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Disorders of Parathyroid Gland

Dr. Jeetendra K Singh

Hypoparathyroidism

• The role played by the parathyroid glands in hypocalcemic infants remains to be clarified, although functional immaturity of the parathyroid glands is invoked as one pathogenetic factor.

• Transient idiopathic hypocalcemia (1-8 wk of age), serum levels of parathyroid hormone (PTH) are significantly lower than those in normal infants.

• It is possible that the functional immaturity is a manifestation of a delay in development of the enzymes that convert glandular PTH to secreted PTH; other mechanisms are possible.

Aplasia/Hypoplasia of Parathyroid Glands

• DiGeorge/velocardiofacial syndrome (1/4000)• In 90% of patients, the condition is caused by a

deletion of chromosome 22q11.2.– Approximately 25% of these patients inherit the

chromosomal abnormality from a parent.

• Neonatal hypocalcemia occurs in 60% of affected patients, but it is transitory in the majority; hypocalcemia can recur or can have its onset later in life.

• Associated abnormalities of the 3rd and 4th pharyngeal pouches are common; Conotruncal defects of the heart in 25%,Velopharyngeal insufficiency in 32%, Cleft palate in 9%, Renal anomalies in 35%, and Aplasia of the thymus with severe immunodeficiency

in 1%.

X-linked Recessive Hypoparathyroidism

• Two large North American pedigrees• The onset of afebrile seizures characteristically

occurs in infants from 2 wk to 6 mo of age.

Autosomal Recessive Hypoparathyroidism With Dysmorphic Features

• Middle Eastern children• Profound hypocalcemia occurs early in life• Dysmorphic features include microcephaly,

deep-set eyes, beaked nose, micrognathia, and large floppy ears.

• Intrauterine and postnatal growth retardation are severe, and mental retardation is common.

• Chromosome 1q42-43

HDR Syndrome

• Hypoparathyroidism, • sensorineural Deafness, and • Renal anomaly• The GATA3 gene is located at chromosome

10p14.

Suppression of neonatal parathyroid hormone secretion due to maternal hyperparathyroidism

• Transient neonatal hypocalcemia results from suppression of the fetal parathyroid glands by exposure to elevated levels of calcium in maternal and hence fetal serum.

• Tetany usually develops within 3 wk but may be delayed by 1 mo or more if the infant is breast-fed.

• Hypocalcemia can persist for weeks or months.

Autosomal Dominant Hypoparathyroidism

• Activating (gain-of-function) mutation of the Ca2+ sensing receptor,

• forcing the receptor to an “on” state with subsequent depression of PTH secretion even during hypocalcemia.

• The patients have hypercalciuria. • The hypocalcemia is usually mild and might not

require treatment beyond childhood.

Hypoparathyroidism associatedwith Mitochondrial Disorders

• Should be considered in patients with unexplained symptoms such as ophthalmoplegia, sensorineural hearing loss, cardiac conduction disturbances, and tetany

Surgical Hypoparathyroidism

• Removal or damage of the parathyroid glands can complicate thyroidectomy.

• Symptoms of tetany can occur abruptly postoperatively and may be temporary or permanent.

• In some instances, symptoms develop insidiously and go undetected until months after thyroidectomy.

• Deposition of iron pigment or of copper in the parathyroid glands (thalassemia, Wilson disease) can produce hypoparathyroidism.

Autoimmune Hypoparathyroidism

• Parathyroid antibodies• Autoimmune polyglandular disease type I

autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APCED).

• Autosomal recessive• AIRE gene (autoimmune regulator);

chromosome 21q22• One third of patients with this syndrome have all

3 components; 66% have only 2 of 3 conditions.

• The candidiasis almost always precedes the other disorders (70% of cases occur in children <5 yr of age);

• The hypoparathyroidism (90% after 3 yr of age) usually occurs before Addison disease (90% after 6 yr of age).

• Alopecia areata or totalis, malabsorption disorder, pernicious anemia, gonadal failure, chronic active hepatitis, vitiligo, and insulin dependent diabetes

Idiopathic Hypoparathyroidism

• No causative mechanism can be defined.• Autoimmune condition- after few years of life.

Clinical Manifestations

• No symptoms to those of complete and long-standing deficiency.

• Muscular pain and cramps are early manifestations;

• They progress to numbness, stiffness, and tingling of the hands and feet.

• Convulsions with or without loss of consciousness can occur at intervals of days, weeks, or months.

• 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.• The candidal infection- nails, oral mucosa,

angles of the mouth, and less often, the skin; it is difficult to treat.

