticoid therapy without attention to the hypoparathyroidism can be fatal.25–27,36,91,153 Serum calcium concentrations can rise in adrenocortical insufficiency, but may suddenly decrease after corticosteroid therapy is begun, because of diminished gastrointestinal absorption and increased renal excretion of calcium.27 Similarly, estrogen replacement therapy for ovarian failure can slow bone resorption and diminish serum calcium concentrations.69 Patients with hypoparathyroidism and additional disorders are, therefore, especially likely to show fluctuations of serum calcium concentrations, and require particularly careful regulation of doses of vitamin D sterols, etc.36 This is discussed further below.
Hypoparathyroidism
Management of hypoparathyroidism in patients with APS1 is essentially the same as for patients with isolated idiopathic hypoparathyroidism (see also Chapters 56 and 57Chapter 56Chapter 57). However, APS1 is a far more complex disorder and many potentially interacting medical problems will likely complicate the therapy. As stated above, a major factor can be Addison’s disease for which glucocorticoid treatment may importantly affect serum calcium levels. Severe vascular insufficiency due to diffuse vascular calcification was reported in APS1 in 2011 by Wallace et al.,154 who highlighted that fluctuations in serum calcium concentrations may lead to vascular calcification. Another factor is revealed in the case report of a child who seemed to have defective 25-hydroxylation of vitamin D due to giant cell hepatitis and severe cirrhosis.155 Here, 1,25-dihydroxyvitamin D3 was considered the best form of vitamin D therapy.155 Steatorrhea could also determine which type of vitamin D would be best. In 2004, Bertelloni and co-workers156 described their long-term follow-up of hypoparathyroidism due to APS1. That same year, Jork et al.157 reported on the potential for cell therapies to treat hypoparathyroidism. In 2013, Matarazzo et al.158 reported on teriparatide (rhPTH) treatment for children with syndromic hypoparathyroidism, including APS1.
Addison’s Disease
Among the major confounding factors when treating hypoparathyroidism in APS1 is the likelihood of Addison’s disease.159 Prior to the 1950s, adrenocortical insufficiency was a fatal disorder. More than 80% of patients were dead 2 years after receiving this diagnosis.73 By 1969, with the availability of replacement treatment, one-third of patients succumbed.52 Now, conventional therapy using glucocorticoids and mineralocorticoids enables long-term survival.
Addison’s disease typically follows the hypoparathyroidism in APS1. Addison’s disease and its treatment both impact significantly on the manifestations of hypoparathyroidism. When untreated hypoadrenalism supervenes in APS1, the clinical and biochemical features of hypoparathyroidism can diminish considerably, but will rapidly return when glucocorticoid replacement therapy is begun.36 If hypocalcemia is present, it may be rapidly and severely exacerbated by glucocorticoid treatment. Glucocorticoids can lower blood calcium levels by decreasing dietary absorption of calcium, and by enhancing renal excretion of calcium because the glomerular filtration rate is increased. Accordingly, hypocalcemia and hypoparathyroidism must be excluded or promptly dealt with before glucocorticoid therapy is started for Addison’s disease. An example is case 2 described in 1961 by Morse and colleagues.61 Here, a child with hypoparathyroidism and a serum total calcium concentration of 5.5 mg/dl experienced a spontaneous “remission,” with a serum calcium level of 10.3 mg/dl, as Addison’s disease developed. When glucocorticoid replacement treatment (without additional vitamin D therapy) was initiated, the serum calcium level abruptly fell to 4.7 mg/dl. Similar clinical scenarios have been described by Leonard,25 Leifer and Hollander,159 Papadatos and Klein,36 and Quichaud and colleagues.160 Conversely, in 1964, Kenny and Holliday50 reported that the onset of Addison’s disease in a patient with well-controlled hypoparathyroidism was followed by marked hypercalcemia of 14.5 mg/dl.
Candidiasis
Ectodermal changes from hypoparathyroidism per se include brittleness of the nails that can respond to successful treatment of the mineral disturbance. However, the candidiasis often will not.23 Intractable superficial candidiasis involving mucous membranes, skin, and nails is one of the most perplexing and frustrating problems associated with autoimmune hypoparathyroidism. Candidiasis, once established, may be difficult to eradicate, even when serum calcium concentrations are maintained in the normal range.
