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Hyperparathyroidism Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Classification

Classification of hyperparathyridism
Features	Primary hyperparathyroidism	Secondary hyperparathyroidism	Tertiary hyperparathyroidism
Pathology	Hyperfunction of parathyroid cells due to hyperplasia, adenoma or carcinoma.	Physiological stimulation of parathyroid in response to hypocalcaemia.	Following long term physiological stimulation leading to hyperplasia.
Cause
Associations	May be associated with multiple endocrine neoplasia.	Usually due to chronic renal failure or other causes of Vitamin D deficiency.	Seen in chronic renal failure.
Serum calcium	High	Low/Normal	High
Serum phosphate	Low/Normal	High	High
Management	Usually surgery if symptomatic. Cincacalcet can be considered in those not fit for surgery.	Treatment of underlying cause.	Usually cinacalcet or surgery in those that don't respond.

Causes

Common Causes

• Post-surgical (most common cause)
  • Thyroidectomy
  • Parathyroidectomy
  • Radical neck dissection
• Autoimmune (2nd most common cause)
  • Polyglandular autoimmune syndrome type 1
    • Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or APECED), or acquired hypoparathyroidism associated with autoimmune hypothyroidism
  • Isolated autoimmune hypoparathyroidism

Less Common Causes

• Infiltration and/or destruction of parathyroid glands
  • Metal overload
    • Iron overload
      • Hemochromatosis
      • Thalassemia (due to repeated blood transfusion)
    • Copper overload
      • Wilson's disease
    • Aluminium deposition
      • Usually seen in patients with end-stage renal disease on hemodialysis
    • Hypermagnesemia
  • Radiation-induced destruction parathyroid glands
  • Hypomagnesemia (reversible)
  • Metastatic disease
  • Granulomatous disease
    • Amyloidosis
  • Syphilis
• Progressive systemic sclerosis
• Neonatal cause
  • Maternal hyperparathyroidism
• Genetic causes

Genetic Causes

• Autoimmune hypoparathyroidism
• Isolated hypoparathyroidism
  • Autosomal dominant inheritence
    • Autosomal dominant familial isolated hypoparathyroidism caused by PTH gene mutation
    • Autosomal dominant familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation
      • Dominant negative mutation
    • Autosomal dominant hypocalcemia
      • Autosomal dominant hypocalcemia type 1
        • Calcium-sensing receptor gene activating mutation.
        • Most common genetic form of hypoparathyroidism.
        • Also known as familial hypercalciuric hypocalcemia.
        • The activating mutation results in gain in function.
        • Calcium-sensing receptor gene activating mutation can also cause Bartter syndrome type 5.This mutation cause the inhibition of apical potassium channel in the thick ascending limb of the loop of Henle in the kidney.
      • Autosomal dominant hypocalcemia type 2
        • G protein G11 (GNA11) mutation.
  • Autosomal recessive inheritence
    • Autosomal recessive familial isolated hypoparathyroidism caused by PTH gene mutation
    • Autosomal recessive familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation
  • X-linked inheritence
    • X-linked recessive familial isolated hypoparathyroidism
      • Caused by mutation in gene variant FHL1 (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27.
• Congenital multisystem syndromes
  • DiGeorge syndrome
    • Autosomal dominant inheritance pattern in present.
    • Presents with thymus dysfunction, cardiac defects, immunodeficiency, hypocalcemia, and other clinical problems.
    • Caused by 22q11.2 deletion.
    • Also known as 22q11.2DS, CATCH 22 syndrome, Cayler cardiofacial syndrome, conotruncal anomaly face syndrome (CTAF), deletion 22q11.2 syndrome, Sedlackova syndrome, Shprintzen syndrome, VCFS, velocardiofacial syndrome, and velo-cardio-facial syndrome.
    • CATCH 22 stands for cardiac defects, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia with 22q11.2 deletion.
  • CHARGE syndrome
    • Autosomal dominant inheritance pattern in present.
    • Presents with coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary abnormalities, and ear anomalies and/or deafness.
    • Caused by CHD7 G744S missense mutation.
  • Kenny-Caffey syndrome type 1
    • Autosomal recessive inheritance pattern in present.
    • Deletion of the TBCE gene responsible for encoding a protein that participates in beta-tubulin folding.
    • Presents with hypoparathyroidism due to absent parathyroid tissue, growth retardation, medullary stenosis of tubular bones.
  • Kenny-Caffey syndrome type 2
    • Autosomal dominant inheritance pattern in present.
    • Mutation of “family with sequence similarity 111, member A″ (FAM111A) gene located on chromosome locus 11q12.1.
    • Patients with Kenny-Caffey sundrome type 2 have same clinical features as Kenny-Caffey syndrome type 1 except for mental retardation.
  • Sanjad-Sakati syndrome
    • Sanjad-Sakati syndrome in exclusively found in arabian descent population.
    • Autosomal recessive inheritance pattern in present.
    • Mutation in TBCE gene.
    • Presents with hypoparathyroidism, intellectual disability, dysmorphism.
  • Barakat syndrome
    • Autosomal recessive inheritance pattern in present.
    • Mutations in the GATA3 gene
    • Also known as hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome
    • Presents with primary hypoparathyroidism, nerve deafness, steroid-resistant nephrosis.
• Metabolic diseases
  • Mitochondiral polyneuropathies
    • Kearns–Sayre syndrome
    • Maternally inherited diabetes and deafness (MIDD)
  • Mitochondrial enzyme deficiencies
    • Mitochondrial trifunctional protein deficiency (MTP deficiency)
    • Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)
  • Heavy metal storage disorders
    • Hemochromatosis
    • Wilson's disease

