PARATHYROID DISEASE

Primary Hyperparathyroidism (PHPT)

Incidence:
• PHPT is present in about 1% adult population.
• Usually presents in the 6th decade and rarely before puberty
• 2 to 3 times more common in women than in men.
• 50% women with PHPT are post menopausal
• Increasing incidence because of Auto analysers

Aetiology:
PHPT is caused by
• Single parathyroid adenoma in 80 to 85%of cases
• Multiple gland hyperplasia 10-15%
         – can be sporadic
         – or as a part of MEN syndrome
• Double adenomas in 4%
• Parathyroid carcinoma in 1%.

Clinical forms:
1) Asymptomatic- (Calcium levels generally whithin1mg/dl of normal). Most patients presenting in this way are from developed countries
2) Psychological, bone or renal disorders (more common in developing countries)
3) Acute Primary hyperparathyroidism (S. calcium in life threatening ranges)
4) As an association with MEN syndromes, Familial hyperparathyroidism, neonatal primary hyperparathyroidism.

Investigations:
To diagnose primary hyperparathyroidism (triad)
1. S. Calcium (Elevated)
2. S. Parathormone (Elevated)

However, techniques that measure the whole molecule are more accurate in distinguishing primary from secondary hyperparathyroidism
E.g.
IRMA- Double antibody ImmunoRadioMetric Assay
ICMA- Immuno Chemiluminescent Assay

3. Renal Function (Normal)

Other investigations for diagnosis
4. S. Phosphorus (decreased)
5. Alkaline Phosphatase (increased)
6. Urinary calcium (increased > 200mg/day. Useful to distinguish patients with familial hypercalcemic hypocalciuria)
7. S. Chlorides (increased > 102 meq/L)
8. S. Chloride/phosphate ratio (>33 diagnostic of PHPT)
9. Bone Densitometry (decreased bone density)
10. Radiography- Skeletal survey not recommended as routine for screening
        • Skull bones- moth eaten appearance
        • Orthopantomogram- loss of lamina dura and jaw tumours
        • Clavicle-subperiosteal resorption of distal 1/3rd of clavicle
        • Subperiosteal resorption of metacarpals, metatarsals and long bones
        • Spine- wedging of thoracic vertebra resulting in kyphoscoliosis

Localisation studies
• Localisation techniques for enlarged glands have improved, but no single study is more than 80% accurate. All tests have varying incidence of false positive and false negative results.
• Localisation techniques are a must in re-surgery for hyperparathyroidism
• In primary surgery for PHPT
    – Experienced parathyroid surgeon required
    – Localization techniques indicated, however not cost effective
• Localisation required because
    – Most adenomas are not clinically palpable
    – 5% adenomas are intrathoracic
• Techniques used
    – Ultrasound
    – MRI/CT scan
    – Thallium- Technetium scan
    – Sestamibi scan.
• 80-90% of adenomas are diagnosed using either of the above techniques
• However the sensitivity of these techniques is best when the adenoma is >1gm and there are no thyroid nodules
• To note- the sensitivity of all localization techniques falls to 20% when dealing with detection of multiple gland enlargements.

Investigations to test for heritable disease
• Screening for the MEN1 gene mutation (in recurrent cases and in suspected multiple gland hyperplasia)
• Parathyroidadenomatosis 1 (PRAD 1) genetic testing

Management
In Asymptomatic patients
Treatment for asymptomatic patients is controversial. A follow-up conference of the NIH and the National Institute of Diabetes and Digestive and Kidney Diseases in 2002 recommended parathyroidectomy for the following patients:

(1) those <50 years of age,
(2) who cannot participate in appropriate follow-up
(3) with a serum calcium level >1.0 mg/dL above the normal range
(4) with urinary calcium>400 mg/24 h
(5) with a 30% decrease in renal function or
(6) with complications of PHPT, including nephrocalcinosis, osteoporosis (T-score <2.5 SD at the lumbar spine, hip, or wrist),
(7) or a severe psychoneurologic disorder.

