Hypoparathyroidism

Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Deficiency of PTH results in hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, which leads to increased neuromuscular excitability and osteosclerosis, as well as cardiac and neuropsychiatric manifestations. Treatment is based on calcium and vitamin D supplementation.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Hypoparathyroidism is a condition associated with insufficient secretion of parathyroid hormone (PTH). Hypocalcemia and hyperphosphatemia are the pathognomonic biochemical features of hypoparathyroidism, and result directly from a lack of PTH action on the kidney.

Epidemiology

  • Prevalence in the US is 37 per 100,000 person years
  • 74% of patients are 45 years or older.
  • More common in women (75%)

Etiology

  • Iatrogenic (most common):
    • Thyro/parathyroidectomy
    • Neck dissection
    • Radiation
  • Idiopathic/familial hypoparathyroidism
  • Autoimmune parathyroid destruction: autoimmune polyendocrine syndrome type 1
  • Genetic: DiGeorge syndrome DiGeorge syndrome DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). DiGeorge Syndrome (triad of: conotruncal cardiac anomalies, hypoplastic thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System (→ T cell immunodeficiency), and hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia (from parathyroid hypoplasia)
  • Infiltrative disease of the parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands
    • Hemochromatosis
    • Wilson’s disease

Pathophysiology and Clinical Presentation

Pathophysiology

Normal physiology of PTH: 

  • Hormone produced by the parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands
  • Essential for the regulation of serum calcium (Ca) and phosphate levels
  • Regulates Ca and phosphate levels by:
    • Activation of osteoclasts: ↑ release of Ca and phosphate from bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones
    • ↓ Excretion of renal Ca
    • ↑ Excretion of renal phosphate
    • ↑ Synthesis of 1,25-dihydroxyvitamin D, which increases intestinal Ca absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

Effects of hypoparathyroidism: 

  • ↓ PTH → ↓ serum Ca levels (and ↑ phosphate levels)
  • Physiological effects are related to hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia:
    • Uninhibited activity of voltage-gated sodium (Na) channels
    • Increased neuromuscular irritability → tetany 
Parathyroid hormone (pth) schematic diagram role and function

Parathyroid hormone has only one function: to correct hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia and maintain the serum level of calcium within narrow limits.
If the serum calcium is low, the four parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands secrete PTH, which is made and stored in the glands. When released, PTH works with and through vitamin D to restore the calcium level to normal.

Image by Lecturio.

Clinical presentation

Acute:

  • Tetany (increased neuromuscular excitability):
    • Mild:
      • Perioral numbness
      • Paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Respiratory Alkalosis
      • Muscle cramps/spasms
    • Severe:
      • Carpopedal spasm
      • Laryngospasm
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Cardiac findings:
    • Prolongation of the QT interval
    • Arrhythmias
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Heart failure
  • Neuropsychiatric symptoms:
    • Depression
    • Fatigue
    • Irritability/anxiety

Chronic:

  • Basal-ganglia calcifications:
    • Parkinsonism
    • Dementia
  • Coarse, brittle hair and dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Tetanic cataracts (paradox intraocular lens calcification)
  • Decreased insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion
  • Osteosclerosis, cortical thickening, craniofacial abnormalities
  • Dental abnormalities when hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia is present in early childhood
  • Idiopathic familial hypoparathyroidism may be associated with immune disorder and moniliasis.

Diagnosis and Management

Diagnosis

History:

  • Recent neck surgery/thyroidectomy/parathyroidectomy
  • Family history
  • Genetic syndromes

Physical exam:

  • Chvostek’s sign: Tapping on the facial nerve in the area of the cheek results in the twitching of the mouth musculature.
  • Trousseau’s sign: muscle spasms of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand (“claw”) after BP-cuff inflation of the arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm
  • Dry, puffy skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia, thin/brittle hair

Laboratory studies:

  • ↓ Serum PTH levels
  • ↓ Ca and ↑ phosphate levels in serum
  • ↓ Phosphate levels in urine
  • Urine Ca level can be low or high depending on the degree of serum Ca correction.
  • Document normal levels of serum magnesium, creatinine, and 25-hydroxyvitamin D
Table: Laboratory findings associated with different causes of hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia
Diagnosis PTH Phosphate Vitamin D Magnesium Clinical clues
Hypoparathyroidism Low High High/low Normal History of neck surgery, irradiation, or autoimmune disease
Vitamin D deficiency High or normal Low Low (25-hydroxyvitamin D) Normal Bone tenderness, weakness, and osteomalacia Osteomalacia Rickets and osteomalacia are disorders of decreased bone mineralization. Osteomalacia affects the sites of bone turnover in children and adults. Although most cases are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Osteomalacia can present with bone pain, difficulty with ambulation and pathologic fractures. Osteomalacia and Rickets
Hungry bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones syndrome Low Low Low Acute bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones uptake of Ca/P and Mg after parathyroidectomy
Magnesium deficiency (impaired PTH secretion and PTH resistance) Normal or low Normal Normal Low
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, loop and thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics, alcohol use
  • Often associated with hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease High High Low
  • Elevated creatine, BUN
  • Features of renal insufficiency
P: phosphate; Mg: magnesium; PTH: parathyroid hormone

Management

Acute hypoparathyroidism:

  • Usually occurs post surgery
  • Severe symptoms or Ca ≤ 7.5 mg/dL:
    • Emergent treatment with IV Ca gluconate
    • Oral calcitriol (vitamin D)
    • Transition to oral Ca supplements when Ca > 7.5 mg/dL
  • Mild-to-moderate symptoms and Ca > 7.5 mg/dL:
    • Oral Ca supplements
    • Oral calcitriol (vitamin D)

Chronic hypoparathyroidism:

  • Usually occurs due to autoimmune or infiltrative disease, or post radiation
  • Insidious onset
  • Long-term vitamin D and Ca supplementation:
    • Need to measure urinary Ca excretion periodically to prevent hypercalciuria, nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis, and nephrocalcinosis
    • Phosphate binders may be required.
  • Recombinant human PTH

Differential Diagnosis

  • Pseudohypoparathyroidism: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder with end-organ resistance to PTH secondary to a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in G protein (GNAS). Parathyroid hormone is secreted normally, but kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and bones are resistant to its effects, which leads to hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, hyperphosphatemia, and increased serum PTH levels. Treatment is with Ca and vitamin D supplementation.
  • Secondary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism: secondary elevation of serum PTH due to hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia usually associated with CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease. Diagnosis is established based on elevated PTH levels in the setting of hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia and hyperphosphatemia. Management is focused on treating the underlying disease.
  • Hypomagnesemia: low serum magnesium levels. Hypomagnesemia causes hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia by impairing PTH release in response to low serum Ca levels as well as by inducing bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones PTH resistance. Hypocalcemia responds promptly to the restoration of normal magnesium levels.

References

  1. Abate, E.G., Clarke, B.L. (2017). Review of Hypoparathyroidism. Front Endocrinol (Lausanne). 16(7),172. https://pubmed.ncbi.nlm.nih.gov/28138323/
  2. Goltzman, D. (2020). Hypoparathyroidism. Retrieved February 9, 2021, from https://www.uptodate.com/contents/hypoparathyroidism
  3. Gonzalez-Campoy, J.M. (2020). Hypoparathyroidism. Retrieved February 9, 2021, from https://emedicine.medscape.com/article/122207-overview
  4. Hans, S.K., Levine, S.N. Hypoparathyroidism. (2020). StatPearls. Retrieved February 9, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK441899/

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