Medicine – Hyperparathyroidism

Hyperparathyroidism is a disorder in which the parathyroid glands produce excessive parathyroid hormone (PTH). PTH normally maintains serum calcium by acting on the kidneys and bone and by increasing renal production of active vitamin D, which enhances intestinal calcium absorption.

Hyperparathyroidism is divided into three major forms:

Primary hyperparathyroidism – autonomous excessive PTH secretion from the parathyroid glands.

Secondary hyperparathyroidism – compensatory PTH elevation in response to a chronic stimulus, especially chronic kidney disease or vitamin D deficiency.

Tertiary hyperparathyroidism – autonomous PTH secretion developing after prolonged secondary hyperparathyroidism, most often in advanced CKD.

1. Normal Actions of PTH

PTH is secreted by the:

Parathyroid glands.

Its major physiological purpose is to maintain an adequate concentration of:

Ionised calcium.

When serum calcium falls:

↓ Ca²⁺

↓

Parathyroid calcium-sensing receptors detect the change

↓

↑ PTH secretion

↓

Serum calcium is restored toward normal.

2. PTH and Calcium

PTH raises serum calcium through several mechanisms.

In the kidney, PTH:

Increases calcium reabsorption.

It also stimulates:

1α-hydroxylase

which increases production of:

1,25-dihydroxyvitamin D – calcitriol.

Calcitriol then increases intestinal:

Calcium absorption.

PTH also increases bone turnover and, through its effects on osteoblast-lineage cells and osteoclast activation, can increase calcium release from bone when persistently elevated.

3. PTH and Phosphate

PTH has the opposite effect on serum phosphate.

In the proximal renal tubule, PTH:

Decreases phosphate reabsorption.

Therefore:

↑ PTH

↓

↑ Urinary phosphate excretion

↓

Phosphaturia

↓

↓ Serum phosphate.

A useful rule is:

PTH RAISES CALCIUM AND LOWERS PHOSPHATE.

4. Primary Hyperparathyroidism

Primary hyperparathyroidism occurs when one or more parathyroid glands secrete PTH autonomously.

The excessive PTH secretion is inappropriate for the patient’s serum calcium concentration.

Therefore the typical biochemical pattern is:

PTH ↑ or inappropriately normal

with:

Calcium ↑.

5. Parathyroid Adenoma

The original notes correctly state that the most common cause is:

A single parathyroid adenoma.

A solitary benign adenoma accounts for the large majority of sporadic cases, traditionally quoted as approximately:

80–85%.

Therefore:

PRIMARY HYPERPARATHYROIDISM → THINK SINGLE PARATHYROID ADENOMA FIRST.

6. Other Causes of Primary Hyperparathyroidism

Other causes include:

Multigland parathyroid hyperplasia.

Less commonly:

Multiple adenomas.

Very rarely:

Parathyroid carcinoma.

Therefore not every patient with primary hyperparathyroidism has a single adenoma.

7. Familial Primary Hyperparathyroidism

Primary hyperparathyroidism may occasionally occur as part of inherited endocrine syndromes.

Important associations include:

Multiple endocrine neoplasia type 1 – MEN1.

MEN2A.

Other inherited hyperparathyroidism syndromes also exist.

In familial disease, involvement of:

Multiple parathyroid glands

is more likely than in a typical sporadic single adenoma.

8. Epidemiology

The original notes correctly identify a predominance in:

Women.

Primary hyperparathyroidism is more common in women than men and becomes increasingly common with age, particularly around and after:

Menopause.

The traditional teaching of:

Women aged 40–60 years

captures an important demographic group, although the disorder can occur outside this age range.

9. Clinical Presentation

Many patients are now diagnosed when routine blood tests reveal:

Hypercalcaemia.

Therefore primary hyperparathyroidism may initially be:

Asymptomatic.

When symptoms occur, many are manifestations of:

Hypercalcaemia

or chronic PTH excess.

10. “Stones, Bones, Groans and Psychiatric Overtones”

The traditional mnemonic for symptomatic hyperparathyroidism/hypercalcaemia is:

Stones.

Bones.

Abdominal groans.

Psychiatric overtones.