Although treatment for mucocutaneous candidiasis had been disappointing generally, success was reported years ago for a significant number of patients who received “transfer factor” prepared from lymphocytes of healthy individuals immunized against C. albicans in addition to amphotericin B. However, Kirkpatrick and colleagues161 in 1979 studied 19 patients with chronic mucocutaneous candidiasis, the majority of whom had abnormalities in cell-mediated immunity. All had normal numbers of circulating T- and B-lymphocytes and normal lymphocyte responses to phytohemagglutinin and concanavalin A. Nevertheless, most had negative skin tests for C. albicans. Transfer factor administered for several months (with only local treatment with antifungal agents) was ineffective. Amphotericin B alone given intravenously induced remissions in most of the patients.62 Face and scalp lesions cleared most readily and relapsed least frequently. Nevertheless, complete and lasting eradication proved elusive.102
Local hypochlorite treatment has been suggested, because candidiasis of skin and nails improves in patients who swim frequently in chlorinated pools. Infected nails have been avulsed, but recurrence during nail regrowth ensues unless the candidiasis is controlled elsewhere.62
Long-term therapy with oral ketoconazole is now considered the treatment of choice for mucocutaneous candidiasis.162 Ketoconazole orally is very effective for extensive and resistant disease.163,164 Nystatin applied topically, as well as administered orally (to reduce intestinal colonization), may prevent the spread of the fungal lesions, but will rarely eradicate the infection.
Additional Disorders
Patients with features of APS1 must be screened regularly for the associated abnormalities.4 Genetic testing for mutations in AIRE-1 may confirm the diagnosis and support this process, and can also direct screening of apparently healthy siblings. In the absence of genetic testing, siblings should be examined for endocrine defects during at least the first decade of life.165 Because ≈13% of individuals with APS1 will develop chronic active hepatitis, liver function tests and assays for smooth muscle and mitochondrial antibodies should be included.4
Medical therapy for keratoconjunctivitis can include corticosteroid eye drops. Surgical treatment involves keratectomy or corneal transplantation.74,76 Wagman and colleagues76 recommended medical management of the corneal disease without surgical intervention. The active phase is helped by topical antibiotic/corticosteroid medication—systemic corticosteroids or immunosuppression were not required.76 Of importance, these authors noted an apparent transition to a quiescent phase approximately 10 years after the onset. Interestingly, cimetidine has also been reported to have some efficacy, perhaps acting as an immunomodulator.166
Ward and colleagues reported complete resolution of photophobia and considerable hair regrowth, with minimal side effects, in a girl who received oral cyclosporine for severe APS1-associated exocrine pancreatic failure and keratoconjunctivitis.167
Absence of intrinsic factor production by gastric mucosa can lead to pernicious anemia in APS1. Vitamin B12 is given, as for any other form of intrinsic factor deficiency. Steatorrhea is also a complication of autoimmune hypoparathyroidism. Patients with hypocalcemia, steatorrhea, and megaloblastic anemia have, on occasion, mistakenly been thought to have folate deficiency. When steatorrhea is severe, with its potential for vitamin D malabsorption, etc., hypoparathyroidism can be especially difficult to treat. Calcitriol (1,25-dihydroxyvitamin D) is more water soluble than other forms of vitamin D, and thus may be the treatment of choice. It may be necessary to give calcium intravenously for a period of time.68 A diet enriched with medium-chain triglycerides has been helpful, perhaps by decreasing calcium loss due to saponification.68 One patient with APS1 who suffered recurrent episodes of severe intractable diarrhea, steatorrhea, and hypocalcemia was successfully treated only when given immunosuppression using intravenous high-dose methylprednisolone and oral methotrexate maintenance therapy.168
Of interest, a 10-year-old girl with APS1 who developed pure red cell aplasia resistant to conventional therapy showed hematologic remission after intramuscular injections of gamma globulin.20 The investigators postulated an idiotype–antiidiotype interaction in which specific suppression by antiidiotype antibodies corrected the hematologic disease.169
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Thyroid and Parathyroid Diseases in Pregnancy
Mark B. Landon MD, in Gabbe's Obstetrics: Normal and Problem Pregnancies, 2021
Hypoparathyroidism
The most common etiology of hypoparathyroidism is damage to or removal of the parathyroid glands in the course of surgery for thyroid gland pathology. The incidence of permanent hypoparathyroidism after thyroid surgery has been estimated to be between 0.2% and 3.5%. In many cases, hypocalcemia in the immediate postoperative period is only transitory. Idiopathic hypoparathyroidism is much less common and is frequently associated with other autoimmune endocrinopathies as part of the polyglandular autoimmune syndrome type 1.
