Introduction

Tetany is a clinical condition characterised by involuntary muscle spasms (contractions) arising from disturbances in calcium metabolism. Low calcium levels (hypocalcemia) in the blood generates high neuromuscular excitability.¹

The Parathyroid Hormone (PTH) is a polypeptide hormone produced by the parathyroid gland that plays a primary role in regulating calcium homeostasis. By modulating bone resorption, renal calcium reabsorption and vitamin D activation, the PTH maintains stable serum calcium levels in the gastrointestinal tract. Any deficiency in this process leads to symptoms such as tetany.²

This article aims to explore the relationship between PTH deficiency and tetany as a clinical symptom. By understanding the relationship between these processes, clinicians and researchers can better recognise, diagnose and manage conditions pertaining to calcium regulation.

Understanding PTH

The parathyroid hormone (PTH) is primarily produced by the chief cells in the parathyroid glands, which are small endocrine glands located in the posterior surface of the thyroid glands. PTH plays a crucial role in maintaining serum calcium and phosphate level homeostasis. Secretion levels of the PTH are triggered by low calcium serum levels, detected by the calcium-sensing receptors (CaSR) on the surface of the chief cells.³

PTH exerts on three major organ systems – the bones, kidneys and intestines.

In the bones, the PTH indirectly affects the cells involved in bone remodelling – osteoclast ( bone resorption) and osteoblast (bone formation) and this leads to the release of RANKL (Receptor Activator of Nuclear Factor-κB Ligand),⁴ a signalling molecule involved in the regulation of bone cell formation. RANKL activates precursors of the osteoclast, releasing calcium and phosphate into the bloodstream. 

Within kidneys, PTH increases calcium reabsorption in a component of the kidney known as the distal convoluted tubule by upregulating TRPV5⁵ (a calcium transport protein). Simultaneously, it also reduces phosphate reabsorption , promoting phosphate excretion. It also enhances activity of 1-alpha hydroxylase, an enzyme that converts inactive vitamin D into its active form, calcitriol.

In the intestines, the PTH exerts an indirect effect wherein the converted calcitriol increases the intestinal absorption of calcium and phosphate, achieved by upregulating calcium transport proteins such as TRPV6 and calbindin.⁶

Thus, the PTH maintains serum calcium levels within a normal range (8.5-10.2 mg/dL)⁷, using calcium and vitamin D to regulate PTH secretion and ensure homeostasis. Thus, disruptions in PTH levels lead to clinical symptoms such as tetany and hypocalcemia. 

PTH deficiency

Deficiency in the PTH, referred to as hypoparathyroidism, occurs when the parathyroid glands fail to produce sufficient levels of PTH thereby promoting dysregulation of calcium and phosphate homeostasis. This deficiency may arise from various causes, each cause having its distinct pathophysiological mechanism.

One of the most common causes of pathology within the PT glands is autoimmune destruction. Here, auto-antibodies target glandular tissue which reduce PTH secretion.⁸ Other common causes are surgical removal or damage of PT glands during procedures such as thyroidectomy, parathyroidectomy, neck surgeries etc, which lead to permanent or transient hypoparathyroidism.⁹ Underdevelopment or congenital absence of PT glands such as in the case of DiGeorge Syndrome (22q11.2 deletion) leads to birth defects in the parathyroid gland, such as primary hypoparathyroidism.¹⁰

Certain genetic mutations affect the function of the parathyroid gland. Certain commonly noted mutations include CASR gene at the calcium sensing receptor, engendering autosomal dominant hypocalcemia, characterised by altered receptor sensitivity suppressing PTH release even during low calcium levels. Mutations in the GCM2 gene (essential for the development of the parathyroid gland) are linked to defects in PTH synthesis, which impact glandular function.¹¹

Hypocalcemia also disrupts neuromuscular excitability, as calcium stabilises the voltage-gated sodium channels in neurons. Low calcium increases sodium influx, which lowers the threshold for the generation of action potential. Thus, the induced hyperexcitability provokes symptoms such as tetany, paraesthesia (tingling sensations), muscle cramps, seizures and laryngospasm (involuntary muscle contractions in the vocal cords).¹²

Pathophysiology of tetany in PTH deficiency

In normal circumstances, extracellular calcium binds to the voltage-gated sodium channels, thereby via maintaining a higher activation threshold, it inhibits depolarisation. When calcium levels drop, the threshold required to activate the sodium channels is lowered, and the neurons thus fire more easily and at inappropriate times. This results in tetany – excessive and uncontrolled stimulation of muscle fibres, leading to muscle cramps, spasms and contractions.

There are various clinical manifestations of tetany, which are directly linked to the nervous and muscular systems being hyperexcitable.¹³

Chvostek’s sign

Tapping of the facial nerve which is anterior to the ear induces involuntary twitching in facial muscles, reflecting the excitability of the peripheral nerves.

