Primary Hyperparathyroidism

DEFINITION

High PTH levels, resulting in hypercalcaemia, as a result of parathyroid tumours or hyperplasia

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EPIDEMIOLOGY

Most common cause of hypercalcaemia.

Genetics
HPT occurs in virtually all patients with MEN1 and 25% of MEN2
'Jaw Tumour Syndrome':
- AD, hyperparathyroidism, fibromas of maxilla and mandible, kidney (possible: polycystic, Wilm's, nephroblastoma)
'Familial isolated hyperparathyroidism':
- AD, may be a variant of MEN1 but with HPT only.

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AETIOLOGY

1. Parathyroid Hyperplasia (5% or less; probably much over-reported and prob 1.5%)

2. Parathyroid Adenomas (95%+)
-2x adenomas in up to 15% of pts

3. Parathyroid Cancer (<1%; over-reported; actually extremely rare <<1%)


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BIOLOGICAL BEHAVIOUR

See below


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MANIFESTATIONS

Most patients are diagnosed incidentally during lab tests or work-up for other diseases.

Hypercalcaemia:

Bone pain, osteopenia, joint pain.
Kidney stones
Constipation
Urinary frequency and incontinence
Pancreatitis
Fatigue, muscle weakness, difficulty concentrating
Nausea and vomiting
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INVESTIGATIONS

PTH Values
Normal PTH 10-72 pg/mL (in Aus/NZ we use units 1-7)
- if Calcium elevated and PTH elevated (e.g. 92), then PTH (i.e. 9)
- if Calcium elevated and PTH normal (e.g. 49), then mild disease definite as non-suppressed; quite common;
- if Calcium normal and PTH high (e.g. 81), then mild disease probable (normocalcaemic hyperparathyroidism); need to do a urinary calcium (only indication).
Note:
- Classic disease shows both elevated calcium and PTH = vast majority of patients
- But may only have a high calcium or PTH on some days or testing.
- And many can have elevated calcium and normal but nonsuppressed PTH
- PTH should be suppressed to NEAR ZERO if hypercalcaemia due to another cause.
- 'mild' disease above probably not so mild and will strongly benefit from surgery; just that Ca may not be dramatic on the measured day
- Cancer suspected with very high levels (Ca grossly elevated and PTH >300 pg/mL) (>30 here)
- beware pts with past gastric bypass or intestinal resection / other GI disease who may be malabsorbing calcium; here physiological response is elevated PTH to maintain Ca++, causing bone density depletion; need supplements.

Familial hypocalciuric hypercalcemia
Is very very rare, your patient is extremely unlikely to have this.
Asymptomatic, with high blood calcium and low urinary calcium
But note : a significant proportion of pts with hyperparathyroidism will have low urinary calcium as well, and this is far more common / likely diagnosis than FHH
--> if blood calcium is high and pth>4 then they have primary hyperparathyroidism.
--> if blood calcium and high and pth is 2-4, then they still probably have primary hyperparathyroidism
The only time you need to measure 24h calcium is if the calcium is normal or perhaps only mildly elevated and pth <6
Even then, if urinary Ca is low, pt still very likely has PHP rather than FHH, which is exceedingly uncommon
--> need a familial lineage / genetic test to diagnose FHH, and that genetic test is often equivocal.

Vitamin D?
Most patients with PHP will have very low or low Vit D levels; some will have normal.
Low vitamin D does not cause a high PTH or resultant hypercalcaemia; does not happen.
Finding a low vitamin D makes the diagnosis of PHP more likely (and in particular tumour); not less likely.
- physiological response to hypercalcaemia is to reduce Vit D to reduce gut absorption of calcium
Don't go chasing secondary hyperparathyroidism due to low Vit D.

Calcium
Normal 2.1 - 2.5
PTH causes increase bone resporption, decreased bone calcium and increased urinary Ca absorpotion.

Differentiation from Secondary Hyperparathyroidism
Response to hyperphosphataemia; leads to elevated PTH.
These patients generally have such severe renal dysfunction that they are on dialysis.
Confusion arises because PHP can cause significant deterioration in renal function; but if severe renal dysfx and on dialysis for years then secondary.

Do not image for diagnostics
Sestamibi is not a diagnostic test but a pre-op localization test; if negative it means nothing for diagnosis

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MANAGEMENT

Indications for Surgery
Surgery is the only curative therapy for Primary HPT.
Any patient with features of HPT should be referred for surgery.

Asymptomatic?