This summarises renal, skeletal, gastrointestinal and neuropsychiatric manifestations.

11. Renal Features – “Stones”

Hypercalcaemia and increased filtered calcium can predispose to:

Nephrolithiasis – renal stones.

Patients may therefore develop:

Renal colic.

Haematuria.

Recurrent calcium-containing renal calculi.

Chronic disease can also be associated with:

Nephrocalcinosis

and impaired renal function.

12. Urinary Calcium

The original notes state:

Urinary calcium ↑.

This is often true in primary hyperparathyroidism because the increased serum calcium raises the filtered calcium load.

However, urinary calcium is not invariably elevated, so this should not be treated as an absolute diagnostic requirement.

Urinary calcium measurement is particularly useful when distinguishing primary hyperparathyroidism from:

Familial hypocalciuric hypercalcaemia – FHH.

13. Familial Hypocalciuric Hypercalcaemia

FHH can resemble primary hyperparathyroidism because it can produce:

Hypercalcaemia

with:

PTH that is normal or mildly elevated.

However, FHH characteristically has:

Low urinary calcium excretion.

Therefore assessment of urinary calcium, often using the:

Calcium-to-creatinine clearance ratio,

can help distinguish FHH from primary hyperparathyroidism.

This distinction matters because FHH generally does not benefit from routine parathyroidectomy.

14. Skeletal Features – “Bones”

Persistent PTH excess increases:

Bone turnover.

Severe longstanding disease can cause:

Bone pain.

Reduced bone mineral density.

Osteoporosis.

Fragility fractures.

A classical severe skeletal manifestation is:

Osteitis fibrosa cystica.

15. Osteitis Fibrosa Cystica

Severe PTH excess can produce marked bone resorption and fibrous replacement.

Radiological findings may include:

Subperiosteal bone resorption, classically affecting the phalanges.

Brown tumours.

Salt-and-pepper appearance of the skull.

These findings are much less common in modern patients diagnosed early.

16. Brown Tumours

A brown tumour is not a true neoplasm.

It represents an area of excessive bone resorption with:

Fibrous tissue.

Haemorrhage.

Hemosiderin deposition.

It can occur in severe:

Primary, secondary or tertiary hyperparathyroidism.

17. Gastrointestinal Features – “Groans”

Hypercalcaemia can cause:

Constipation.

Nausea.

Abdominal discomfort.

Reduced appetite.

More severe hypercalcaemia may produce:

Vomiting and dehydration.

18. Neuropsychiatric Features

Hypercalcaemia may produce:

Fatigue.

Muscle weakness.

Poor concentration.

Low mood or other neuropsychiatric symptoms.

Severe hypercalcaemia can cause:

Confusion

and eventually impaired consciousness.

19. Investigations in Primary Hyperparathyroidism

The original notes give:

↑ PTH

↑ serum calcium

↑ urinary calcium

↑ ALP

↓ serum phosphate.

This is a useful classical pattern, but several points require qualification.

20. Serum Calcium

The defining biochemical abnormality in classical primary hyperparathyroidism is:

Hypercalcaemia

together with PTH that is:

Elevated or inappropriately normal.

Why “inappropriately normal”?

When calcium is high, normal physiology should:

Suppress PTH.

Therefore even a PTH concentration within the laboratory reference range may be abnormal if it fails to suppress in the presence of hypercalcaemia.

21. Serum Phosphate

PTH causes:

Phosphaturia.

Therefore serum phosphate is commonly:

Low

or:

Low-normal.

Hence:

↑ Ca²⁺ + ↓ PO₄³⁻ + non-suppressed PTH → strongly suggests primary hyperparathyroidism.

22. Alkaline Phosphatase

The original notes state:

ALP ↑.

This can occur when PTH excess produces increased:

Bone turnover.

However, ALP may be:

Normal in mild disease.

Therefore a more accurate pattern is:

ALP normal or ↑.

Marked elevation suggests substantial skeletal involvement or another source of ALP that should be considered.

23. Vitamin D and Renal Function

Assessment commonly also includes:

Renal function.

25-hydroxyvitamin D.

