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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

• Isolated hypoparathyroidism
  • Autosomal dominant
    • Autosomal dominant familial isolated hypoparathyroidism caused by PTH gene mutation
    • Autosomal dominant familial isolated hypoparathyroidism caused by caused by glial cells missing 2 (GCM2) gene mutation - Dominant negative effect
    • Autosomal dominant hypocalcemia
      • Autosomal dominant hypocalcemia type 1
        • Calcium-sensing 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
    • 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
    • X-linked recessive 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 disorder
    • Presents with thymus dysfunction, cardiac diseases, immunodeficiency, hypocalcemia, and other clinical problems
    • Caused by 22q11.2 deletion
    • Also known as 22q11.2DS, autosomal dominant Opitz G/BBB syndrome, CATCH 22 Syndromes, 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, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia with 22q deletion
  • CHARGE syndrome
    • Autosomal dominant disorder
    • 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
    • Autosomal recessive inheritence
    • 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)
  • Sanjad-Sakati syndrome
    • Sanjad-Sakati syndrome in exclusively found in arabian descent popultion.
    • Autosomal recessive disorder
    • Mutation in TBCE gene.
    • Presents with hypoparathyroidism, intellectual disability, dysmorphism
  • Barakat syndrome
    • Autosomal recessive inheritance
    • Mutations in the GATA3 gene
    • Also known as hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome
    • Presents with primary hypoparathyroidism, nerve deafness, steroid-resistant nephrosis
  • Kearns-Sayre syndrome
    • Mitochondrial inheritence
    • Presents with mitochondrial myopathy, ophthalmoplegia, retinal degeneration, cardiac conduction defects, primary hypoparathyroidism)
  • Pearson marrow pancreas syndrome
    • Mitochondrial inheritence
    • Presents with lactic acidosis, neutropenia, sideroblastic anemia, pancreatic exocrine dysfunction, and hypoparathyroidism
  • Mitochondrial encephalopathy

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	Key features	Laboratory findings
				Serum PTH	Serum Calcium	Serum Phosphate	Other findings
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			↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 1b			↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 1c			↑	↓	↑	↓ 1,25 Dihydroxy vitamin D ↓ Urinary cAMP ↓ Urinary phosphate
	Type 2			↑	↓	↑	↓ 1,25 Dihydroxy vitamin D Normal urinary cAMP ↓ Urinary phosphate
	Pseudopseudohypoparathyroidism			Normal	Normal	Normal	--
Hypomagnesemia				Inappropriately ↓	Normal/↓	--	↓ serum magnesium ↓/Normal serum potassium
Hypoalbuminemia					Normal albumin-corrected serum total calcium Normal ionised calcium.		↓ serum albumin
Hypovitaminosis D				↑	↓	↓/Low-normal
Chronic kidney disease				↑	↓/Normal	↑