The requirement for calcium supplementation and vitamin D may decrease in some women with hypoparathyroidism during the second half of pregnancy and lactation. In a few cases, hypocalcemic symptoms ameliorate with progression of pregnancy. The explanation for these findings is not clear but may be related to the increased intestinal absorption of calcium and/or the production of vitamin D by the placenta.
Clinical clues for the diagnosis of hypoparathyroidism include a previous history of thyroid or parathyroid surgery and clinical, radiologic, and laboratory information.Typical symptoms of hypocalcemia are numbness and tingling of the fingers and toes and around the lips. Patients may complain of carpopedal spasm, laryngeal stridor, and dyspnea. Seizures may be a manifestation of severe hypocalcemia. On physical examination, patients with idiopathic hypoparathyroidism demonstrate changes in the teeth, skin, nails, and hair as well as papilledema and cataracts. Chvostek sign, a twitch of the facial muscles—notably those of the upper lip—when a sharp tap is given over the facial nerve, is seen in many patients with hypocalcemia. Chvostek sign has also been described in 10% of normal adults. Trousseau sign is another manifestation of hypocalcemia. It is the induction of spasm of the hand and forearm by reducing the circulation in the arm with a blood pressure cuff. The constriction should be maintained above the systolic blood pressure for 2 minutes before the test is considered negative.
The diagnosis of hypoparathyroidism is confirmed by the presence of persistent low serum calcium and high serum phosphate levels. Serum PTH is low in primary hypoparathyroidism. The differential diagnosis of hypocalcemia includes rickets and osteomalacia.
Radiologic bone changes characterized by generalized skeletal demineralization may be present in the newborn as a consequence of transient intrauterine hyperparathyroidism, as well as subperiosteal bone resorption, bowing of the long bones, osteitis fibrosa cystica, and rib and limb deformities.15
Treatment of hypoparathyroidism in pregnancy does not differ from that in the nonpregnant state, including a high-calcium diet and vitamin D supplementation.14 Normal calcium supplementation during pregnancy is approximately 1.2 g/day. Calcitriol, 1 to 3 µg/day, is used almost routinely in most patients affected with hypoparathyroidism. Calcitriol must be given in divided doses because its half-life is much shorter than that of vitamin D. If vitamin D is used, the dose is in the range of 50,000 to 150,000 IU/wk. Vitamin D requirements may decrease in some patients by the second half of gestation. The importance of compliance with medications should be strongly emphasized, particularly when calcitriol is prescribed, in view of its short half-life. The major problem in the treatment of hypoparathyroidism is the recurrence of both hypercalcemia and hypocalcemia; therefore serum calcium determinations should be performed at regular intervals. Care should be taken to continue monitoring maternal levels during the postpartum period and during lactation.16
Autoimmune polyglandular syndromes
Michael J. Haller MD, ... Desmond A. Schatz MD, in Pediatric Endocrinology (Fourth Edition), 2014
Autoantibodies in hypoparathyroidism
Autoimmune hypoparathyroidism is a characteristic disorder essentially unique to APS I. Hypoparathyroidism is absent in subjects with APS II. In the original report of parathyroid autoantibodies detected using indirect immunofluorescence, nearly 40% of patients with autoimmune hypoparathyroidism were found to have parathyroid cytoplasmic autoantibodies versus 6% of controls.169,170 However, other laboratories did not confirm the initial reports of the existence of such parathyroid cytoplasmic autoantibodies.171,172 It was shown that autoantibodies detected by indirect immunofluorescence directed against the parathyroid gland could be preabsorbed with human mitochondria, indicating that such autoantibodies were not tissue specific.172
