Hyperparathyroidism

Excess synthesis and secretion of PTH by abnormal parathyroid glands

Primary: autonomous overproduction by one or more abnormal parathyroid glands (most common type)

Risk factors
- Female (4:1)
- Age 50-60
- Exposure to external beam radiation in the cervical region, with a latency period of 15-40 years
  - Exposure during nuclear accidents
  - Exposure during external radiotherapy
  - Exposure during RAI
- Lithium therapy
  - Decreases the parathyroid cells' sensitivity to calcium by interfering with the CaSR
  - Usually stopping lithium reverts the calcium to normal
- Thiazide diuretics
  - If the calcium remains abnormal after stopping the drug, treat it as unrelated
Aetiology
- 80% of PHPT results from clonal expansion of Chief cells in a single gland (parathyroid adenoma)
- 15% from four-gland parathyroid hyperplasia
- 4% adenomatous expansion in two or three of the four glands
- 1% parathyroid carcinoma
  - Very high blood calcium and PTH levels (>14mg/dL and >300pg/mL respectively)
Pathophysiology
- Increased serum calcium levels from PTH-mediated increases in bone resorption, renal calcium reabsorption, and indirectly from increased dietary absorption
- This should normally suppress PTH production, but parathyroid cells in parathyroid adenoma/carcinoma have a lower than normal sensitivity to the inhibitory action of calcium, so a higher than normal calcium level is maintained
- With parathyroid hyperplasia, the cells have the same sensitivity to calcium, but there are more of them, which is sufficient to cause hypercalcaemia
- Multi-gland disease (either four-gland hyperplasia or double adenoma) occurs in about 10-15% of all patients with PHPT
Genetic syndromes (3-5% of all patients with PHPT)
- MEN1: PHPT in 100%
- MEN 2a: PHPT in 20-30%
- Familial isolated HPT (FIHP)
  - Autosomal dominant
- HPT-JT - primary HPT in 80%, ossifying fibromas of mandible and maxilla, renal cysts, hamartomas, Wilms tumours, uterine tumours. Mutation in CDC73 leading to a defect in parafibromin.
Presentation
- 80% diagnosed from incidental hypercalcaemia
- 35% of patients have objective end-organ effects at time of diagnosis; 62% develop end-organ effects within 5 years of diagnosis
Diagnosis
- Defined by hypercalcaemia associated with an elevated intact PTH level or inappropriately normal intact PTH level
  - Differentials for high calcium and PTH:
    - Primary vitamin D deficiency - if vitamin D is low, this should be fixed with supplementation for six months before retesting for PHPT
    - Familial Hypocalciuric Hypercalcaemia - need to exclude with 24 hour urine calcium levels (<100mg in 24 hours is diagnostic. Most PHPT patients will have high urine calcium, by contrast)
      - Rare autosomal dominant disorder affecting renal CaSR that results in a higher set point for renal calcium excretion, hypocalciuria, asymptomatic hypercalcaemia, and normal or mildly elevated PTH levels.
      - Won't have the clinical manifestations of primary HPT
      - High penetrance - if they have it, they will normally develop high calcium by the age of 30, so it is uncommon to be the reason a post-menopausal woman is getting symptomatic hypercalcaemia
      - No treatment is required
    - Prolonged lithium or thiazide therapy - see above
    - Tertiary hyperparathyroidism
- Normal calcium and high PTH is a recognised variant - generally found during workup for kidney stones. Up to 16% of those patients will progress to standard PHPT
  - Consider other causes of elevated PTH - vitamin D deficiency, renal insufficiency, primary hypercalciuria, malabsorption syndromes, bisphosphonates, denosumab
- High calcium and normal PTH is another variant - normohormonal HPT. This is very uncommon and something of a diagnosis of exclusion. Rule out other causes of hypercalcaemia and obtain biochemical measurements at multiple time points. Hard to know who to operate on, but consider operating on those with positive localising studies. Same signs and symptoms, with similar cure rates after surgery, are reported.
Workup
- If PHPT is suspected, consider parathyroid adenoma, parathyroid hyperplasia, and parathyroid carcinoma
  - Serum total calcium (classically on three separate occasions)
  - Intact PTH
  - Creatinine
  - 25(OH)D levels
  - LFTs for albumin and ALP (marker of bone turnover)
  - Serum phosphate (low in 50% of patients with primary HPT)
  - Parathyroid imaging has no role in confirming or excluding the diagnosis of HPT
- After diagnosis of PHPT is confirmed:
  - All patients should be screened for osteoporosis/osteopaenia with DXA bone mineral density scan
  - 24-hour urine calcium and creatinine (exclude FHH, and check indication for surgery) - done for every patient at Alfred
  - Abdominal imaging to look for kidney stones
  - Vertebral spine assessment (can be seen on DXA)
  - Genetic testing (MEN1) - patients with PHPT <40yo with multi-gland disease, and patients with either a family history PHPT or syndromes associated with it
  - Parathyroid imaging - helps focus the exploration and to identify ectopic parathyroid glands, but does not alter the recommendation for exploration
    - Start off with USS and Sestamibi-SPECT
    - See 'thyroid imaging' section for further

