Idiopathic hypoparathyroidism--an overview (2023)

Clinical manifestations

There is a spectrum of parathyroid deficiencies with clinical manifestations ranging from no symptoms to complete and prolonged deficiency. A slight deficiency can only be detected by appropriate laboratory tests. Muscle aches and cramps are early manifestations; They progress to numbness, stiffness, and tingling in the hands and feet. There may be only a positive Chvostek or Trousseau sign, or laryngeal and carpopedal spasms. Seizures, with or without loss of consciousness, may occur days, weeks, or months apart. These episodes may begin with abdominal pain, followed by tonic rigidity, head retraction, and cyanosis. Hypoparathyroidism is often confused with epilepsy. Headaches, vomiting, increased intracranial pressure and papilledema may be accompanied by cramps and indicate a brain tumor.

In patients with longstanding hypocalcemia, teeth erupt late and irregularly. Enamel formation is irregular and teeth can be extraordinarily soft. The skin may be dry and flaky, and the nails may have horizontal lines. Mucocutaneous candidiasis, if present, precedes the development of hypoparathyroidism; Candida infection most commonly affects the nails, oral mucosa, corners of the mouth and less frequently the skin; it is difficult to treat.

Cataracts in patients with long-standing untreated disease are a direct consequence of hypoparathyroidism; other autoimmune eye diseases such as keratoconjunctivitis may also occur. Manifestations of Addison's disease, lymphocytic thyroiditis, pernicious anemia, alopecia areata or totalis, hepatitis, and primary gonadal insufficiency may also be associated with those of hypoparathyroidism.

Delaying initiation of treatment for too long leads to permanent physical and mental deterioration.

laboratory findings

Serum calcium is low (5 to 7 mg/dL) and phosphate is high (7 to 12 mg/dL). Blood levels of ionized calcium (generally about 45% of the total) tend to reflect physiological adequacy but are also low. The serum alkaline phosphatase level is normal or low and the 1,25(OH)₂D₃it is usually low, but elevated levels have been found in some children with severe hypocalcemia. Magnesium levels are normal but should always be checked in patients with hypocalcemia. PTH levels are low when measured by an immunometric assay. Bone radiographs occasionally show increased density confined to the metaphyses, suggestive of heavy metal toxicity, or increased lamina dura density. X-rays or CT scans of the skull can show 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 shows extensive slow activity; the curve normalizes after serum calcium has been within the normal range for a few weeks, unless there is irreversible brain damage or parathyroid insufficiency associated with epilepsy. When hypoparathyroidism occurs concurrently with Addison's disease, serum calcium levels may be normal, but hypocalcemia occurs after effective treatment of adrenal insufficiency.

hypoparathyroidism

Treatment of hypoparathyroidism in patients with APS1 is essentially the same as in patients withidiopathic hypoparathyroidism(See tooChapters 56 and 57Chapter 56Chapter 57). However, APS1 is a much more complex disease, and many potentially interacting medical issues are likely to complicate therapy. As mentioned above, an important factor can be Addison's disease, for which treatment with glucocorticoids can have a significant impact on serum calcium levels. Severe vascular insufficiency due to diffuse vascular calcification was described in 2011 by Wallace et al. reported in APS1,¹⁵⁴who emphasized that fluctuations in serum calcium concentration can lead to vascular calcification. Another factor is evident in the case report of a child who appeared to have defective 25-hydroxylation of vitamin D due to giant cell hepatitis and severe cirrhosis.¹⁵⁵Yesterday 1,25-Diidroxivitamin D₃was considered the best form of vitamin D therapy.¹⁵⁵Steatorrhea can also dictate which type of vitamin D would be best. 2004 Bertelloni and associates¹⁵⁶described their long-term follow-up for hypoparathyroidism due to APS1. In the same year, Jork et al.¹⁵⁷reported the potential of cell therapies to treat hypoparathyroidism. In 2013, Matarazzo et al.¹⁵⁸reported the treatment of children with syndromic hypoparathyroidism, including APS1, with teriparatide (rhPTH).

addison's disease

One of the most important confounders in the management of hypoparathyroidism in APS1 is the likelihood of Addison's disease.¹⁵⁹Prior to the 1950s, adrenal insufficiency was a fatal condition. More than 80% of patients died within 2 years of receiving this diagnosis.⁷³In 1969, with the availability of alternative treatments, a third of patients succumbed.⁵²Today, conventional therapy with glucocorticoids and mineralocorticoids allows for long-term survival.

