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Scientifically formulated and clinically tested nutritional supplements

January 20, 1994
S. Mark Overholt, M.D.

Primary hyperparathyroidism (HPT) is the number one cause of hypercalcemia in the non-hospitalized patient. The male to female ratio is 1:2, and the incidence increases with age. Prevalence figures show a peak level in females over the age of 40 with 1 in 500 having primary HPT. The overall prevalence in males is 1 in 2000.

Hyperparathyroidism can be classified into three distinct entities. Primary hyperparathyroidism is the result of an adenoma, glandular hyperplasia, or carcinoma. Secondary hyperparathyroidism is a reactive hyperplastic phenomenon. Tertiary hyperparathyroidism is a term used to describe the instance where secondary hyperparathyroidism has become "autonomous."

The parathyroid gland was first discovered in 1880 by Ivan Sandstrom, a 25-year-old Swedish medical student. A French professor of physiology, Eugene Gley, was the first to associate the removal of the parathyroid glands with resulting tetany which had been previously noted in Billroth's thyroidectomy patients. In 1907 Halstead showed that removal of parathyroid glands in dogs followed by reimplantation could prevent tetany. In 1925 the first parathyroidectomy was performed by Felix Mandl on Albert J., a 38-year-old Viennese streetcar conductor. Early in 1926 the first parathyroidectomy in the U.S. was performed at the Massachusetts's General Hospital by Eugene Dubois. Later in 1975 Samuel Wells reported the first successful autotransplantation of cryopreserved parathyroid tissue.

The normal weight of a parathyroid gland is 35-50 mg. The blood supply for all four parathyroid glands arises predominantly from the inferior thyroid artery and during the neck dissection attention towards preservation of these vessels is prudent. Embryologically the superior glands arise from the fourth branchial pouch and the inferior glands form the third. The inferior glands have a greater descent to their usual final destination and subsequently have greater variability in location. They can be found form the angle of the mandible or carotid bifurcation to the pericardium.

Primary HPT can be divided pathologically into adenoma, hyperplasia, and carcinoma. Adenomas clearly are the most prevalent entity representing 80-85% of cases. Hyperplasia is the second most common diagnosis constituting 15% of cases. Carcinoma represents <1% of total cases. Double adenoma has been found in approximately 5% of the time, and complicates the clinical distinction between adenoma and hyperplasia. Histologically, normal parathyroid tissue shows a cell to fat ratio of 1:1. Hypercellular parathyroid tissue is typified by the loss of the normal amount of fat.

With the advent of multiple serum chemistry analyzers in the mid 1960s, many new cases of "asymptomatic" hypercalcemia have been noted. Close reviews however, have refuted the allegation that these patients were actually asymptomatic. Clark investigated 103 consecutive patients with primary hyperparathyroidism. He found that only 2 of the 103 patients had truly asymptomatic hyperparathyroidism

To make the diagnosis of primary hyperparathyroidism a compatible history suggests the underlying pathology. Cope, in his classic monograph reporting the first 343 cases of primary hyperparathyroidism from the Massachusetts's General Hospital, described the classic symptoms of nephrolithiasis, bone diseases, abdominal groans from peptic ulcer disease and pancreatitis, psychic moans from fatigue and CNS disturbance, and hypertension that characterize this disease. Serum calcium and parathyroid hormone levels should be elevated on three different occasions. The newer double antibody (IRMA) assays to the carboxyl and amino terminals of the 84 amino acid PTH polypeptide are both extremely specific and sensitive. Finally, if malignancy is suspected, new assays for PTH-RP are available to rule out a paraneoplastic cause of hypercalcemia.

The major areas of debate surrounding primary hyperparathyroidism include the previously discussed issues of differentiating an adenoma from hyperplasia and the question whether asymptomatic hyperparathyroidism truly exists. Other areas of controversy include the question of 1) when medical treatment of mild hyperparathyroidism is appropriate; 2) the value of performing preoperative localization studies; and, 3) unilateral versus bilateral neck dissection.

Some feel that patients with mild disease may be closely observed and treated medically. Lafferty examined 100 patients with mild hyperparathyroidism who were followed closely and found progression of disease in up to 22% of cases. His conclusion was that only selective patients can be closely followed, however, as is espoused by prominent endocrine surgeons, with an initial cure rate of 95%, low morbidity, and the potential risk of irreversible progression of the disease, most other studies conclude that surgery remains a logical choice even in the patient with very mild disease.

In fact, a recent epidemiologic study by Melton of the Mayo clinic looking at national statistics from primary hyperparathyroidism concluded that it is more expensive to follow a patient clinically for 5 years than it is to treat initially with surgery. Benefits of treating early mild disease surgically include reversal of malaise, fatigue, gastrointestinal complaints, and much of the bone density loss. Only hypertension has been shown to be completely irreversible. The mechanism for this persistent condition is unclear.

Whether to localize or not to localize preoperatively is a greatly debated subject. Ninety to ninety-five percent of adenomas of hyperplastic glands can be found at neck exploration. Only 75-80% can be found by very experienced technicians using a single technique. After 2 to 3 tests glands can be localized in approaching 90% of cases. Given the added cost and no benefit, bilateral neck explorations without previous localization is recommended for initial treatment. Localizing studies should be reserved for reoperation when persistent hypercalcemia is present or when the patient's medical condition demands the briefest surgery possible. Thallium-technetium subtraction scans, ultrasound, selective venous sampling, CT, MRI, and arteriography have all been employed in the search for parathyroids.

