Hyperparathyroidism

Hyperparathyroidism is a condition characterized by excessive secretion of parathyroid hormone, leading to disturbances in calcium and phosphate metabolism. It can result in a range of clinical manifestations affecting the bones, kidneys, and other organs. Understanding the classification and underlying mechanisms is essential for accurate diagnosis and effective management.

Introduction

The parathyroid glands play a critical role in regulating calcium homeostasis through the secretion of parathyroid hormone (PTH). Hyperparathyroidism occurs when there is abnormal overproduction of PTH, causing hypercalcemia and related complications. It is an important endocrine disorder with both primary and secondary causes, and its recognition is crucial for preventing long-term organ damage.

Classification

Hyperparathyroidism can be classified based on the underlying cause and pathophysiology:

• Primary Hyperparathyroidism: Caused by intrinsic abnormalities of the parathyroid glands, such as adenomas, hyperplasia, or rarely parathyroid carcinoma.
• Secondary Hyperparathyroidism: Occurs in response to chronic hypocalcemia, commonly due to chronic kidney disease or vitamin D deficiency.
• Tertiary Hyperparathyroidism: Develops when secondary hyperparathyroidism becomes autonomous, leading to persistent hypercalcemia even after correction of the initial cause.
• Familial and Genetic Forms: Includes inherited syndromes such as Multiple Endocrine Neoplasia types 1 and 2A, which predispose to parathyroid overactivity.

Anatomy and Physiology of Parathyroid Glands

Location and Structure

The parathyroid glands are small, oval endocrine glands typically numbering four, located on the posterior surface of the thyroid gland. They are usually two superior and two inferior glands, although anatomical variations can occur. Microscopically, the glands contain:

• Chief cells: Responsible for the synthesis and secretion of parathyroid hormone.
• Oxyphil cells: Less numerous and of uncertain function, possibly involved in hormone regulation and metabolic activity.

Physiology of Parathyroid Hormone

Parathyroid hormone plays a central role in calcium and phosphate homeostasis through its effects on multiple organ systems:

• Bone: PTH stimulates osteoclast-mediated bone resorption, increasing serum calcium levels.
• Kidneys: Enhances calcium reabsorption, decreases phosphate reabsorption, and stimulates production of active vitamin D.
• Intestine: Indirectly increases calcium absorption through stimulation of 1,25-dihydroxy vitamin D synthesis.
• Feedback Mechanisms: PTH secretion is regulated primarily by serum calcium levels via calcium-sensing receptors on chief cells.

Etiology and Pathogenesis

Hyperparathyroidism arises from a variety of causes, with different mechanisms depending on whether it is primary, secondary, or tertiary:

• Primary Hyperparathyroidism: Usually caused by a single parathyroid adenoma, diffuse hyperplasia of the glands, or, rarely, parathyroid carcinoma.
• Secondary Hyperparathyroidism: Results from chronic hypocalcemia due to conditions such as chronic kidney disease or vitamin D deficiency, leading to compensatory PTH overproduction.
• Tertiary Hyperparathyroidism: Occurs when prolonged secondary hyperparathyroidism causes autonomous PTH secretion, resulting in hypercalcemia even after correction of the initial cause.
• Genetic Syndromes: Inherited disorders like MEN1 and MEN2A can cause parathyroid hyperplasia or adenomas, leading to early-onset hyperparathyroidism.

Clinical Features

The clinical manifestations of hyperparathyroidism are primarily related to elevated serum calcium levels and increased bone resorption. They may be asymptomatic in early stages or present with systemic involvement:

• Symptoms of Hypercalcemia: Fatigue, muscle weakness, polyuria, polydipsia, nausea, vomiting, and constipation.
• Bone Manifestations: Osteitis fibrosa cystica, bone pain, osteoporosis, and increased risk of fractures.
• Renal Manifestations: Nephrolithiasis, nephrocalcinosis, and impaired renal function.
• Neurological and Gastrointestinal Symptoms: Cognitive disturbances, depression, abdominal pain, peptic ulcers, and pancreatitis.

Diagnostic Evaluation

Laboratory Investigations

Laboratory tests are essential for confirming hyperparathyroidism and assessing its systemic impact:

• Serum Calcium: Elevated in primary and tertiary hyperparathyroidism; may be low or normal in secondary forms.
• Serum Phosphate: Often decreased in primary hyperparathyroidism; increased in secondary hyperparathyroidism due to renal impairment.
• Parathyroid Hormone (PTH) Levels: Elevated in primary and secondary hyperparathyroidism; suppressed in hypercalcemia from non-parathyroid causes.
• Vitamin D Levels: Low in secondary hyperparathyroidism, affecting calcium absorption.
• Renal Function Tests: Assess for chronic kidney disease as a cause of secondary hyperparathyroidism.

