Treatments: Hyperparathyroidism

Hyperparathyroidism is a condition in which too much parathyroid hormone is produced. This occurs when one or more parathyroid glands loses its ability to reduce parathyroid hormone production when it is appropriate to do so.

parathyroidectomy

What are the reasons/indications for undertaking parathyroidectomy?

Parathyroidectomy is the only curative treatment for primary hyperparathyroidism (PHPT) and is also indicated in medically refractory secondary and tertiary hyperparathyroidism. The indications vary by clinical context.

1. Primary Hyperparathyroidism:

All patients with symptomatic PHPT (classic features: hypercalcemia symptoms, nephrolithiasis, osteitis fibrosa cystica) should undergo parathyroidectomy (strong recommendation) (JAMA Surg).

For asymptomatic PHPT, the Fifth International Workshop (2022) and the American Association of Endocrine Surgeons (AAES) recommend parathyroidectomy if any one of the following criteria is met: (JAMA Surg , JAMA, Cochrane Library, NEJM).

• Serum calcium >1.0 mg/dL above the upper limit of normal

• Osteoporosis (DXA T-score ≤ −2.5 at lumbar spine, hip, or distal 1/3 radius)

• Vertebral fracture on imaging or fragility fracture

• Renal impairment (GFR <60 mL/min, or consistent annual GFR decline of 3 mL/min toward <60 mL/min)

• Nephrolithiasis or nephrocalcinosis (including subclinical, detected on imaging)

• Hypercalciuria — 24-hour urine calcium >250 mg/day (women) or >300 mg/day (men) per the Fifth Workshop; the AAES uses a threshold of >400 mg/day with increased stone risk (JAMA Surg , JAMA).

• Age <50 years

• Suspected parathyroid carcinoma (JAMA Surg) Parathyroid cancer is very rare, accounting for 1% of cases of primary hyperparathyroidism. Surgical intervention is required for the removal of malignant parathyroid tumors, primarily because of the risks associated with extreme elevation in blood calcium, but also because of the additional risks of cancer, such as invasion into normal structures, such as the recurrent laryngeal nerve, which controls the vocal cord. Reasons to suspect parathyroid carcinoma are Serum calcium ≥14 mg/dL (Cancers, Cancer), PTH >3× the upper limit of normal (AJS, Ann Sur Onc), hypercalcemic crisis (JACS), presence of a palpable parathyroid mass (Cancers,AJS), hoarseness or voice changes due to recurrent laryngeal nerve involvement (Cancer), concurrent bone and kidney disease (Cancers, Lancet), suspicious features on ultrasound (Clin Rad, Acta Rad), Intraoperative finding of invasion into adjacent structures (JAMA Surg, JACS, Lancet), and mutation of the CDC73 gene (Gene Rev, Best Pract Res Clin Endocrinol Metab). A preoperative scoring system has been proposed to predict parathyroid carcinoma (Clin Endocrinol).

• Also, the AAES guidelines additionally include neurocognitive/neuropsychiatric symptoms and cardiovascular disease as potential indications, though evidence for these is weak. (JAMA Surg , JAMA). Importantly, even if no criteria are met, parathyroidectomy remains a reasonable option based on patient preference, as it is the only cure. (JAMA)

The incidence of a single parathyroid adenoma is significantly more common in primary hyperparathyroidism compared to the rarer occurrences of double adenomas or four-gland hyperplasia.

1. Secondary Hyperparathyroidism (chronic kidney disease related): In cases where the hyperparathyroidism is caused by chronic kidney disease and results in severe symptoms that do not respond to (fail) medical management, such as calcimimetics, vitamin D analogs, and phosphate binders.

   Typical criteria include: (CJASN, Kid Int Rep)

   • PTH persistently >800 pg/mL for >6 months despite maximal medical therapy

   • Concurrent persistent hypercalcemia or hyperphosphatemia

   • Calciphylaxis or progressive vascular/tissue calcification

   • Worsening renal osteodystrophy, bone pain, or fractures

   • Pruritus refractory to medical management

   Parathyroidectomy in dialysis patients has been associated with 15%–57% greater survival in observational studies, along with improvements in bone mineral density and quality of life. (CJASN)

1. Tertiary Hyperparathyroidism (Post-transplant): This occurs when parathyroid glands become autonomously functioning after long-standing secondary hyperparathyroidism after the kidney disease is cured (with a kidney transplant) and hypercalcemia persists, threatening the transplanted kidneys. Surgical cure rates approach 98%–100%, compared with ~81% normocalcemia rates with cinacalcet (Br J Surg).

parathyroid autotransplantation into the forearm

On occasion, when all parathyroid glands are overactive, surgery is undertaken whereby all glands are removed, but one half of one gland is re-implanted into a muscle away from the neck. When all parathyroid glands are overactive, this half parathyroid gland can eventually hypertrophy and lead to a recurrence of hyperparathyroidism. Alternatively, recurrence of hyperparathyroidism after thyroid surgery could indicate that an overactive gland in the neck was not identified and removed during previous surgery. A missed parathyroid gland could be the result of the notorious variability in parathyroid glands, not only in their location but also their number as some people have fewer or greater than four parathyroids. Use of the forearm as a recipient site for a transplanted parathyroid is done to prepare for future contingencies. For example, if initial parathyroid surgery yields a cure that then over time gives way to recurrent hyperparathyroidism, one would need to know if there is still hyperfunctioning parathyroid in the neck versus possible over-growth of the implanted half-gland in the arm. Two simultaneous blood draws from the left and right upper arm would indicate whether the overactivity is from the implanted arm or not. If the PTH level is significantly higher in the implanted arm than the other arm, then a relatively safer procedure may be performed to reduce the size of the implanted parathyroid gland may be undertaken. If, on the other hand, the parathyroid hormone level is equal in both arms, then chances are good that a retained parathyroid gland in the neck or chest exists, and a localizing study may be used to help locate it prior to surgery. If the overactive gland is found to be where a half gland had been implanted in the forearm, a safe and simple procedure removing some of this parathyroid gland from the arm may be done, avoiding risk to the laryngeal nerves that would be surrounded by scar tissue from the original neck surgery.