Several different antiparathyroid autoantibodies have been reported in patients with hypoparathyroidism. These include autoantibodies that may bind to cultured bovine endothelial cells.173,174 Unrelated to APS I or APS II, autoantibodies that bind to anti-PTH antibodies (employed in a PTH immunoassay—i.e., anti-idiotypic PTH autoantibodies) have been described.175 Autoantibodies to the extracellular domain of the calcium receptor have also been described.116,176 In contrast, autoantibodies that block the calcium receptor have been described that cause hyperparathyroidism (e.g., “autoimmune hypercalcemia”).177 More recently, screening of human parathyroid complementary DNA libraries with sera from patients with known APS I and hypoparathyroidism identified NACHT leucine-rich repeat protein 5 (NALP5) as an important parathyroid autoantigen. Autoantibodies were detected in 49% of patients with APS I and hypoparathyroidism but were absent in all 293 controls.115 Notably, NALP5 autoantibodies appear to be specific for hypoparathyroidism related to APS I, as they are rarely (0.69%) seen is patients with idiopathic hypoparathyroidism.178
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Endocrine Diseases
William D. James MD, in Andrews' Diseases of the Skin, 2020
Hypoparathyroidism
Varied changes in the skin and its appendages may be evident in parathyroid hormone (PTH, parathormone) deficiency. Most pronounced is faulty dentition when hypoparathyroidism is present during development of the permanent teeth. The skin is dry and scaly. A diffuse scantiness of the hair and complete absence of axillary and pubic hair may be found. The nails are brittle and malformed. Onycholysis with fungal infection may be present. Of patients with idiopathic hypoparathyroidism, 15% develop mucocutaneous candidiasis. Hypoparathyroidism is the most frequent endocrine abnormality present in patients with the APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy) syndrome. In this syndrome caused by mutations in the autoimmune regulator (AIRE) gene, hypoparathyroidism is present in association with Addison disease and chronic candidiasis. Hypoparathyroidism may also occur in DiGeorge syndrome, or with parathyroid infiltration or their inadvertent surgical removal during thyroid surgery. The causative genetic defects and specific autoantibodies responsible for PTH deficiency and pseudohypoparathyroidism are well defined. Hypoparathyroidism with resultant hypocalcemia may trigger bouts of impetigo herpetiformis or pustular psoriasis.
Pseudohypoparathyroidism (PH) is an autosomal dominant or X-linked inherited disorder characterized by end-organ unresponsiveness to PTH. The PTH and phosphorus levels are high, whereas the serum calcium is low. The typical clinical findings include short stature; obesity; round face; prominent forehead; low nasal bridge; attached earlobes; short neck; short, wide nails; delayed dentition; mental deficiency; amenorrhea; blue sclerae; and cataracts. Brachycephaly, microcephaly, and shortened metacarpals or metatarsals, especially of the fourth and fifth digits (Fig. 24.7), occur because of premature epiphyseal closure. This results in short, stubby fingers and toes, with dimpling over the metacarpophalangeal joints (Albright sign). Subcutaneous calcification and ossification occur frequently in PH, as they may in pseudopseudohypoparathyroidism (PPH), which has the same phenotype, but patients have normal serum and calcium levels. Mutations or epigenetic changes in the complex GNAS locus in the mother result in PH, whereas if present in the father PPH results. PH and PPH are two types of Albright hereditary osteodystrophy.
Abate EG, Clarke BL: Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7: 172.
De Martino L, et al: Novel findings into AIRE genetics and functioning. Front Pediatr 2016; 4: 86.
Tafaj O, Jüppner H: Pseudohypoparathyroidism. J Endocrinol Invest 2017; 40: 347.