• Cataracts• Permanent physical and mental deterioration

occur if initiation of treatment is long delayed.

Laboratory Findings

• S. Ca2+ low (5-7 mg/dL)• Phosphorus level is elevated (7-12 mg/dL).• S. ALP is normal or low, and• 1,25(OH)2D3 is usually low.• Mg• PTH is low• Radiographs or CT scans of the skull can reveal

calcifications in the basal ganglia. • Prolongation of the QT interval on ECG.

• EEG- widespread slow activity

• 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.

Treatment

• Emergency treatment of neonatal tetany consists of iv injections 1-3 mg/kg of a 10% solution of calcium gluconate (elemental calcium 9.3 mg/mL) at the rate of 0.5-1 mL/min and a total dose not toexceed 20 mg of elemental calcium/kg.

• Additionally, calcitriol should be given. The initial dosage is 0.25 μg/24 hr; the maintenance dosage ranges from 0.01-0.10 μg/kg/24 hr to a maximum of 1-2 μg/24 hr.

• Calcitriol is supplied as an oral solution.

• Calcitriol has the advantages of rapid onset of effect (1-4 days) and rapid reversal of hypercalcemia after discontinuation in the event of overdosage (calcium levels begin to fall in 3-4 days).

• An adequate intake of calcium should be ensured. • Calcium gluconate or calcium glubionate- rarely

essential. • Foods with high phosphorus content such as milk,

eggs, and cheese should be reduced in the diet.

• Pigmentation, lowering of blood pressure, or weight loss can indicate adrenal insufficiency, which requires specific treatment.

• Patients with autosomal dominant hypocalcemic hypercalciuria can develop nephrocalcinosis and renal impairment if treated with vitamin D.

Pseudohypoparathyroidism(Albright Hereditary Osteodystrophy)

• The parathyroid glands are normal or hyperplastic.

• Serum levels of immunoreactive PTH are elevated even when the patient is hypocalcemic and may be elevated when the patient is normocalcemic.

• The genetic defects in the hormone receptor adenylate cyclase system are classified into various types depending on the phenotypic and biochemical findings.

TYPE IA

• Genetic defect of the α subunit of the stimulatory guanine nucleotide-binding protein (Gsα).

• Chromosome 20q13.2.• Deficiency of the Gsα subunit is a generalized

cellular defect and accounts for the association of other endocrine disorders.

• Autosomal dominant • The paucity of father-to-son transmissions is

thought to be due to decreased fertility in males.

• Tetany is often the presenting sign. • Short, stocky build and a round face.• Brachydactyly with dimpling of the dorsum of the

hand is usually present.• The 2nd metacarpal is involved least often.• Short and wide phalanges, bowing, exostoses,

and thickening of the calvaria.• Subcutaneous calcium deposits and metaplastic

bone formation.• Moderate mental retardation, calcification of the

basal ganglia, and lenticular cataracts.

• Pseudopseudohypoparathyroidism.

• There is some evidence to suggest that the Gsα mutation is paternally transmitted in pseudopseudohypoparathyroidism and maternally transmitted in patients with type Ia disease.

• Resistance to other G protein–coupled receptors for thyroid-stimulating hormone (TSH), gonadotropins, and glucagon can result in various metabolic effects.

• Clinical hypothyroidism is uncommon.• Moderately decreased levels of thyroxine and

increased levels of TSH in newborns.• In adults, gonadal dysfunction is common.• S. Ca2+ low, and phosphorus & ALP elevated.• Attenuated response in urinary phosphate and

cAMP to human PTH.

TYPE IB

• Normal levels of G protein activity and a normal phenotypic appearance.

• These patients have tissue-specific resistance to PTH but not to other hormones.

• Serum levels of calcium, phosphorus, and immunoreactive PTH are the same as those in patients with type Ia PHP.

• Paternal uniparental isodisomy of chromosome 20q and resulting GNAS1 methylation.

• Loss of the maternal GNAS1 gene, leads to PTH resistance in the proximal renal tubules, which leads to impaired mineral ion homeostasis.

TYPE II

• Differs from type I in that the urinary excretion of cAMP is elevated both in the basal state and after stimulation with PTH but phosphaturia does not increase.

• Phenotypically, patients are normal and hypocalcemia is present.

• The defect appears to be distal to cAMP because it is normally activated, but the cell is unable to respond to the signal.