Symptoms

• Clinical symptoms depends on two features:
  • Acuteness of hypocalcemia
  • The absolute level of serum calcium
• Patients presents dramatically and tends to have more symptoms if there is an acute drop in serum calcium compared to patients with chronic hypocalcemia.

Common symptoms

Common symptoms of hypoparathyroidism include:

• Tetany (hallmark of acute hypocalcemia)
• Paresthesia in fingertips, toes, perioral area
• Carpopedal spasms
• Circumoral numbness
• Abdominal pain
• Biliary colic
• Dysphoria
• Fatigue
• Muscle cramps
• Myoclonic jerks
• New onset seizure due to hypocalcemia or worsening of seizures
• Painful menstruation

Less common synptoms

Less common symptoms of hypoparathyroidism include:

• Cognitive impairment
• Decreased concentration
• Hoarseness (due to laryngospasm)
• Neuromuscular irritability
• Palpitations due cardiac dysarrhythmias
• Personality disturbances and/or mood changes
• Symptoms of acute cardiomyopathy
• Wheezing and dyspnea (due to bronchospasm)
• Electrocardiographic changes that mimic myocardial infarction, or congestive heart failure (decreased cardiac contractility is related to low serum calcium and possibly parathyroid hormone deficiency, as there are PTH receptors in cardiac myocytes).

• Cardiac manifestations
  • prolonged QT interval and T-wave alternans, , and congestive heart failure due to decreased cardiac contractility related to low serum calcium and possibly PTH deficiency, as there are PTH receptors in cardiac myocytes.

Differential Diagnosis

Differential diagnosis of hyperparathyroidism on the basis of hypocalcemia
Disorders		Mechanism of hypocalcemia	Laboratory findings
			Serum PTH	Serum Calcium	Serum Phosphate	Other findings
Hypoparathyroidism		There is deficiency of parathyroid hormone in hypoparathyroidism. Deficiency of parathyroid hormone causes body to decrease: Reabsorption of calcium from bone. Excretion of phosphate. Reabsorbtion of calcium from distal tubules. Vitamin D mediated absorption of calcium from intestine.	↓	↓	↑	↓ 1,25 Dihydroxy vitamin D Normal urinary cAMP Normal urinary phosphate
Pseudohypoparathyroidism	Type 1a	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 1b	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Familial- heterozygous deletions in STX16, NESP55, and/or AS exons or loss of methylation at GNAS	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 1c	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 2	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH).	↑	↓	↑	↓ 1,25 Dihydroxy vitamin D Normal urinary cAMP ↓ Urinary phosphate
	Pseudopseudohypoparathyroidism	Genetic defect causing end organ resistance to the action of parathyroid hormone (PTH). Combination of inactivating mutations of GNAS1 and Albright's osteodystrophy	Normal	Normal	Normal	--
Hypomagnesemia		Decreased parathyroid hormone (PTH) secretion Skeletal resistance to PTH	Inappropriately ↓	Normal/↓	--	↓ serum magnesium ↓/Normal serum potassium
Hypoalbuminemia		Majority of calcium in blood is bound to albumin. So when there is a decrease in concentration of albumin due to any condition, there is a relative hypocalcemia as well.	--	↓	--	↓ serum albumin Normal albumin-corrected serum total calcium Normal ionised calcium
Hypovitaminosis D		Decrease in vitamin D meediated calcium absorption from gut.	↑	↓	↓/Low-normal	↓ 25 Hydroxy vitamin D
Chronic kidney disease		Chronic renal failure leads to high serum inorganic phosphate and low serum calcium and deficiency of active form of vitamin D (1,25-dihydroxy vitamin D/calcitriol)	↑	↓/Normal	↑	↓ Glomerular flitration rate