Hypoparathyroidism is caused by a relative or absolute deficiency in plasma parathyroid hormone (PTH) synthesis & secretion. This leads to low calcium and high phosphate levels in the blood and resultant signs and symptoms.
Pseudohypoparathyroidism is characterised by similar findings but PTH is elevated due to PTH resistance.
Pathophysiology
Hypoparathyroidism is uncommon. The resultant outcomes of hypocalcaemia and hyperphosphataemia derive from a lack of PTH:
- Hypocalcaemia - PTH aids reabsorption of calcium from kidneys, resorption of calcium from bone and absorption of calcium from the intestinal tract. Absence of these mechanisms results in the low calcium. Hypocalcaemia, both acutely and chronically, produces irritability within the nerves leading to muscle cramping and stiffness, tetany, paraesthesias, altered mentation, and even seizures. Chronic hypocalcaemia impairs left ventricular contractility.
- Hyperphosphataemia - PTH acts on the kidneys to promote phosphate excretion. Hence the raise with the absence of PTH.
Let’s discuss the causes of hypoparathyroidism:
- ⭐️ Post-operative - this is the most common cause. It most commonly occurs as the result of accidental injury to parathyroids (or their vasculature) during thyroidectomy, parathyroidectomy, or radical neck dissection.
- ⭐️ Autoimmune - second most common cause.
- Congenital:
- DiGeorge syndrome - this is caused by the deletion of genes on chromosome 22 (22q11.2), which causes developmental defects of the heart, thymus, parathyroid glands, and other tissues. Hypoparathyroidism arises from parathyroid gland hypoplasia or aplasia as part of this syndrome. It's also a cause of congenital heart disease and cleft lip/palate.
- PTH gene mutation
- Autosomal dominant hypocalcaemia - this is a mutation of calcium-sensing receptors, that causes these receptors to be active even at normal calcium levels. So, these receptors then bind calcium, decreasing levels of free serum calcium.
- Infiltrative disorders:
- Wilson disease
- Haemochromatosis
- Granulomas
- Functional hypoparathyroidism:
- Hypomagnesaemia - increases PTH resistance. Chronic alcoholism causes magnesium wasting through renal mechanisms.
- Hypermagnesaemia - suppresses PTH synthesis & secretion through activation of the calcium-sensing receptor.
- Other, non-autoimmune causes of destruction include:
- Metastases
- Radiation-induced destruction
- Gram-negative sepsis
- Toxic shock syndrome
- HIV infection
- Some high-risk neonates (ie, infants of mothers with diabetes, preterm infants and infants with perinatal asphyxia), may develop hypocalcaemia.
😷 Presentation
Let’s first take a look at the acute manifestations. These derive from hypocalcaemia:
- Hypocalcaemia features:
- Neurological:
- Tetany (Chvostek and Trousseau signs)
- Laryngospasm
- Seizures 2º raised ICP
- Perioral paraesthesia
- Cardiovascular:
- Arrhythmias - palpitations, irregular rhythm, syncope.
- Congestive heart failure (LV dysfunction)
- Chronic manifestations of hypoparathyroidism
- Extrapyramidal symptoms -refers to structures in the brain outside the pyramidal tract, which is involved in voluntary motor control. In hypoparathyroidism, hypocalcemia can disrupt neurotransmitter function and neuronal excitability in various brain regions, including those related to motor control.
- Parkinsonism
- Dystonia
- Hemiballismus - rare hyperkinetic movement disorder, that is characterized by violent involuntary limb movements, on one side of the body.
- Choreoathetosis - rapid (chorea) or slow (athetosis) involuntary movements of the fingers or toes (flexion–extension, adduction–abduction, writhing, sometimes piano-playing movements) which are irregular, nonrhythmic, and purposeless.
- Oculogyric crises - a form of dystonic movement disorder characterized by paroxysmal, conjugate, and typically upward deviation of the eyeball, which occurs for seconds to hours.
