Hyperparathyroidism and hypercalcaemic crisis Flashcards
Approach to hypercalcaemia
Hyperparathyroidism is a disorder of calcium metabolism associated with increased bone resorption
There are 3 types of hyperparathyroidism:
1. Primary hyperparathyroidism
2. Secondary hyperparathyroidism
3. Tertiary hyperparathyroidism
Primary hyperparathyroidism is the excessive PTH secretion causing increased bone resorption and resulting in hypercalcaemia.
Prevalence: 42 in 100,000
Gender predisposition: female > male (3:1), increases with age and post-menopausal women
Causes of primary hyperparathyroidism
_Causes-
1. Parathyroid adenoma (85%)
2. 4-gland hyperplasia (10%)
3. Multiple adenomas (<5%)
4. Parathyroid carcinoma (<1%)
5. Multiple endocrine neoplasia (MEN1 and 2a)
(Parathyroid adenomas can weigh 5-25g, world record 120g)
Pathogenesis of primary hyperparathyroidism
1. Reduced expression of CaSR reduces PTH suppressibility
2. Higher set point and non-suppressible PTH secretion results in bone turnover and hypercalcaemia
Clinical features of primary hyperparathyroidism
(Clinical features of hypercalcaemia)
85% patients are asymptomatic
Symptomatic - hypercalcaemia
(Stones, bones, groans, moans, overtones)
A. Renal
1. Polyuria, polydipsia
2. Chronic kidney disease
3. Renal tubular acidosis (type 1 - distal)
4. Hypercalciuria, nephrolithiasis, nephrocalcinosis
B. Neuromuscular and psychiatric
1. Proximal muscle weakness
2. Myalgia
3. Paraesthesia
4. Memory loss, fatigue, lethargy, confusion
5. Depression
6. Psychosis, neurosis
C. Skeletal
1. Bone pain
2. Osteoporosis
3. Subperiosteal resorption
4. Osteitis fibrosa
5. Arthralgia, synovitis, arthritis
D. Gastrointestinal
1. Abdominal pain, nausea
2. Heartburn
3. Peptic ulcer
4. Constipation
5. Pancreatitis
E. Others
1. Ophthalmology - band keratopathy
2. Haematology - anaemia
3. Hypertension (PTH/hyperCa vasoconstriction)
4. Prolonged QTc
5. Bradycardia
What are the ECG manifestations of hypercalcaemia?
- Prolonged QTc
- Bradycardia
Band keratopathy is an irregular region of calcium phosphate deposition at medial and lateral limbic margins of outer edges of cornea
Diffusion of carbon dioxide from air-exposed areas of cornea causes reduced acidity and alkaline environment that favours precipitation of calcium phosphate crystals
Diagnosis made by slit lamp examination
Diagnostic investigations for primary hyperparathyroidism
Diagnostic Investigations
1. Elevated serum PTH level
2. Hypercalcaemia
3. Hypophosphataemia and hyperchloraemia (CI/PO4 ratio > 33)
4. Hypercalciuria - 24H urine Ca > 200-300mg/day
5. Calcium to creatinine ratio > 0.02
Elevated PTH + hypercalcaemia in 80-90%
Normal PTH + hypercalcaemia in 10-20%
Rarely elevated PTH + normocalcaemia in 1%
Supportive Investigations
1. Elevated urine pH > 6
2. Increased ALP
3. Vitamin D level
4. Radiological findings - subperiosteal bone resorption, salt and pepper skull, osteopenia, osteoporosis
5. Bone mineral density scan
Localising PTH tumour
1. SPECT
2. Ultrasound of parathyroid gland
3. CT parathyroid gland with contrast
Hypercalcaemia diagnosis algorithm
- Serum calcium level
- PTH level
- 24-hour urine calcium
- Vitamin D level
- PTHrP
- Multiple myeloma panel
- TFT - hyperthyroidism
Diagnostic dilemmas of hyperparathyroidism
- Age
- CKD
- Familial hypocalciuric hypocalcaemia
How does age complicate diagnosis of hyperparathyroidism?
With aging - PTH increases and calcium decreases
1. Age-related renal function decline
2. Reduced vitamin D synthesis
3. Reduced calcium absorption, hypoalbuminaemia
PTH in normal upper range more suspicious of primary hyperparathyroidism in younger age than those > 50 years old
How does CKD complicate diagnosis of PHPT?