Imaging Studies

Imaging helps localize abnormal parathyroid glands and assess bone involvement:

• Neck Ultrasound: Identifies enlarged parathyroid glands and differentiates adenomas from hyperplasia.
• Sestamibi Scan: Nuclear imaging technique for preoperative localization of hyperfunctioning glands.
• CT and MRI: Useful for ectopic or mediastinal parathyroid glands when ultrasound is inconclusive.
• Bone Densitometry (DEXA Scan): Evaluates bone mineral density and risk of fractures.

Differential Diagnosis

Several conditions can mimic hyperparathyroidism or cause hypercalcemia and must be considered:

• Familial Hypocalciuric Hypercalcemia: Genetic condition causing mild hypercalcemia with low urinary calcium excretion.
• Vitamin D Intoxication: Excess vitamin D leading to hypercalcemia without elevated PTH.
• Other Causes of Hypercalcemia: Malignancy-related hypercalcemia, medications such as thiazide diuretics, and granulomatous diseases like sarcoidosis.

Management and Treatment

Conservative Management

Initial management may be appropriate for asymptomatic patients or those with mild hypercalcemia:

• Hydration: Encourages renal calcium excretion and prevents kidney stones.
• Monitoring: Regular assessment of serum calcium, phosphate, renal function, and bone density.
• Pharmacologic Therapy: Includes bisphosphonates to reduce bone resorption and calcimimetics to suppress PTH secretion in selected patients.

Surgical Management

Parathyroidectomy is the definitive treatment for symptomatic or severe primary hyperparathyroidism:

• Indications: Symptomatic hypercalcemia, renal stones, osteoporosis, age under 50, or markedly elevated serum calcium.
• Preoperative Localization: Ultrasound and sestamibi scan guide surgical planning.
• Surgical Approaches: Focused minimally invasive parathyroidectomy or bilateral neck exploration depending on gland localization.
• Postoperative Care: Monitoring for hypocalcemia, ensuring adequate calcium and vitamin D supplementation, and follow-up PTH levels.

Complications

Complications of hyperparathyroidism can arise from the disease itself or from treatment interventions:

• Osteoporosis and Fractures: Chronic bone resorption increases fracture risk.
• Renal Complications: Nephrolithiasis, nephrocalcinosis, and chronic kidney disease.
• Cardiovascular Complications: Hypertension, left ventricular hypertrophy, and increased cardiovascular risk.
• Hungry Bone Syndrome: Post-parathyroidectomy rapid bone remineralization leading to hypocalcemia.

Prognosis

The prognosis of hyperparathyroidism depends on the underlying cause, severity of hypercalcemia, and presence of end-organ complications. Early diagnosis and appropriate treatment, particularly surgical intervention in primary hyperparathyroidism, generally result in excellent outcomes.

• Outcomes after Surgery: Most patients experience normalization of serum calcium and improvement in bone density and renal function.
• Factors Affecting Prognosis: Age, comorbid conditions, duration of hypercalcemia, and severity of bone or kidney involvement can influence recovery and long-term health.

Prevention and Screening

Prevention focuses on early detection and management of conditions that predispose to hyperparathyroidism, particularly in high-risk populations:

• Monitoring High-Risk Groups: Individuals with familial syndromes, chronic kidney disease, or vitamin D deficiency should have periodic calcium and PTH assessments.
• Early Detection: Routine biochemical screening can identify asymptomatic primary hyperparathyroidism and prevent complications.
• Management of Underlying Conditions: Correcting vitamin D deficiency, optimizing renal function, and addressing metabolic disorders can reduce secondary hyperparathyroidism risk.

References

1. Marx SJ. Hyperparathyroid and Hypoparathyroid Disorders. N Engl J Med. 2000;343(25):1863-1875.
2. Silverberg SJ, Bilezikian JP. Clinical review 103: Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab. 1996;81(6):2036-2040.
3. Brown EM, Gardner DG. Parathyroid Hormone and Calcium Homeostasis. In: Jameson JL, De Groot LJ, editors. Endocrinology. 7th ed. Philadelphia: Elsevier; 2016. p. 1519-1542.
4. Khan AA, Hanley DA, Rizzoli R, et al. Primary hyperparathyroidism: Review and recommendations on evaluation, diagnosis, and management. Osteoporos Int. 2017;28(1):1-19.
5. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67(9):1959-1966.
6. Udelsman R, Pasieka JL, Sturgeon C, et al. Surgery for primary hyperparathyroidism: An evidence-based approach. World J Surg. 2010;34(5):1123-1133.
7. Silverberg SJ, Clarke BL. Secondary and tertiary hyperparathyroidism. In: De Groot LJ, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2022.
8. Walker MD, Silverberg SJ. Diagnosis and management of hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 2018;32(6):801-814.