Consensus guidelines recommend surgery for asymptomatic patients with:
-  reduced renal function (EGFR<60) or calculi
-  osteoporosis (T score <-2.5 and <50y)
-  serum calcium >3
But probably all should be offered surgery as there are multiple benefits that may become apparent:
- better renal function and bone density improves; ALL pts will develop osteoporosis
- neuropsychiatric symptoms
- QOL improves
- 10% reduction in survival duration if untreated
- increased cardiovascular complications
- low complications and lower cost than surveillance.
- natural history is worsening disease.
Also if peptic ulcer; consider MEN
--> all patients fit for relatively minor surgery should undergo MIP

Risks?
RLN<1%
Failure 2% or so in the right hands
Haematoma or infection = 1% or less each in the right hands

Pre-Op Localization
The old adage is that the best localization study is an experienced surgeon;
But all patients should still undergo imaging localization prior to surgery
- note that localization studies should isolate the lesion; patients with negative studies still have primary HPT
Algorithm:
image

70-75% will have +ve SPECT
--> proceed to minimally invasive surgery
- sestamibi retained in parathyroids a lot longer than thyroid;
- 12-25% FN rate, often unrevealing in hyperplasia, multiple adenomas, coexisting thyroid disease
Negative SPECT;
--> proceed to USS; if positive, proceed to minimally invasive surgery.

Jugular venous sampling
is a highly specialised procedure performed in some institutions intra-operatively.
- USS guidance, retrieve blood from jugulars; sent for PTH
--> if >10% difference, positive for lateralizing.
--> can attempt minimally invasive parathyroidectomy on that side.
Sometimes MRI can be helpful in recurrent disease.

Ultrasound
image
SPECT
image

Combined SPECT and USS modalities essential
SPECT alone may be confused for a thyroid nodule
USS will show any thyroid nodules
IF SPECT AND USS AGREE = 99% likely to be a parathyroid adenoma.
- USS may miss lesions deep in neck and in upper mediastinum
What if co-localization -ve?
Do a triple phase CT = parathyroid handles contrast differently and will wash out differently cf thyroid tissue.

Word from Victoria Training Day
Eligible for MIP if:
- Primary HPT
- positive pre-op localization
- non-familial disease
You do not need:
- gamma probes (unless you're a high volume pro)
- intra-operative PTH
- nerve monitoring
- videoscopic
Instead, you need:
- experienced surgeon with good technique
- good radiology / nuclear med unit.

Intra-operative Adjuncts
1. Gamma-probe
- inject 10 mCi sestamibi 1h prior to surgery
- radioguided by hyperfunctioning glands that take up and retain sestamibi longer than surrounding tissues.
- handheld gamma probe can localize and confirm hyperfunctioning gland.
- scan for in-vivo counts higher than background, resect, the recount; if 20% increase in count from resected tissue then positive.
--> helpful for all patients, even those with apparently negative sestamibi scans.
--> decreases operative failures and improves operating time.
2. Intra-operative PTH testing
Confirms all hyperfunctioning parathyroid tissue excised.
PTH has a half life of only 2-4 minutes.  Turnaround time 8-20min.
- so after 5mins from resection, PTH level should fall 50%. Requires at least 4 samples (vs pre-incision or pre-excision)
- but if a 2nd hyperfunctioning gland is present, then this will become clear and it will need to be found.
--> increases operative success

Minimally Invasive Parathyroidectomy
Preparation
Target lesion on imaging with unilateral exploration
Give 10 mCi Tc-99m sestamibi IV 1h pre-op
Second IV for blood sampling.
Steps
1. Place patient with neck extended, head ring, IV bag behind shoulders.
- infuse local at Erb's point
2. Transverse incision below the cricoid (1.5-3cm)
- divide platysma transversely.
- no need to raise flaps.
3. Strap muscles separated vertically in the midline.
- muscles separated off thyroid
4. Thyroid rolled gently medially with a dissector
- may need to divide the middle thyroid vein if in the way
5. Scan with gamma probe
- find, then dissect off gland with a sharp clamp and divide its vascular pedicle with a clip.
- send for frozen section to confirm parathyroid tissue
- (pros in high volume centres do not do frozen sections as they don't need it for reassurance and maybe use gamma probes instead).
- e.g. see parathyroid.com
6. PTH levels from second peripheral IV 5,10,15 minutes later
--> decrease of 50% from baseline is confirmatory.
7. Close in layers with 2-0 vicryl / 3-0 vicryl then monocryl
8. Post-op PTH level in recovery to confirm
--> if does not fall, bilateral exploration indicated due to small rate of having 2 adenomas.