A. Secondary hyperparathyroidism due to:
1. Hyperphosphataemia
2. Reduced vitamin D (calcitriol) levels
3. Resultant hypocalcaemia and vicious cycle further increasing PTH secretion
B. Similar signs and symptoms
- Lethargy, depression, anorexia, nausea
- Constipation
- Weakness
Changes in renal failure on PTH assay
- Stimulatory effect of hyperphosphataemia and low calcitriol level increases PTH level
- Non-PTH molecular fragment (with PTH antagonistic action) accumulation due to failure to excrete
PTH may be 1.5 to 3 times higher in renal failure
What differentiates familial hypocalciuric hypercalcaemia from PHPT?
Autosomal dominant
Loss of function mutation in CaSR
Family history of hypercalcaemia
Serum calcium and PTH levels both elevated
Urine calcium < 50mg/day
Fraction excretion of calcium (FECa) low < 1%
(PHPT usually > 2%)
Pathophysiology of secondary hyperparathyroidism
- Excessive PTH secretion as compensatory response to consequence of renal failure
- Hyperphosphataemia, hypocalcaemia, low calcitriol level and excess FGF23 - Parathyroid hyperplasia to enhance PTH secretory capacity
Pathophysiology of tertiary hyperparathyroidism
- Prolonged secondary hyperparathyroidism results in parathyroid hyperplasia and autonomous secretion of PTH
- Eventual change from hypocalcaemia to normocalcaemia to hypercalcaemia
- PTH levels > 15 times upper limit normal - Treatment involving resection of at least 3 and 1/2 parathyroid glands
Differentiating humoral hypercalcaemia of malignancy (HHM) from PHPT
Levels of intact PTH and PTHrP
What types of cancer most commonly cause hypercalcaemia of malignancy?
A. Squamous cell carcinoma
1. Lung cancer - squamous cell carcinoma
2. Head and neck squamous cell ca
3. Oesophageal squamous cell ca
B. Adenocarcinoma
1. Breast cancer
2. Renal cell carcinoma
3. Bladder cancer
4. Pancreatic cancer
5. Ovarian cancer
C. Haematological
1. Non-Hodgkin’s lymphoma
2. CML
How do PTHrP and PTH differ?
PTHrP is structurally similar to iPTH allowing to bind and stimulate same receptor causing hypercalcaemia
PTHrP secretion is continuous by malignant cells; PTH secretion is intermittent and affected by negative feedback mechanism
Continuous PTHrP secretion reduces vitamin D levels via reduced 1-alpha-hydroxylase activity
What are the indications for parathyroidectomy in asymptomatic PHPT?
- Serum calcium above ULN
- Reduced BMD T < -2.5
- eGFR < 60
- Calcium nephrolithiasis or nephrocalcinosis
- 24-hour urine calcium > 400mg/day
- Age < 50 years
- Patient preference
Management of PHPT
- Aggressive management of hypercalcaemia crisis
- Biphosphonate - inhibit osteoclast bone resorption
(Alternative raloxifen, denosumab) - Calcimimetics: cinacalcet, etelcalcetide
- Parathyroid resection
Hypercalcaemic crisis occurs when serum calcium > 3.5mmol/L with associated symptoms:
- Nausea, vomiting
- Dehydration and AKI
- Altered mental status
- ECG changes and arrhythmias: short QTc, first degree block, scooped STe V1-V5, STd inferior
Management of hypercalcaemic crisis
- Hyperhydration (200-300mL/hr)
- Maintain urine output 100-150mL/hr - Calcitonin - SC or IM 4-8 IU/kg, repeat 6-12 hours for up to 48 hours
- Zoledronic acid - IV 4mg over 15 minutes
- Denosumab - SC 120mg every 4 weeks
- Prednisolone 60mg OD for up to 10 days
- Dialysis in refractory case
Mechanism of actions of management of hypercalcaemic crisis
- Hydration
- Furosemide
- Calcitonin
- Biphosphonates
- Denosumab
- Calcimimetics
- Dialysis
Hydration: increases NaCl delivery to proximal tubules, causing increased calcium excretion
Furosemide: inhibits transport of NaCl at loop of Henle
Calcitonin: reduces bone resorption via interface with osteoclastic function (careful of tachyphylaxis)
Biphosphonates: Inhibit calcium release by interfering with osteoclast-mediated bone resorption (slow)
Denosumab: Monoclonal antibody against RANK ligand preventing activation of osteoclast
Calcimimetics: Reduces calcium by causing allosteric activation of the calcium-sensing receptor (correction of hyperparathyroidism)
Dialysis: removes calcium
