Hypoparathyroidism Review

• Hypoparathyroidism is reviewed
• Dilek Gogas Yavuz from Marmara University Medical School is credited

Terminology

• Hypocalcemia is when there are low serum levels of albumin-corrected total calcium, or low ionized calcium levels
• Hypoparathyroidism is defined as hypocalcemia resulting from inadequate parathyroid hormone (PTH) secretion or receptor activation

Calcium Balance

• Parathyroid hormone (PTH) increases renal tubular calcium absorption
• Parathyroid hormone (PTH) increases intestinal calcium absorption
• Parathyroid hormone (PTH) increases bone calcium mobilization
• Hypocalcemia results from decreased PTH

Hypoparathyroidism

• Primary hypoparathyroidism is a state of decreased PTH secretion or inadequate PTH activity

Etiology

• Parathyroid destruction can cause hypoparathyroidism
• Surgery is a main reason for parathyroid destruction
• Autoimmune issues, cervical irradiation, infiltration by metastasis or systemic diseases can destroy the parathyroid
• Reduced parathyroid function can cause hypoparathyroidism
• Hypomagnesemia, PTH gene defects, or Ca sensing receptor (CaSR) mutations reduce parathyroid function
• Parathyroid agenesis and Familial diseases are causes of hypoparathyroidism

Clinical Symptoms of Hypocalcemia

• Paresthesias involving fingertips, toes, or the perioral area
• Hyperirritability and fatigue
• Anxiety and mood swings or personality disturbances
• Seizures, especially in patients with epilepsy
• Hoarseness due to laryngospasm
• Wheezing and dyspnea due to bronchospasm
• Muscle cramps, diaphoresis, and biliary colic
• Hypomagnesemia, hypokalemia, and alkalosis

Acute and Chronic Signs

• Acute:
• Neuromuscular irritability
• Overt or latent tetany
• Convulsions
• Laryngeal spasm and muscle spasms
• Abdominal pain mimicking surgical abdomen
• ECG changes
• Chronic:
• Diarrhea and dry skin
• Fatigue and dental issues
• Lenticular posterior cataract
• Coagulopathies and cardiomyopathy

Neuromuscular Irritability

• The rate of decrease in serum calcium is the major determinant for the development of neuromuscular complications
• Neuromuscular Irritability presents as:
• Paresthesia, Tetany, and Hyperventilation
• Adrenergic symptoms
• Convulsions are more common in young patients, and can cause generalized tetany, prolonged tonic spasms, and epileptiform seizures
• Signs of latent tetany
• Chvostek’s sign
• Trousseau sign
• Extrapyramidal signs from basal ganglia calcification

Chvostek's Sign

• Existing nerve hyperexcitability seen in hypocalcemia
• Abnormal reaction to stimulation of the facial nerve
• Tapping the facial nerve at the angle of the jaw(masseter muscle) causes facial muscles on the same side to contract due to hyperexcitability of nerves

Trousseau's Sign of Latent Tetany:

• More sensitive than Chvostek's sign for hypocalcemia detection
• Inflating a blood pressure cuff around the arm to greater than systolic BP for 3 minutes occludes blood flow in the brachial artery
• Absence of blood flow, hypocalcemia and subsequent neuromuscular irritability induce spasm of the muscles of the hand and forearm
• The wrist and metacarpophalangeal joints flex. Distal and proximal interphalangeal joints extend, and fingers adduct
• Also know as "hand of the obstetrician"

Muscle Spasms

• Muscle cramps are common in the lower back, legs, and feet
• Laryngospasm and bronchospasm can be life threatening
• Extrapyramidal choreo-athetoid syndromes in patients with basal ganglia calcifications are seen (Fahr syndrome)
• Parkinsonism, dystonia, hemi-ballismus, and oculogyric crises may occur in approximately 5%
• Spastic paraplegia, ataxia, dysphagia, and dysarthria
• Emotional instability, anxiety, depression, confusion, hallucinations, and psychosis occurs when calcium level is low

Cardiac Manifestation

• Prolonged QT interval in the ECG(severe hypocalcemia)
• Resistance to digitalis
• Hypotension
• Refractory congestive heart failure with cardiomegaly
• Long QT interval with normal T waves
• Prolongation of the ST segment with little shift from the baseline

Evaluation

• History:
• Neck surgery
• Family history
• Other autoimmune endocrinopathies
• PE (Chvostek’s sign and Trousseau sign)
• Laboratory:
• Intact PTH, Ca(corrected with albumin)
• Corrected total Ca=measured total calcium + 0.8 x (4.0 − serum albumin)
• P, 25(OH)2D3, Mg
• ECG, Brain MR/CT

Diagnosis of Hypoparathyroidism

• In the absence of renal failure:
• Presence of hypocalcemia with hyperphosphatemia
• Low iPTH

Differential Diagnosis

• Hypocalcemia can be due to other causes
• Pseudohypoparathyroidism

Hypocalcemia Other Causes

• Hypoparathyroidism
• Hypovitaminosis D(COMMON)
• Hypomagnesemia
• Malabsorption
• Renal impairment
• Other reasons