Autoimmune Polyglandular Syndromes
MICHAEL J. HALLER MD, ... DESMOND A. SCHATZ MD, in Pediatric Endocrinology (Third Edition), 2008
AUTOANTIBODIES IN HYPOPARATHYROIDISM
Autoimmune hypoparathyroidism is a characteristic disorder essentially unique to APS I. Hypoparathyroidism is absent in subjects with APS II. In Blizzard's original report of parathyroid autoantibodies detected using indirect immunofluorescence, nearly 40% of patients with autoimmune hypoparathyroidism were found to have parathyroid cytoplasmic autoantibodies—versus 6% of controls.136,137 However, other laboratories did not confirm the initial reports of such parathyroid cytoplasmic autoantibodies.138,139 It was shown that autoantibodies detected by indirect immunofluoresence directed against the parathyroid gland could be preabsorbed with human mitochondria, indicating that such autoantibodies were not tissue specific.139
Autoantibodies have also been identified that are cytotoxic for cultured bovine parathyroid cells in patients with hypoparathyroidism.140 These autoantibodies also bind to cultured bovine endothelial cells.141 Unrelated to APS I or APS II, autoantibodies that bind to anti-PTH antibodies employed in a PTH immunoassay (e.g., anti-idiotypic PTH autoantibodies) have also been described in a patient with hypoparathyroidism.142 More recently, autoantibodies to the extracellular domain of the calcium receptor have been described in patients with hypoparathyroidism.143 Similarly, autoantibodies that block the calcium receptor have been described that cause hyperparathyroidism (e.g., autoimmune hypercalcemia).144
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Epidemiology of Hypoparathyroidism
Monica Therese B. Cating-Cabral, Bart L. Clarke, in The Parathyroids (Third Edition), 2015
Autoimmune Hypoparathyroidism
Autoimmune hypoparathyroidism is thought to be the second most common cause of hypoparathyroidism in adults. Autoimmune isolated hypoparathyroidism may occur sporadically, in which case there may be a low remission rate of 3.8%.16 Autoimmune hypoparathyroidism may also occur in combination with other autoimmune endocrine disorders as part of an autoimmune polyglandular syndrome type 1 (APS-1), otherwise known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).17 This disorder causes hypoparathyroidism, Addison’s disease, and candidiasis, and at least two of the following: insulin-dependent diabetes mellitus, primary hypogonadism, autoimmune thyroid disease, pernicious anemia, chronic active hepatitis, steatorrhea, alopecia, or vitiligo. More than 80% of APS-1 patients have hypoparathyroidism, sometimes as the only manifestation of the disorder. APS-1 is usually an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene, although autosomal dominant versions have been reported. The AIRE gene product is a zinc-finger transcription factor found in thymus and lymph nodes, and is critical for mediating central tolerance by the thymus.18 In contrast to other immune conditions, this disorder is monogenic, not associated with the major histocompatibility complex, and there does not appear to be a genotype–phenotype correlation.19
Most patients with APS-1 are diagnosed in childhood or adolescence, but these patients need to be followed long term for the gradual appearance of other conditions associated with the syndrome. The worldwide incidence of APS-1 is estimated to be 1 per 1,000,000 person-years, but the incidence is more common in three genetically distinct populations: 1:25,000 in Finns, 1:14,500 in Sardinians, and 1:9000 in Iranian Jews.20
NACHT leucine-rich repeat protein 5 (NALP5) is an intracellular signaling molecule expressed in the parathyroid gland that may be a parathyroid-specific autoantigen present in APS-1 patients with hypoparathyroidism. Patients without APS-1 do not have antibodies to NALP5.21 The extracellular domain of the CaSR may also be an autoantigen in patients with autoimmune hypoparathyroidism. Activating antibodies to this region of the receptor have been reported in both APS-1 and acquired hypoparathyroidism.22–24 These findings suggest that, even though the majority of patients with APS-1 do not have CaSR antibodies, there may be a subset of patients who have hypoparathyroidism due to functional suppression of parathyroid gland activity, rather than irreversible destruction of the parathyroid glands.25,26
The calcium-sensing receptor (CaSR) is a G-protein coupled receptor (GPCR) of the same family (family 3 or C) as those sensing glutamate, gamma-aminobutyric acid (GABA), odorants, sweet taste, and pheromones.27 This family of receptors has large amino-terminal extracellular domains, comprising 612 amino acids in the human CaSR, and the seven membrane-spanning helices characteristic of the superfamily of GPCRs. The CaSR is heavily glycosylated and resides on the cell surface as a disulfide-linked dimer. The extracellular domain contains important determinants for binding calcium, the receptor’s principal biologically relevant ligand, although there are additional calcium-binding sites within the seven membrane-spanning domain, since a “headless” receptor entirely lacking the extracellular domain still responds to calcium. The CaSR’s best-established roles in calcium homeostasis are to inhibit parathyroid cellular proliferation, PTH secretion, and PTH gene expression, to stimulate calcitonin secretion, and to directly inhibit renal tubular calcium reabsorption.28 Less well-documented actions are promoting proliferation, chemotaxis, differentiation of osteoblasts and their mineralization of bone, as well as inhibiting osteoclastic differentiation and activity.29