- Dementia
- Ocular disease:
- Cataracts
- Keratoconjunctivitis
- Papilloedema (2º raised ICP)
- Skeletal manifestations:
- Increased bone mineral density
- Osteosclerosis
- Dental abnormalities:
- Dental hypoplasia
- Failure of tooth eruption
- Defective root formation
- Cutaneous manifestations:
- Dry, puffy coarse skin
- Brittle nails
- Dry hair
- Renal stones
🔍 Investigations
- Serum calcium - low. Reported as calcium adjusted for albumin or ionised calcium. Ionised is preferred as it is more accurate.
- Mild hypocalcaemia - 2-2.13 mmol/L
- Moderate hypocalcaemia - 1.88-2.00 mmol/L
- Severe hypocalcaemia - <1.88 mmol/L
- Plasma PTH - low or inappropriately normal. Measured through PTH assay. It may be ↑ in the rare patient with pseudohypoparathyroidism with PTH resistance.
- Serum albumin - as low albumin will give falsely low total serum calcium.
- Serum magnesium
- Serum 25-hydroxyvitamin D (inactive form) - normal.
- Serum 1,25 dihydroxyvitamin D (active form) - low or normal.
- Serum phosphorus - elevated.
- Serum creatinine - to check renal function
- ECG - prolonged QT interval indicates severe life-threatening hypocalcaemia.
🧰 Management
The focus of treatment is to rectify any of the electrolyte abnormalities.
- Severe hypocalcaemia (<1.88mmol/L)
- IV calcium gluconate - this is to relieve acute symptoms and to correct the albumin-corrected serum calcium to approximately 2mmol/L. Continuous ECG monitoring is needed.
- IV/IM magnesium - if there is concomitant hypomagnesaemia.
- Treatment of alkalosis - alkalosis promotes binding of albumin to calcium which reduces the free serum calcium levels in the blood and can worsen the hypocalcaemia.
⚠️ One should be wary of extravasation of the medication as it may lead to tissue necrosis around the iv insertion site.
- Temporary hypocalcaemia or chronic hypocalcaemia
- Oral calcium ± calcitriol
Pseudohypoparathyroidism (PHP) occurs due to resistance of end-organs to the actions of PTH due to a loss of intracellular signalling. However, the parathyroid glands sufficiently secrete PTH.
Pseudohypoparathyroidism results from resistance to the actions of parathyroid hormone (PTH) produced by a loss of G-protein-mediated signalling, depsite sufficient PTH secretion from the parathyroid glands.
🔢 We can classify PHP as type 1 or type 2:
- Type 1 PHP
- Low IQ
- Short stature
- Shortened 4th and 5th metacarpals
- Type 2 PHP
Occurs due to gene mutations (in the GNAS gene) which result in a defective response by the G-protein coupled receptor resulting in end-organ resistance to PTH.
It presents the same as hypoparathyroidism but additionally with Albright hereditary osteodystrophy (AHO) which has distinct features of:
This differs as it is an isolated renal resistance to PTH. However, there are no features of AHO. Its mechanism is not fully understood. Biochemically it is the same as type 1 PHP but without the physical stigmata seen. There is no issue with cAMP but further signalling is believed to be affected.
🔍 Investigations
It presents the same as hypoparathyroidism but with elevated PTH levels.
- Hypocalcaemia
- Elevated PTH levels
⭐️ We can confirm the diagnosis using urinary cAMP and phosphate levels after an infusion of PTH. In hypoparathyroidism, this causes an increase in cAMP and phosphate levels (as there is no issue with the response to PTH) but in type 1 PHP there is no change in cAMP or phosphate. Type 2 PHP elevates cAMP but not phosphate.
🧰 Management
- IV calcium gluconate or calcium chloride and ECG monitoring - if symptomatic.
- Oral calcium - if asymptomatic.
This is when there are morphological features consistent with PHP and there are no issues with PTH release but there is also no end-organ resistance to PTH.
The biochemistry of the patient will also be normal, indicating no abnormalities with the endocrine system. Albright hereditary osteodystrophy is seen once again.
The issue once again arises in the GNAS gene but phenotypically it is milder, leading to partial loss of function of the Gs-protein.