Treatment
- Approach
  - If meet an indication for surgery - surgery
  - If not - surveillance with six-monthly bloods and USS
  - If meet an indication for surgery but can't or won't have surgery - medical treatment
- Indications for surgery:
  - Symptomatic/complicated hypercalcaemia 'stones, bones, abdominal groans, psychiatric overtones'
    - Nephrolithiasis
    - Fractures, osteoporosis/osteopaenia
    - Depression/other neurologic symptoms including trouble concentrating
    - Abdominal pain - PUD, pancreatitis
  - Asymptomatic PHPT
    - Age <50 (more cost-effective to operate than surveil)
    - Serum calcium >0.25mmol/L above ULN
    - 24 hour urine calcium >400mg (10mmol)
    - eGFR < 60 or nephrolithiasis/nephrocalcinosis
    - BMD with T-score <-2.5 or significant reduction or documented vertebral fracture
    - When active surveillance and routine long-term follow-up is not a good option
- Medical treatment
  - For patients who meet surgical criteria but aren't candidates
  - Indication: symptomatic/severe hypercalcaemia: cinacalcet (expensive, non-durable)
    - Binds to the calcium-sensing receptor on parathyroid cells to increase its sensitivity for the high serum calcium, and thus reduce serum PTH
  - Indication: osteoporosis: bisphosphonates (alendronate)
  - If neither of the above, then use neither
- Non-op management for those asymptomatic patients not having surgery
  - Annual serum calcium and creatinine
  - Bone density every one to two years
  - Investigate symptoms that may suggest develop of an indication for surgery
  - If progression, surgery
  - Preventative measures
    - Avoid thiazide diuretics + lithium
    - Encourage physical activity to minimise bone resorption
    - Encourage adequate hydration to prevent nephrolithiasis
    - Maintain moderate calcium and vitamin d intake
Localisation
- Concordant USS Technitium-99m sestamibi scan +/- SPECT has a sensitivity 94-99% for finding a single adenoma
- Sestamibi can also locate ectopic disease, including abnormal inferior parathyroid glands descending into mediastinum
- Other modalities
  - 4D CT (use if USS and sestamibi fail)
  - MRI
  - Venography with venous sampling
- If unable to localise with imaging: often have multi-gland disease, and should undergo bilateral neck/four gland exploration
- Intra-operative adjuncts
  - Blood PTH testing - half life is 2-4 minutes, so levels should drop rapidly after successful excision. Failure to drop should prompt further exploration. Successful drop should conclude operation and remove need for further exploration.
  - Gamma probe parathyroid adenoma localisation - sestamibi is preferentially retained by parathyroid glands compared to thyroid tissue. However this is apparently not that useful in practice.
Prognosis/outcomes
- Cure rates (defined as normal calcium at 6 months) 95-99%
- Surgical cure is followed by increased BMD by 2-4% in the first year
- Decreases hip and wrist fracture by 50-64% at 10 years
- Decreased rate of recurrent kidney stones
- Further decline in eGFR will be prevented
- Neurocognitive symptoms attributed to HPT show variable improvement

Secondary: appropriate elevation in PTH levels due to a separate source of hypocalcaemia e.g. renal failure

Aetiology
- CKD - 90% of patients on dialysis have SHPT
  - Chronic hypocalcaemia secondary to hyperphosphataemia and low levels of biologically active vitamin D
  - Leads to PTH hypersecretion, parathyroid cell proliferation, and parathyroid gland hyperplasia
- Vitamin D deficiency - causes increased secretion PTH
- GIT malabsorption due to chronic disease
  - Coeliac
  - CF
  - Short gut syndrome
  - Bariatric procedures
- Medications
  - Lithium
  - Diuretics
- Metabolic abnormalities
  - Hypermagnesaemia
  - Hyperphosphataemia
- Congenital disorders
  - Transient neonatal hyperparathyroidism
  - DiGeorge syndrome
Symptoms
- As above - also calciphylaxis - painful cutaneous purpuric lesions - if this is present, severe HPT is probably present, and parathyroidectomy should be offered
Treatment
- Initially managed medically
  - Vitamin D deficiency/hypocalcaemia
    - 1000-1200mg calcium per day + vitamin D supplementation to maintain serum 25(OH)D >30ng/mL
  - CKD - most can be managed medically
    - Dietary phosphate reduction, phosphate binders, oral calcium and calcitriol supplementation, IV vitamin D analogues, and dialysis
    - Calcium and calcitriol slow progression of HPT until patient can undergo renal transplantation
    - Calcimimetics - cinacalcet - reduces PTH secretion through direct action on parathyroid gland. Used in non-transplant candidates, but not generally used on transplant candidates.
- Parathyroidectomy
  - Required in almost half of dialysis patients eventually, if they live long enough
  - Indications (highly variable between surgeons)
    - PTH > 800pg/mL
    - Sustained hypercalcaemia
    - Refractory hyperphosphataemia
    - Elevation of calcium-phosphorus product > 55mg/dL
    - Severe symptomatic bone disease
    - Calciphylaxis
      - Calcific uraemic arteriolopathy
      - Microvascular calcification, intimal proliferation, fibrosis, and thrombotic occlusion of small subcutaneous vessels
      - Predominantly seen in ESKD and secondary HPT
      - Painful non-healing wounds with areas of skin necrosis, which can lead to secondary infection, sepsis and death
      - Debride only to control sepsis, but not dry eschar
    - Consider for intractable pruritis, profound muscle weakness, intolerance to cinacalcet, and symptomatic ectopic extraosseous calcification (calcinosis)
  - Pre-op
    - Should have pre-op localisation to ensure no supernumerary glands
  - Choice of procedure
    - Total parathyroidectomy
    - Total parathyroidectomy with autologous transplantation
    - Subtotal parathyroidectomy - preferred
      - Higher rate of recurrence, but lower rate of hypoparathyroidism