Trousseau’s sign

When a blood pressure cuff is pumped and left inflated, it results in the arm squeezed tightly. This halts the blood flow to the hand, temporarily reducing oxygen supply to muscles and nerves, causing muscle cramps and spasms. This sign thus helps measure calcium levels in the blood and causes the hand to twist into a cuff-like position called carpopedal spasm.

Role of magnesium

Along with hypocalcemia, magnesium deficiency is frequently observed in PTH deficiency, further worsening calcium levels. Magnesium is essential for PTH secretion and is responsible for the sensitivity of target tissues to PTH.¹⁴ Magnesium ions also modulate the resting membrane potential by stabilising calcium-sodium channel interactions in neurons and muscle cells. Magnesium deficiency amplifies inappropriate neuronal firing, worsening tetany symptoms.

In some severe cases, tetany also progresses beyond localised muscle spasms. Chronic hypocalcemia affects cardiac function, causing arrhythmias (irregularities in the heart rhythm), delays cardiac repolarisation and prolongs QT intervals (An ECG indicator reflecting time taken for ventricles to depolarize and repolarize during a heartbeat). Furthermore, low calcium levels impair the functioning of smooth muscles, leading to issues in gastrointestinal motility such as abdominal cramps.¹⁵

Diagnosis of PTH deficiency related tetany 

Diagnosis of tetany due to PTH deficiency requires a methodical approach involving clinical evaluation, laboratory investigations and imaging studies:

Clinical examination

Involves a thorough assessment of symptoms and physical signs suggesting neuromuscular hyperexcitability.

Patients may report muscle cramps, spasms or stiffness, and tingling sensations around the mouths, hands or feet. Specific tests such as assessing for the Chvostek’s sign and Trousseau’s Sign incorporate neurological examinations for tetany.

Laboratory investigations are necessary to identify the underlying cause of tetany

Assessing serum calcium levels (both total and ionised levels) for hypocalcemia is a hallmark biomarker to identify tetany.

Phosphate levels are also assessed as hyperphosphatemia (elevated phosphate levels) occur along with PTH deficiency (as it promotes phosphate excretion in kidneys).¹⁶ 

Additionally, Vitamin D Status (25-hydroxyvitamin D deficiency) ¹⁷and Renal Function tests (to assess for chronic kidney disease) help assess for factors that exacerbate hypocalcaemia.¹⁸

EEG imaging

One of the side effects of tetany is seizures and altered mental states, and thus an EEG may be conducted to check for abnormal activity such as slowing of brain waves or epileptiform discharge arising from hypocalcemia and neuronal hyperexcitability.¹⁹

Additional diagnostic tools for a thorough picture of hypocalcemia and tetany include ultrasounds to assess pathology in parathyroid glands. Genetic testing may be conducted to assess for congenital or familial hypoparathyroidism.²⁰

Treatment and prognosis

First and foremost, the primary treatment goal to treat tetany caused by PTH deficiency is to correct hypocalcemia and stabilise calcium levels, in order to minimise any risks or complications, and prevent further episodes of tetany. This is achieved by a combination of pharmacological and supportive therapies:

• Calcium supplementation (such as oral calcium salts like calcium carbonate or calcium citrate) to raise calcium levels
• Vitamin D supplementation (such as calcitriol or D3 to facilitate calcium absorption in intestines and support calcium channels in kidneys and bones)
• PTH replacement – recombinant human parathyroid hormone (rhPTH) may be an option to consider for long term management, which has shown promising results to substitute vitamin D supplementation and calcium, reducing the frequency of tetany episodes
• Magnesium Supplementation – to combat comorbid PTH deficiency and hypomagnesemia, to improve tissue responsiveness

With appropriate treatment combating all symptoms arising from PTH deficiency and tetany, studies have shown a good prognosis with good quality of life. However, in cases where PTH deficiency is chronic in nature, care must be taken to ensure life-long management of symptoms and medications. Adjustments to diet may be made such as in supplementation and attention to detail in monitoring medication to avoid calcium deposits in kidneys. Furthermore, tetany can result in various symptoms that maybe debilitating; ensuring symptoms such as muscle cramps, fatigue etc, uncommitted in daily activities involves effective treatment and instrumental support to improve independence in daily living.²¹

Summary

Tetany related to PTH deficiency is a serious condition, which presents due to neuromuscular hyperexcitability arising from disruptions in calcium balance. A multidisciplinary treatment involving both supplementary, dietary and quality of life treatments (calcium, vitamin D replacement, PTH replacement, and correction of magnesium imbalance) is crucial to help manage PTH deficiency and reduce recurrence of tetany. With adequate treatment and careful follow-up, good long-term results can be obtained in such patients. Prevention strategies such as lifestyle changes and regular follow-up in a clinical setting contribute to maintaining the balance of calcium and preventing recurrent tetany.