Vitamin D deficiency may coexist with primary hyperparathyroidism and can influence:

PTH concentration and skeletal disease.

24. Imaging the Parathyroid Glands

An important principle is:

Primary hyperparathyroidism is diagnosed biochemically, not by imaging.

Imaging is generally performed after the biochemical diagnosis when surgery is being considered.

Its purpose is to:

Localise the abnormal gland or glands.

25. Localisation Studies

Localisation may involve:

Neck ultrasound.

Technetium-99m sestamibi imaging.

Additional imaging may be used in selected patients.

Therefore:

Blood tests establish the diagnosis.

Imaging helps plan surgery.

26. Treatment of Primary Hyperparathyroidism

The definitive treatment for appropriate patients is:

Parathyroidectomy.

Surgery is particularly considered when disease is symptomatic or when established guideline criteria are met, such as significant hypercalcaemia, skeletal involvement, renal involvement or particular age/risk considerations.

Patients who do not undergo surgery require appropriate:

Biochemical, renal and skeletal monitoring.

27. Secondary Hyperparathyroidism

The original notes correctly state that secondary hyperparathyroidism results from:

Compensatory enlargement and increased activity of the parathyroid glands in response to a chronic stimulus lowering calcium or disturbing mineral metabolism.

The glands themselves are initially responding appropriately.

Therefore:

Secondary hyperparathyroidism is compensatory rather than initially autonomous.

28. Chronic Kidney Disease – Major Cause

The classic cause is:

Chronic kidney disease.

As renal function declines:

Phosphate excretion decreases

and:

Calcitriol production decreases.

These changes disturb calcium-phosphate homeostasis and stimulate:

PTH secretion.

29. Mechanism in CKD

The sequence can be simplified as:

CKD

↓

↓ Phosphate excretion

↓

Phosphate retention

• ●

↓ Renal 1α-hydroxylation

↓

↓ Calcitriol

↓

↓ Intestinal calcium absorption

↓

Low/low-normal Ca²⁺

↓

↑ PTH.

FGF23 also increases early in CKD and contributes to reduced calcitriol production.

30. Parathyroid Hyperplasia

Persistent stimulation causes the parathyroid glands to undergo:

Hyperplasia.

Therefore:

LONG-STANDING CKD → CHRONIC PTH STIMULATION → PARATHYROID HYPERPLASIA → SECONDARY HYPERPARATHYROIDISM.

This contributes to:

CKD–mineral and bone disorder.

31. Biochemical Pattern in CKD Secondary Hyperparathyroidism

A typical pattern in advanced CKD is:

PTH ↑

Calcium ↓ or normal

Phosphate ↑

Calcitriol ↓

ALP normal or ↑, depending on bone turnover.

The combination of:

HIGH PTH + HIGH PHOSPHATE

is particularly suggestive of advanced CKD-related secondary hyperparathyroidism.

32. Renal Osteodystrophy

Longstanding secondary hyperparathyroidism can cause high-turnover bone disease known as:

Osteitis fibrosa.

This forms part of the broader spectrum of:

Renal osteodystrophy.

Patients may develop:

Bone pain.

Fractures.

Skeletal abnormalities.

33. Vitamin D Deficiency – Another Major Cause

Secondary hyperparathyroidism is not limited to renal failure.

Another very important cause is:

Vitamin D deficiency.

Reduced vitamin D causes:

↓ Intestinal calcium absorption

↓

Tendency toward ↓ Ca²⁺

↓

Compensatory ↑ PTH.

34. Pattern in Vitamin D Deficiency

Vitamin D deficiency with secondary hyperparathyroidism typically produces:

PTH ↑

Calcium ↓ or low-normal

Phosphate ↓

ALP ↑

25(OH) vitamin D ↓.

The phosphate is low because increased PTH causes:

Renal phosphate wasting.

35. Other Causes of Secondary Hyperparathyroidism

Other causes can include conditions that impair calcium or vitamin D availability, such as:

Malabsorption.

Low calcium intake in appropriate circumstances.

Disorders of vitamin D metabolism.

The unifying principle is:

The parathyroid glands are responding to a chronic physiological stimulus.