Hyperparathyroidism

• Primary hyperparathyroidism

• Secondary hyperparathyroidism

Etiology

• Childhood hyperparathyroidism is rare. • Onset during childhood is usually the result of a

single benign adenoma. • It usually becomes manifested after 10 yr of age.• Autosomal dominant• Multiple endocrine neoplasia (MEN)• Hyperparathyroidism–jaw tumor syndrome• Neonatal severe hyperparathyroidism (rare)

Neonatal severe hyperparathyroidism

• Symptoms develop shortly after birth• Anorexia, irritability, lethargy, constipation, and

failure to thrive. • Radiographs reveal subperiosteal bone

resorption, osteoporosis, and pathologic fractures.

• Most cases have occurred in kindreds with the clinical and biochemical features of familial hypocalciuric hypercalcemia.

• Infants with neonatal severe hyperparathyroidism may be homozygous or heterozygous for the mutation in the Ca2+-sensing receptor gene, whereas most persons with 1 copy of this mutation exhibit autosomal dominant familial hypocalciuric hypercalcemia.

MEN

• MEN type I- Autosomal dominant• Hyperplasia or neoplasia of the

– endocrine pancreas (which secretes gastrin, insulin, pancreatic polypeptide, and occasionally glucagon),

– anterior pituitary (which usually secretes prolactin),

– parathyroid glands.

• In most kindreds occurr only rarely in children <18 yr of age.

• With appropriate DNA probes, it is possible to detect carriers of the gene with 99% accuracy at birth, avoiding unnecessary biochemical screening programs.

Hyperparathyroidism–jaw tumor syndrome

• Autosomal dominant• Parathyroid adenomas and fibro-osseous jaw

tumors.• Affected patients can also have polycystic

kidney disease, renal hamartomas, and Wilms tumor.

• Although the condition affects adults primarily, it has been diagnosed as early as age 10 yr.

Transient neonatal hyperparathyroidism

• Occurs in few infants born to mothers with hypoparathyroidism (idiopathic or surgical) or with pseudohypoparathyroidism.

Clinical Manifestations

• Muscle weakness, fatigue, headache, anorexia, abdominal pain, nausea, vomiting, constipation, polydipsia, polyuria, weight loss, and fever.

• Nephrocalcinosis• Renal calculi- renal colic and hematuria.• Osseous changes can produce pain in the back

or extremities, disturbances of gait, genu valgum, fractures, and tumors.

• Height can decrease from compression of vertebrae; the patient can become bedridden.

• Abdominal pain is occasionally prominent and may be associated with acute pancreatitis.

• Parathyroid crisis can occur, manifested by serum calcium levels >15 mg/dL and progressive oliguria, azotemia, stupor, and coma.

• In infants, failure to thrive, poor feeding, and hypotonia are common.

• Mental retardation, convulsions, and blindness can occur as sequelae of long-standing hypercalcemia.

• Psychiatric manifestations include depression, confusion, dementia, stupor, and psychosis.

Laboratory Findings

• S. Ca2+ elevated• The hypercalcemia is more severe in infants with

parathyroid hyperplasia; concentrations ranging from 15 to 20 mg/dL are common, and values as high as 30 mg/dL have been reported.

• Even when the total serum calcium level is borderline or only slightly elevated, ionized calcium levels are often increased.

• Serum phosphorus- low• Serum magnesium- low

• Urine- low and fixed specific gravity• Serum levels of nonprotein nitrogen and uric

acid may be elevated. • In patients with adenomas who have skeletal

involvement, serum phosphatase levels are elevated, but in infants with hyperplasia the levels of alkaline phosphatase may be normal even when there is extensive involvement of bone.

• PTH are elevated• Calcitonin levels are normal- Acute

hypercalcemia can stimulate calcitonin release, but with prolonged hypercalcemia, hypercalcitoninemia does not occur.

• The most consistent and characteristic radiographic finding is resorption of subperiosteal bone, best seen along the margins of the phalanges of the hands.

• Skull- gross trabeculation or a granular appearance resulting from focal rarefaction;

• Lamina dura may be absent. • In more advanced disease, there may be

generalized rarefaction, cysts, tumors, fractures, and deformities.

Treatment

• Surgical exploration is indicated in all instances.• Most neonates with severe hypercalcemia

require total parathyroidectomy.• A portion of a parathyroid gland may be

autografted into the forearm.• The patient should be carefully observed

postoperatively for the development of hypocalcemia and tetany; intravenous administration of calcium gluconate may be required for a few days.

• The prognosis is good if the disease is recognized early.

• When extensive osseous lesions are present, deformities may be permanent.