Calcium
600 mg caltrate tds
- calcitriol 0.5mcg bd
reduced dose of calcium long term as osteoporotic
dormant parathyroids take a few weeks to recover.

Bilateral Exploration
Indications:
- PTH level does not fall after unilateral exploration
- localization studies were negative.
- suspected dual adenomas or 4-gland hyperplasia, e.g. MEN1
- surgeon or patient preference.
- some surgeons do this routinely.
Steps.
1. Incision as above (~3cm)
2. Gamma-probe and intraoperative PTH testing in same manner.=(?)

Inferior glands
Usually located just posterior to the inferior lobe
- and superficial and medial to the RLN
- within 2cm of where RLN crosses inf. thyroid artery
Sometimes found within the thyrothymic ligament or even thymus.

Superior gland
Frequently found posterior to the upper pole, just lateral to the insertion of the recurrent nerve into the larynx.
- commonly on the tubercle of Zuckerkandl
- deep to RLN

How many glands?
80-90% have 4
4-20% have 5
1-4% have 3
<1% have 2,6, or 7

How big is a normal gland?
30-60mg ie pretty tiny

Hyperplasia?
Subtotal (3.5 gland) or total (reimplantation into forearm) implicated
- prefer total and reimplantation of 5-10 pieces of 1-3mm in size into non-dominant forearm muscle.
- or subtotal in older people
- can cryopreserve non-transplanted tissue in case needed
Patients with MEN1 and young patients with  non-familial 4 gland disease.

Steps to Find a Missing Parathyroid Gland
1. Perform bilateral IJV sampling for PTH
2. Look into retroesophageal space
3. Perform cervical thymectomy
4. Open carotid sheath
5. Search for undescended gland, occasionally in undescended thymic tissue.
6. Intra-operative USS of thyroid gland.
7. If gland still cannot be found, terminate the operation; leave normal gland intact.
- never resect a normal gland.
- never perform a median sternotomy in absence of definitive localization.
Locations:
image

Post-op Care
1. If total, then it takes 2-4w for glands to recover.
- Need oral calcium and calcitriol for 2-4 weeks.
2. Review at 1 week, obtain calcium and PTH levels.
- n.b. 20-25% will have elevated PTH with normal post-op calcium; physiological adaption / reactionary secondary HPT.
--> fixed by vitamin D and calcium supplementation; serum Ca and PTH after 6m
- (but persistent PTH and calcium = a worry for persistent disease; below)
- all pts with elevated Calcium post-op should have 24h urinary calcium measurements; <30 mg suggests benign familial hypocalciuric hypercalcemia.
Cure is defined as normal serum calcium >6m post-op
3. Yearly serum calcium after successful parathyroidectomy, because 2-3% pts get recurrence.


Persistent / Recurrent Hyperparathyroidism

Persistent HPT
Continuation or redevelopment of HPT within 6m of previous surgery.
--> usually because original resection was inadequate.
- minimized by high-volume surgeons and adjuncts e.g. intraoperative rapid PTH assay.

Recurrent HPT
:
Development of HPT 6m+ after successful surgery
-- > due to development of hyperfunctioning parathyroid tissue
 E.g. adenoma, hyperplasia, carcinoma, parathyromatosis (seeding of aberrant parathyroid cells after contamination of the operative field).
Less common than persistent disease, but frequent in familial HPT.


Algorithm for management
image

Indications for Reoperation
Morbidity from high PTH / Ca includes:
Hypercalcaemia causes neophrolithiasis, which can damage the kidneys
Ostopenia, osteoporosis and pathological fractures.
Depression, emotional lability,
Careful evidence of bone resorption and neurocognitive symptoms
--> improve following successful surgery.
Indications include:
-
Ca++ >0.25mmol/L above normal.
- creat clearance <60 mL/min
- bone mineral density T <2.5 at any site or prevoius fragility fractures
- age <50
- unable to comply with biannual surveillance

Supernumerary glands
Remember that supernumerary glands are present in 8% of the population.
- normal glands can also occur in ectopic locations:
- mediastinum / thymus, carotid sheath, adjacent to cervical vertebral bodies, within thyroid gland.

Operative Principles

1. High volume surgeons = better outcomes.
2. Full personal, family and medical history
3. Confirm biochemistry.
4. Preoperative localization.
- US and MIBI
+/- FNA; if aspirate PTH > 1000 pg/mL, confirmative; helps planning
- MRI and CT also useful in remedial cases.
--> be cautious if cannot localize the gland.
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REFERENCES

Cameron 10th