Tertiary: Persisting hyperparathyroidism after correction of the cause of secondary hyperparathyroidism.

Occurs due to permanent changes in parathyroid gland that persist after correction of hypocalcaemia - increase in parathyroid cell mass, rather than the calcium set-point
Needs correcting with parathyroidectomy (cures >90% of cases)
Often occurs after renal transplant (25% of patients with secondary HPT will have tertiary at 1 year post transplant, which is associated with graft loss and poor survival)
Diagnosis
- Elevated serum calcium and intact PTH levels
Treatment
- Approach
  - Surgery is superior to cinacalcet in normalising calcium and PTH at 1 year post-op, as well as lower rates of graft failure
- Medical
  - Cinacalcet
- Surgical indications
  - Severe hypercalcaemia (>3.12mmol/L)
  - Persistent hypercalcaemia >3 months after surgery (>2.54mmol/L)
  - Osteoporosis
  - Symptomatic hyperparathyroidism
  - Renal phosphorus wasting
  - Nephrocalcinosis
  - Consider pretransplant parathyroidectomy in patients with tertiary HPT
- Post-op care
  - Profound hypocalcaemia is common - attributed to renal osteodystrophy and 'hungry bone syndrome' and occurs due to the sudden decline in circulating PTH levels after surgery, causing a surge in bone uptake of calcium/phosphate/magnesium as a result of remineralisation
  - May or may not experience symptoms
  - Usually require admission for 3-5 days with oral and IC calcium and calcitriol
  - Correction of associated hypomagnesaemia is often required
  - Calcitriol should be loaded beforehand for 5 days - it takes 48 hours to work

Recurrent PHPT

Epidemiology
- 1-5% of sporadic primary HPT, higher familial/renal HPT
Aetiology
- Persistent (PTH never normalises post-op)
  - Missed glands (most common)
    - Commonly there will be an ectopic gland
  - Multi-gland disease
  - Incomplete resection of a single gland
  - Parathyroid cancer
- Recurrent HPT (calcium normalises then goes up again)
  - Multi-gland disease
  - MEN type 1
  - Parathyroid cancer
  - Regrowth of remnant
  - Parathyromatosis
Workup
- Biochemical tests all over again, but need to wait 6 months post-op for equilibration of PTH
- Be sure to consider genetic syndromes especially in young patients
- Exclude FHH if not already done
- Minimum of two concordant imaging studies for operative planning
- If re-operating will need laryngoscopy
Treatment
- If location of single missed gland is confirmed, CAN re-operate
  - Stricter indications second time around: (higher rate of RLN injury and hypoparathyroidism)
    - Worrisome hypercalcaemia
    - Ongoing nephrolithiasis
    - Worsening bone disease
    - Worsening renal function
    - Associated psychiatric symptoms
    - Associated neuromuscular symptoms
- If multifocal disease is suspected, review location of glands removed, plan completion, subtotal parathyroidectomy
- If culprit glands are not identified, continue monitoring and re-evaluate with new imaging in 1-2 years
  - Blind explorations should not be performed
Technique for re-operation
- Can use lateral incision if initial approach was central

Differential diagnosis of primary hyperparathyroidism, typical laboratory findings

Disease	Laboratory test
	Intact PTH	Serum calcium	Urinary calcium (mg/24 hours)	Ca/Cr clearance	25OHD
PHPT	High-normal or elevated	Elevated	Normal or elevated	0.01 to 0.05 (>0.02)	Normal, low-normal, or low
Malignancy	Low (<20 pg/mL)	Elevated	Generally high		Depends on malignancy*
FHH	Normal, mildly elevated in 15 to 20 percent	Elevated	Generally low (<100)	<0.01	Normal
PHPT with vitamin D deficiency	Elevated	Normal or elevated	Low-normal or low (<200)		Low (<20 ng/mL)
Normocalcemic PHPT	Elevated	Normal	Normal		Normal
Secondary hyperparathyroidism due to vitamin D deficiency	Elevated	Normal or low	Low		Low (<20 ng/mL)