36. Treatment of Secondary Hyperparathyroidism

Treatment focuses primarily on:

Correcting the underlying stimulus.

In vitamin D deficiency this means:

Vitamin D replacement and adequate calcium intake.

In CKD, management may involve:

Phosphate control.

Dietary measures.

Phosphate binders when indicated.

Vitamin D or active vitamin D therapy in selected patients.

Calcimimetics such as cinacalcet in selected dialysis patients.

Management is guided by the overall pattern of:

Calcium + phosphate + PTH + ALP, rather than PTH alone.

37. Tertiary Hyperparathyroidism

The original notes correctly state that tertiary hyperparathyroidism develops as a consequence of:

Long-standing secondary hyperparathyroidism.

It is classically associated with:

Longstanding advanced CKD.

38. Development of Autonomy

During prolonged secondary hyperparathyroidism:

Chronic stimulation

↓

Parathyroid hyperplasia

↓

Progressive gland enlargement

↓

Reduced responsiveness to normal regulatory signals

↓

Autonomous PTH secretion.

At this point, PTH secretion continues even when calcium is no longer low.

This represents:

Tertiary hyperparathyroidism.

39. Calcium Rises in Tertiary Hyperparathyroidism

This is the key difference from secondary hyperparathyroidism.

In secondary disease:

PTH ↑

but calcium is usually:

Low or normal.

In tertiary disease:

PTH becomes autonomously very high

and calcium becomes:

High.

Therefore:

TERTIARY HYPERPARATHYROIDISM = HIGH PTH + HYPERCALCAEMIA AFTER LONG-STANDING SECONDARY HYPERPARATHYROIDISM.

40. Biochemical Pattern of Tertiary Hyperparathyroidism

The characteristic pattern is:

PTH ↑↑

Calcium ↑

Phosphate is often:

↑ in advanced CKD

because renal phosphate excretion remains impaired.

ALP may also be elevated when there is substantial:

High-turnover bone disease.

41. Secondary Versus Tertiary Hyperparathyroidism

The easiest distinction is the serum calcium.

SECONDARY HYPERPARATHYROIDISM DUE TO CKD

PTH:

↑

Calcium:

↓ or normal

Phosphate:

↑

TERTIARY HYPERPARATHYROIDISM

PTH:

↑↑

Calcium:

↑

Phosphate:

Often ↑ in advanced CKD.

Therefore:

CKD + HIGH PTH + LOW/NORMAL Ca → SECONDARY.

CKD + VERY HIGH PTH + HIGH Ca → CONSIDER TERTIARY.

42. Treatment of Tertiary Hyperparathyroidism

The original notes state:

Parathyroidectomy is the treatment of choice.

Surgery remains an important definitive treatment for severe or refractory autonomous hyperparathyroidism, particularly when there is significant:

Hypercalcaemia.

Bone disease.

Symptoms.

or failure of appropriate medical management.

However, modern management is individualised, and selected patients may also be treated medically with agents such as:

Calcimimetics.

Therefore parathyroidectomy should not be interpreted as automatically required in every patient.

43. Primary Hyperparathyroidism – Note Form

MECHANISM

Autonomous PTH secretion.

MOST COMMON CAUSE

Single parathyroid adenoma:

Approximately 80–85% of sporadic cases.

OTHER CAUSES

Multigland hyperplasia.

Multiple adenomas.

Rare parathyroid carcinoma.

Familial syndromes such as MEN1/MEN2A.

BIOCHEMISTRY

PTH:

↑ or inappropriately normal

Calcium:

↑

Phosphate:

↓ or low-normal

ALP:

Normal or ↑

Urinary calcium:

Often ↑, but variable.

CLINICAL FEATURES

Renal stones.

Bone disease.

Constipation/abdominal symptoms.

Fatigue and weakness.

Neuropsychiatric symptoms.

Often asymptomatic and detected through hypercalcaemia.

44. Secondary Hyperparathyroidism – Note Form

MECHANISM

Appropriate compensatory increase in PTH caused by chronic disturbances of calcium/phosphate/vitamin D metabolism.

MAJOR CAUSES

Chronic kidney disease.