Treatment

• Ca salts like Ca carbonate, Ca citrate, or Ca gluconate
• Active Vitamin D prep like calcitriol
• Recombinant human parathyroid hormone(rhPTH)
• Patients face a lifelong risk of symptomatic tetany, and without access to calcium, may die
• Patients should wear identification for having primary hypoparathyroidism

Asymptomatic Hypocalcemia

• Calcium orally(1000 mg/day)
• Active Vitamin D orally(Calcitriol 0.25–0.5 mcg/day)
• Magnesium(3-4 gr p.o)
• Phosphate restriction in diet with or without aluminum hydroxide gel to lower serum phosphate levels

Emergency Treatment for Hypocalcemia

• Hunger bone syndrome post parathyroidectomy may cause serve hypocalcemia), tetany, laryngeal spasm
• Administer Calcium parenterally until adequate serum calcium level is reached -2 amp Calcium gluconate(10%) which contains 100 elemental calcium/10 mL IV over 10-30 minutes
• Add 6 ampules to 500 mL 5% Dextrose and infuse at 1mg/kg/hr under monitoring
• Follow with:
• Active Vitamin D (Calcitriol 0.25-1 mcg/day)
• Supplementation with oral calcium (1-2 elemental calcium/day)

Complications of Treatment

• Nephrocalcinosis
• Nephrolithiasis

Familial Hypoparathyroidism

• Autosomal dominant: CaSR gene mutation
• The set point for calcium-induced suppression of parathyroid hormone is shifted to the left, causing mildly reduced calcium and parathyroid hormone levels with marked hypercalciuria
• Autosomal recessive:
• PTH gene mutation
• Parathyroid gland agenesis

Pseudohypoparathyroidism

• Lack of G protein and inability of PTH to generate cyclic AMP
• Target organ unresponsiveness to PTH in bone/kidney
  • Hypocalcemia
  • Hyperphosphatemia
  • Elevated PTH
• Ellsworth-Howard test detects a lack of increased cAMP in urine after administration of exogenous PTH

Genetic Defects

• Lack of receptors
• Lack of binding
• Lack of Post receptor effects
• GNAS coding region mutation
• GNAS regulatory region mutation or deletion
• Generalize unresponsiveness
• PHP Type IA, IB
• PHP II
• PPHP (Pseudopseudo Hypoparathyroidism)

Pseudohypoparathyroidism Types

• PHP la
• Has Albright's phenotype
• Serum calcium is decreased
• cAMP response to PTH is decreased
• Response to Phosphorus decreased
• Resistance to All hormones
• Molecular defect has GNAS coding region mut
• PHP lb
• No Albright's phenotype
• Serum calcium is decreased
• cAMP response to PTH is decreased
• Response to Phosphorus decreased
• Resistance to PTH target tissues only
• Molecular defect has GNAS regulatory region mut
• PHP II
• No Albright's phenotype
• Serum calcium is decreased
• cAMP response to PTH is decreased
• Response to Phosphorus has decreased or normal
• Resistance to PTH target tissues only
• Molecular defect is Unknown
• PPHP
• Has Albright's phenotype
• Serum calcium is Normal
• cAMP response to PTH is Normal
• Response to Phosphorus is Normal
• Resistance to None
• Molecular defect has GNAS coding region mut

Albright’s phenotype

• Short stature & limbs
• Obesity
• Round, flat face Short 4e/5e metacarpals
• Archibald sign
• Brachydactyly
• Potter's thumb
• Eye problems
• IQ problems Basal ganglia calcifications
• Type IA: Generalized target organ unresponsiveness and generalized hormone resistance

Pseudo-pseudohypoparathyroidism (PPHP)

• Has Albright phenotype
• GNAS coding region mutation (+)
• Ca and P levels are normal
• Non PTH resistance
• Mimics PHP with AHO phenotype

Idiopathic Hypoparathyroidism

• Autoimmune Polyglandular Syndrome (APS)
• APS Type I:Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)=Whitaker syndrome
• Candidiasis + hypoparathyroidism + adrenal failure
• PTH / CaSR antibodies
• Age onset 5-9 years , F > M
• APS Type II:Addison disease + thyroid autoimmune diseases + Type 1 DM
• Primary hypogonadism, myasthenia gravis, and celiac disease also are commonly observed in this syndrome. Pathogenesis is poorly understood
• Middle-aged women have shown an increased prevalence of PGA-II
• APS Type III: Failure of the glands to produce their hormones
• APS IIIA - Autoimmune thyroiditis + immune mediated DM (IMD)
• APS IIIB - Autoimmune thyroiditis with pernicious anemia
• APS IIIC - Autoimmune thyroiditis + vitiligo and/or alopecia and/or other organ-specific autoimmune disease

Summary

• Familial syndromes usually cause chronic hypocalcemia without severe symptoms