Addison's disease usually follows hypoparathyroidism in APS1. Addison's disease and its treatment have a significant impact on the manifestations of hypoparathyroidism. When untreated hypoadrenalism is added to APS1, the clinical and biochemical features of hypoparathyroidism can significantly decrease, but quickly return when glucocorticoid replacement therapy is started.³⁶If hypocalcaemia is present, it can be rapidly and severely aggravated by treatment with glucocorticoids. Glucocorticoids can lower blood calcium levels by decreasing calcium absorption from food and increasing calcium excretion by the kidneys by increasing the glomerular filtration rate. Consequently, hypocalcemia and hypoparathyroidism must be ruled out or promptly treated before initiating glucocorticoid therapy for Addison's disease. An example is Case 2, described by Morse and colleagues in 1961.⁶¹Here, a child with hypoparathyroidism and a total serum calcium concentration of 5.5 mg/dl went into spontaneous "remission" with a serum calcium level of 10.3 mg/dl when Addison's disease developed. When glucocorticoid replacement therapy (without additional vitamin D therapy) was started, the serum calcium level dropped abruptly to 4.7 mg/dl. Similar clinical scenarios have been described by Leonard,²⁵Laives and Dutch,¹⁵⁹papadatos and small,³⁶and Quichaud and colleagues.¹⁶⁰On the other hand, 1964, Kenny and Holliday⁵⁰reported 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 due to hypoparathyroidismegg yolkinclude nail brittleness, which may respond to successful treatment of mineral deficiency. However, candidiasis often does not.²³Persistent superficial candidiasis affecting the mucous membranes, skin and nails is one of the most confusing and frustrating problems associated with autoimmune hypoparathyroidism. Candidiasis, once established, can be difficult to eradicate, even when serum calcium levels are maintained within the normal range.

Although the treatment of mucocutaneous candidiasis has been generally disappointing, years ago successes were reported for a significant number of patients who received a "transfer factor" made from lymphocytes from healthy individuals who were immunized againstC. albicansalong with amphotericin B. Kirkpatrick and colleagues¹⁶¹studied 19 patients with chronic mucocutaneous candidiasis in 1979, most of whom had abnormalities in cell-mediated immunity. All had normal circulating T and B lymphocyte counts and normal lymphocyte responses to phytohemagglutinin and concanavalin A. However, most were negativeskin tests forC. albicans. Transfer factor (only local antifungal treatment) administered for several months was ineffective. Amphotericin B alone given intravenously induced remissions in most patients.⁶²Lesions on the face and scalp heal more easily and recur less often. Still, complete and permanent eradication has proven elusive.¹⁰²

Local treatment with hypochlorite has been suggested as candidiasis of the skin and nails improves in patients who frequently swim in chlorinated pools. Infected nails have been plucked out, but recurrence occurs during nail growth unless candidiasis is controlled elsewhere.⁶²

Long-term therapy with oral ketoconazole is now the therapy of choice for mucocutaneous candidiasis.¹⁶²Oral ketoconazole is very effective for disseminated and resistant disease.^163.164Nystatin, given topically and orally (to reduce intestinal colonization), can prevent the spread of fungal lesions but rarely clears the infection.

additional flaws

Patients with features of APS1 require regular evaluation for associated abnormalities.⁴Genetic testing for mutations inAIRE-1can confirm the diagnosis and support this process, and can also guide the screening of apparently healthy siblings. Without genetic testing, siblings should be screened for endocrine defects at least in the first decade of life.¹⁶⁵As ≈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 may include corticosteroid eye drops. Surgical treatment includes keratectomy or corneal transplantation.^74,76wagman and colleagues⁷⁶Recommended medical treatment of corneal disease without surgical intervention. The active phase is supported by topical antibiotic/corticosteroid medications - systemic corticosteroids or immunosuppression were not required.⁷⁶Importantly, these authors noted an apparent transition to a quiescent phase about 10 years after onset. Interestingly, cimetidine has also been reported to have some potency and possibly act as an immunomodulator.¹⁶⁶