Monitoring of asymptomatic patients not qualifying for surgery:
– S. Calcium biannually
– S. Creatinine annually
– Bone Mineral Density (spine, hip forearm) annually

Medical Management:
• Adequate hydration and ambulation
• Moderate dietary intake of calcium
• Avoid Thiazide diuretics
• In post menopausal patients adequate Hormone Replacement
• Other drugs- Bisphosphonates and calcimimetic drugs (cinacalcet) may be tried

In Symptomatic patients
1) Open exploration (Gold standard)
• Single adenoma: Excision of the affected gland
• Hyperplasia: 3 ½ gland excision
• 4 gland hyperplasia in 20-40% patients

2) Newer Techniques
• Minimally invasive parathyroidectomy-
       – Safe and usually recommended for single adenoma
• Radio guided technique

The best surgical outcomes are achieved when first time adequate neck exploration is performed by an experienced surgeon. This results in cure in excess of 96% of patients with minimal morbidity

Follow Up post Surgery:
a. Serum calcium should be checked within the first 24 hours after surgery and subsequently if abnormal.
b. Patients treated successfully for adenoma should have serum calcium checked at 1 year.
C. Long-term follow-up is recommended for patients with multiple gland disease.

Abstracts
15. Twenty-five year experience with primary hyperparathyroidism at Columbia Presbyterian Medical Center. Dolgin C, Lo Gerfo P, LiVolsi V et al. Head Neck Surg. 1979 Nov-Dec;2(2):92-8

A retrospective review of 500 patients with primary hyperparathyroidism seen from 1951 to 1975 was conducted; the effect of routine screening of calcium and phosphate levels (initiated in 1968) on the incidence and spectrum of the disease was analyzed. The majority of the patients (77%) were diagnosed in the eight-year period after routine biochemical screening was instituted. Comparing the group of patients diagnosed before the advent of biochemical screening and those diagnosed since screening was instituted, we found: (1) a small but significant increase in the number of asymptomatic patients diagnosed (from 2% to 12%); (2) no change in the incidence of related medical disorders, i.e., nephrocalcinosis and hypertension; (3) no change in the incidence of primary hyperplasia and adenoma; and (4) no change in the mean serum calcium level, the mean age at diagnosis, or the number or location of the involved parathyroid glands. Although routine calcium screening has identified significantly more cases of primary hyperparathyroidism, screening apparently does not enable diagnosis at an earlier stage.

16. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. Silverberg SJ, Shane E, Jacobs TP et al. N Engl J Med. 1999 Oct 21;341(17):1249-55.

BACKGROUND AND METHODS: In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned. We studied the clinical course and development of complications for periods of up to 10 years in 121 patients with primary hyperparathyroidism, 101 (83 percent) of whom were asymptomatic. There were 30 men and 91 women (age range, 20 to 79 years). During the study, 61 patients (50 percent) underwent parathyroidectomy, and 60 patients were followed without surgery. RESULTS: Parathyroidectomy in patients with or without symptoms led to normalization of serum calcium concentrations and a mean (+/-SE) increase in lumbar-spine bone mineral density of 8+/-2 percent after 1 year (P=0.005) and 12+/-3 percent after 10 years (P=0.03). Bone mineral density of the femoral neck increased 6+/-1 percent after 1 year (P=0.002) and 14+/-4 percent after 10 years (P=0.002). Bone mineral density of the radius did not change significantly. The 52 asymptomatic patients who did not undergo surgery had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density. However, 14 of these 52 patients (27 percent) had progression of disease, defined as the development of at least one new indication for parathyroidectomy. All 20 patients with symptoms had kidney stones. None of the 12 who underwent parathyroidectomy had recurrent kidney stones, whereas 6 of the 8 patients who did not undergo surgery did have a recurrence. CONCLUSIONS: In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.

Suggested Reading:
AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005 Jan-Feb;11(1):49-54.