Vitamin D deficiency.

Malabsorption and other causes of chronic calcium/vitamin D deficiency.

ADVANCED CKD PATTERN

PTH:

↑

Calcium:

↓ or normal

Phosphate:

↑

Calcitriol:

↓

VITAMIN D DEFICIENCY PATTERN

PTH:

↑

Calcium:

↓ or low-normal

Phosphate:

↓

ALP:

↑

25(OH)D:

↓

45. Tertiary Hyperparathyroidism – Note Form

MECHANISM

Long-standing secondary hyperparathyroidism

↓

Parathyroid hyperplasia

↓

Autonomous PTH secretion.

CLASSIC SETTING

Long-standing:

Advanced CKD.

BIOCHEMISTRY

PTH:

↑↑

Calcium:

↑

Phosphate:

Often ↑ in advanced CKD.

TREATMENT

Control CKD-related mineral abnormalities.

Calcimimetic therapy in selected patients.

Parathyroidectomy for severe/refractory disease when indicated.

46. Important Corrections to the Original Notes

The original:

“Single adenoma in >80%”

is a good high-yield rule.

A solitary adenoma causes approximately:

80–85% of sporadic primary hyperparathyroidism.

The original:

“↑ PTH, ↑ serum and urinary calcium, ↑ ALP and ↓ serum phosphate”

should be refined to:

PTH ↑ or inappropriately normal.

Serum calcium ↑.

Phosphate ↓ or low-normal.

ALP normal or ↑.

Urinary calcium often ↑ but variable.

The original secondary hyperparathyroidism mechanism is correct, but secondary disease is not caused only by:

Renal failure.

Another major cause is:

Vitamin D deficiency.

The original description of tertiary disease as:

“Further gland hyperplasia raises calcium levels”

is broadly correct, but the central concept is:

The hyperplastic parathyroid tissue becomes functionally autonomous after prolonged secondary stimulation.

Therefore:

PTH remains excessively elevated despite hypercalcaemia.

The original:

“Parathyroidectomy is the treatment of choice”

is most applicable to significant, refractory tertiary hyperparathyroidism requiring definitive treatment. Medical therapy, particularly:

Calcimimetics,

may also be appropriate in selected patients.

47. Key Biochemical Patterns

PRIMARY HYPERPARATHYROIDISM

Ca ↑ | PTH ↑ | PO₄ ↓

Think:

Parathyroid adenoma.

SECONDARY HYPERPARATHYROIDISM – CKD

Ca ↓/normal | PTH ↑ | PO₄ ↑

Think:

Phosphate retention + reduced calcitriol.

SECONDARY HYPERPARATHYROIDISM – VITAMIN D DEFICIENCY

Ca ↓/low-normal | PTH ↑ | PO₄ ↓ | ALP ↑

Think:

Reduced intestinal calcium absorption → compensatory PTH elevation.

TERTIARY HYPERPARATHYROIDISM

Ca ↑ | PTH ↑↑ | PO₄ often ↑ in advanced CKD

Think:

Long-standing secondary hyperparathyroidism → autonomous glands.

Key Clinical Pattern

The simplest way to distinguish the three forms is to ask:

WHY IS PTH HIGH, AND WHAT IS THE CALCIUM DOING?

PRIMARY:

The parathyroid gland itself is abnormal.

PTH ↑ → Ca ↑ → phosphate ↓.

SECONDARY:

The parathyroid gland is responding appropriately to another problem.

In CKD:

Ca ↓/normal → PTH ↑, with phosphate ↑.

In vitamin D deficiency:

Ca ↓/low-normal → PTH ↑, with phosphate ↓.

TERTIARY:

After prolonged secondary stimulation, the glands become:

AUTONOMOUS.

Therefore:

PTH ↑↑ + Ca ↑, usually in the setting of long-standing advanced CKD.

For examination recall:

PRIMARY = HIGH PTH + HIGH CALCIUM.

SECONDARY = HIGH PTH + LOW/NORMAL CALCIUM.

TERTIARY = VERY HIGH PTH + HIGH CALCIUM AFTER LONG-STANDING SECONDARY DISEASE.