Ward and colleagues reported complete resolution of photophobia and significant hair growth with minimal side effects in a girl receiving oral cyclosporine for severe exocrine pancreatic insufficiency associated with APS1 and keratoconjunctivitis.¹⁶⁷

The lack of intrinsic factor production by the gastric mucosa can lead to pernicious anemia in APS1. vitamin B₁₂is given, as with any other form of intrinsic factor deficiency. Steatorrhea is also a complication of autoimmune hypoparathyroidism. Patients with hypocalcemia, steatorrhea, and megaloblastic anemia have occasionally been found to be folate deficient. In severe steatorrhea, with its potential for vitamin D malabsorption, etc., hypoparathyroidism can be particularly difficult to treat. Calcitriol (1,25-dihydroxyvitamin D) is more water soluble than other forms of vitamin D and may therefore be the treatment of choice. It may be necessary to administer calcium intravenously for a period of time.⁶⁸A diet enriched in medium-chain triglycerides has been shown to help, possibly reducing calcium loss due to saponification.⁶⁸A patient with APS1 suffering from recurrent episodes of severe and intractable diarrhea, steatorrhea and hypocalcemia was successfully treated only when immunosuppression was administered with high doses of intravenous methylprednisolone and maintenance oral therapy with methotrexate.¹⁶⁸

Interestingly, a 10-year-old girl with APS1 who developed pure red cell aplasia resistant to conventional therapy showed haematological remission after intramuscular injections of gammaglobulin.²⁰The researchers postulated an idiotype-anti-idiotype interaction in which specific suppression by anti-idiotype antibodies corrected hematologic disease.¹⁶⁹

hypoparathyroidism

Treatment of hypoparathyroidism in patients with APS1 is essentially as described inChapter 52for patients with isolationidiopathic hypoparathyroidism. However, APS1 is a much more complex disorder than idiopathic hypoparathyroidism, and many potentially interacting medical issues are likely to complicate therapy. An important factor mentioned above is Addison's disease. Another example is the case of a child with candidiasis and hypoparathyroidism who appeared to have defective 25-hydroxylation of vitamin D due to concurrent giant cell hepatitis and severe cirrhosis (125). Yesterday 1,25-Diidroxivitamin D₃was considered the best form of vitamin D therapy (125). Steatorrhea can also determine the most effective type of vitamin D. As discussed below, the presence or absence of Addison's disease is a particularly important consideration.

addison's disease

One of the most important confounders to consider when treating APS1 hypoparathyroidism is the likelihood of Addison's disease. Prior to the 1950s, adrenal insufficiency was a fatal condition, and over 80% of patients died within 2 years of diagnosis.65). In 1969, one-third of the patients died (48). Today, conventional replacement therapy with glucocorticoids and mineralocorticoids allows long-term survival.

Addison's disease and its treatment have a significant impact on the manifestations of hypoparathyroidism. When hypoadrenalism is added to APS1, the clinical and biochemical features of hypoparathyroidism can significantly decrease, but quickly return when glucocorticoid replacement therapy is started (30). Glucocorticoids can lower blood calcium levels by decreasing calcium absorption from food and increasing calcium excretion by the kidneys by increasing the glomerular filtration rate. Therefore, hypoparathyroidism must be ruled out before initiating glucocorticoid therapy in Addison's disease. If hypocalcaemia is present, it can be rapidly and severely aggravated by treatment with glucocorticoids. An example is Case 2, described by Morse and colleagues in 1961 (53). This child, with hypoparathyroidism and a serum calcium level of 5.5 mg/dl, went into spontaneous "remission" with a serum calcium level of 10.3 mg/dl when Addison's disease developed. When glucocorticoid replacement therapy was started (without additional vitamin D therapy), the serum calcium level suddenly dropped to 4.7 mg/dl. Similar clinical scenarios have been described by Leonard (18), Leifer and Hollander (126), papadatos and small (30) and Quichaud and colleagues (127). Reverse, 1964, Kenny and Holliday (46) 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 resulting from hypoparathyroidism itself, including brittle nails, respond to successful treatment of the mineral imbalance. However, candidiasis is often not (16). Persistent superficial candidiasis affecting mucous membranes, skin and nails is one of the most confusing and frustrating problems associated with it.autoimmune hypoparathyroidism. Candidiasis, once established, can be difficult to eradicate, even when serum calcium levels are maintained within the normal range.