An early study reported the presence of anti-parathy舉roid gland antibodies in 38% of 75 patients with idiopathic hypoparathyroidism, 26% of 92 patients with idiopathic Addison’s disease, 12% of 49 patients with Hashimoto thyroiditis, and 6% of 245 normal control patients.30 Subsequent studies showed that some anti-parathyroid gland antibodies are specific for mitochondrial or endomysial antigens. Li et al. reported that sera from 20% of 25 patients with autoimmune hypoparathyroidism, idiopathic hypoparathyroidism, or autoimmune polyglandular syndrome type 1 contained antibodies directed against the CaSR.31 Patients with autoimmune hypoparathyroidism for less than 5 years were more likely to have anti-CaSR antibodies, whereas no anti-CaSR antibodies were found in 22 healthy control patients or 50 patients with autoimmune disorders without hypoparathyroidism. It is not yet clear whether anti-CaSR antibodies play a causal role in the disease or serve as markers of tissue injury.32 Another report of two patients with activating anti-CaSR antibodies indicated that these antibodies inhibited PTH release by dispersed parathyroid adenoma cells, suggesting that their hypoparathyroidism resulted from an inhibitory effect of the antibodies on the CaSR and not irreversible parathyroid gland damage.33
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Medical Emergencies
Steven W. Salyer PA‐C, ... Chris R. McNeil, in Essential Emergency Medicine, 2007
Hypoparathyroidism
The most common cause of idiopathic hypoparathyroidism is polyglandular autoimmune syndrome type I, a familial disorder that manifests in childhood and is associated with mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.
The most common cause of acquired hypoparathyroidism is surgical, usually iatrogenic parathyroidectomy during thyroidectomy. Hungry bone syndrome can be seen after parathyroidectomy, with hypocalcemia and hypophosphatemia resulting from rapid remineralization of the skeleton after the parathyroid adenoma has been removed. These patients typically require very large amounts of Ca+, phosphate, Mg+, and vitamin D postoperatively and will usually require supplemental Ca and vitamin D supplementation for life.
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Hypocalcemia and Primary Hypoparathyroidism
Edward C. Feldman, in Canine and Feline Endocrinology (Fourth Edition), 2015
Parathyroid Histology in Hypoparathyroidism
Animals have been classified as having idiopathic hypoparathyroidism when there is no evidence of trauma, cervical malignancy, surgical destruction, or other obvious damage to the neck or parathyroid glands. The glands from these dogs have been difficult to locate visually or via ultrasound and are microscopically atrophied. Approximately 60% to 80% of the glands are replaced by mature lymphocytes, occasional plasma cells, extensive degeneration of chief cells, and/or fibrous connective tissue. Chief cells are randomly isolated in multiple small areas or bands at the periphery. In the early stages of an immune-mediated attack, the gland is infiltrated with lymphocytes and plasma cells with nodular regenerative hyperplasia of remaining chief cells. Later, the parathyroid gland is completely replaced by lymphocytes, fibroblasts, and neocapillaries with only an occasional viable chief cell. The final interpretation is one of lymphocytic parathyroiditis (Sherding et al, 1980; Capen and Marten, 1983).
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Pseudohypoparathyroid States
Roderick John Clifton-Bligh, Aidan McElduff, in Encyclopedia of Endocrine Diseases, 2004
PTH Deficiency
A deficiency of PTH as seen in surgical or autoimmune hypoparathyroidism or in patients with congenital absence of parathyroid glands leads to hypocalcemia and hyperphosphatemia. Mild hypocalcemia may be asymptomatic, particularly if it develops slowly. Alternatively, acute development of hypocalcemia may precipitate carpopedal spasm, laryngeal spasm, and/or seizures and may be accompanied by two cardinal physical signs: facial nerve irritability elicited by tapping over the facial nerve (Chvostek's sign) and carpal spasm that can precipitated by increasing the pressure of a tourniquet to above systolic pressure (Trousseau's sign). Chronic hypocalcemia may paradoxically be accompanied by calcification of soft tissues and/or the basal ganglia and frontal lobes.
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