Although the treatment of mucocutaneous candidiasis has been generally disappointing, success has been reported in a significant number of patients who received both transfer factor and amphotericin B. Transfer factor was prepared from lymphocytes from healthy individuals against whom immunization was carried out. carried outC. albicans.Kirkpatrick e Greenberg (128) studied 19 patients with chronic mucocutaneous candidiasis, most of whom had abnormalities of cell-mediated immunity. All had normal circulating T and B lymphocyte counts and normal lymphocyte responses to phytohemagglutinin and concanavalin A. Despite this, most had negative skin tests forC. albicans.Transfer factor (only local antifungal treatment) administered for several months was ineffective. However, amphotericin B alone, administered intravenously, resulted in remissions in most patients.54). However, the complete and permanent eradication of all clinical signs of the disease has proven to be an elusive goal (88). Lesions on the face and scalp heal more easily and recur less often. Candidiasis frequently recurred and remained the most symptomatic lesion (54).

Local treatment with hypochlorite has been suggested as candidiasis of the skin and nails improves in patients who frequently swim in chlorinated pools. Infected nails have been avulsed, but recurrence occurs during nail growth unless candidiasis is controlled elsewhere.54).

Long-term therapy with oral ketoconazole is now considered the treatment of choice for mucocutaneous candidiasis.129). Ketoconazole, 200 to 400 mg/day orally, is very effective in disseminated and resistant disease.130,131). Nystatin, either topically or orally (to reduce intestinal colonization), can prevent the spread of fungal lesions, but it rarely clears the infection.

additional flaws

The lack of intrinsic factor production by the gastric mucosa can lead to pernicious anemia in patients with APS1. The treatment is vitamin B₁₂, as with any other form of intrinsic factor deficiency. However, steatorrhea is also a complication of autoimmune hypoparathyroidism. Patients with steatorrhea, hypocalcemia, and megaloblastic anemia have occasionally been found to be folate deficient. In severe steatorrhea, with its potential for vitamin D malabsorption, etc., hypoparathyroidism can be particularly difficult to treat. Calcitriol is more water soluble than other forms of vitamin D, so it may be the treatment of choice. It may be necessary to administer calcium intravenously over a period of time (60). A diet enriched in medium-chain triglycerides has been reported to be helpful, possibly reducing calcium loss due to saponification.60). A patient with APS1 suffering from recurrent episodes of severe and intractable diarrhea, steatorrhea, and hypocalcemia was successfully treated only when immunosuppression was administered with high doses of intravenous methylprednisolone and maintenance oral methotrexate (132).

Interestingly, a 10-year-old girl with APS1 who developed pure red cell aplasia resistant to conventional therapy experienced haematological remission after intramuscular injections of gammaglobulin (13). The researchers postulated an idiotype-anti-idiotype interaction in which specific suppression by anti-idiotype antibodies corrected hematologic disease.133).

Patients with features of APS1 require regular evaluation for associated abnormalities (32). Genetic testing for mutations inAIRE-1 gene can confirm the diagnosis of APS1 and support this process and can facilitate the screening of healthy siblings. In the absence of genetic testing, these children should be screened for endocrine defects during at least the first decade of life.134). Since approximately 13% of individuals with APS1 will develop chronic active hepatitis, liver function tests and assays for smooth muscle and mitochondrial antibodies should be included (32).

Medical therapy for keratoconjunctivitis may include corticosteroid eye drops. Surgical treatment includes keratectomy or corneal transplantation (66,68). Wagman and colleagues (68) recommend medical treatment of corneal disease without surgery (68). The active phase is maintained by topical antibiotics/corticosteroids; systemic corticosteroids or immunosuppression were not required (68). Importantly, these authors observed an apparent transition from an active phase to a quiescent phase 10 years after onset. Interestingly, cimetidine has also been reported to have some efficacy, possibly as an immunomodulator.135).

Ward and colleagues reported complete resolution of photophobia and significant hair growth with minimal side effects in a girl receiving oral cyclosporine for exocrine pancreatic insufficiency associated with severe APS1 and keratoconjunctivitis (136).