There are two schools of thought regarding surgical approach for hyperparathyroidism. One group supports a unilateral neck exploration with preoperative localization studies and the other supports the use of a bilateral neck dissection without preoperative localization. Those supporting the unilateral approach feel that this approach minimized postoperative hypocalcemia and damage to the recurrent laryngeal nerves, and should be just as successful at controlling the disease process. The vast majority of surgeons however feel that bilateral neck dissection and thorough examination of all normal as well as ectopic sites of parathyroid tissue gives the greatest chance of cure at initial operation. They argue that in the hands of an experienced head and neck surgeon the morbidity should be unchanged and the sensitivity greater. Most studies document this method to be the most effective in curing disease at the initial operation.

Surgical indications were debated by a special NIH consensus panel in 1991. They were unable to set forth rigid guidelines but suggested the following: any patient with symptomatic hypercalcemia, with a serum calcium of 1-1.6 mg/dL above normal values, with a creatinine clearance reduction greater than 30%, a 24-hr. urine calcium excretion >400 mg, or a bone mass <2S.D.'s below the normal would clearly benefit form surgery.

In order to assure control of affected glands a thorough neck exploration is mandatory. This includes both sides of the neck from the carotid bifurcation to the superior mediastinum. Dissection should be carried posteriorly to the prevertebral fascia in order to exclude occult disease. In the event that no affected glands are found at neck exploration several major endocrine surgeons caution against hasty sternotomy. Strategy should also focus on preservation of the inferior thyroid arteries since it is from these vessels that the major blood supply most often originates. Before termination of a case it is always important to reexamine all gland sin the event that they may require reimplantation.

Treatment algorithms follow the following strategy. A single adenoma is first biopsied. If found to be hypercellular parathyroid tissue then one more gland is biopsied. If this proves normal then the diagnosis of an adenoma is made The adenoma is then resected. If the second biopsy revels hypercellular parathyroid or if diffusely enlarged glands are seen the process is most likely hyperplasia. In this case three glands and a portion of the fourth are excised. A well vascularized remnant is left to provide some parathyroid function. Partial resection should be performed first in order to be able to check whether the remnant will be viable before ending the procedure. all tissue should be cryopreserved for future reimplantation should the patient be permanently hypoparathyroid following the resection.

A double adenoma should be treated by removal of the enlarged glands and biopsy of the remaining two to insure that the disease process is not hyperplasia.

All affected glands and the ipsilateral thyroid lobe should be resected for carcinoma. The neck should be addressed with an anterior (zone 6) neck dissection. Wide surgical excision is advised as surgery remains the only viable therapeutic option.

Several surgical pitfalls can interfere with a successful result. Variability in the number of glands occurs approximately 20% of the time. Gilmour in 1937 looked at autopsy specimens and found that 80% of patients have four glands. Six percent were found to have 5 glands and 13% were found to have 3 glands. As stated previously there is also variation in the locations of glands. Both of these facts support a thorough bilateral neck exploration. .Besides locating the glands surgical acumen is important in the identification of normal from abnormal tissue. Frozen section biopsy is indicated if there is any question.

In the event that an odd number of glands is found, a complete search for ectopic tissue must ensue. A missing upper parathyroid gland is likely to have fallen posterior to the esophagus or into the superior-posterior mediastinum. Thus it is vital to always carry dissection to the prevertebral fascia. A missing lower gland requires examination of the thymus gland through the neck incision. They may also be found anterior to the carotid bifurcation. If the inferior and superior recesses of the dissection appear free of ectopic glandular tissue the carotid sheath should be opened and inspected throughout its course and the ipsilateral lobe of the thyroid should be resected to prevent missing an occult intrathyroid parathyroid adenoma.

After a thorough neck exploration greater than 90% of patients have resolution of their hypercalcemia and symptoms. In the event of persistent hypercalcemia, which occurs in around 5% of the time, preoperative localization studies are recommended prior to re-exploration. It is also important to discuss the potential for sternotomy with the patient.

Wang looked at the anatomic locations of parathyroid tissue in 112 reoperations for persistent hypercalcemia. Eight-one percent of glands were note din the neck and 19% in the mediastinum. This illustrates the importance to re-exploring the neck prior to sternotomy. The greatest single location where disease was missed at initial operation was in the deep neck in a retroesophageal location. A wide distribution of sites harbored occult disease. Want pointed out that the vast majority of the mediastinal tumors could be resected through the neck incision alone. Sternotomy for ectopic glands should be avoided at the initial operation. Only in the case of a patient who is extremely ill from hypercalcemia and who has not responded to medical management should sternotomy be performed.

Autotransplantation of parathyroid tissue was first described in humans by Wells. It entails placing 10-20 small pieces of minced glandular tissue into the brachioradialis muscle through separate fascial incisions, marking each site with a nonabsorbable suture which will direct exploration of the forearm in the event that the implanted tissue becomes hyperfunctional. Within 18 weeks on average the grafts are functioning and supplementation of calcium can be ceased. It is important to cryopreserve all parathyroid tissue if it is not reimplanted at the initial operation.

Complications of parathyroidectomy include hematoma formation, vocal cord paralysis, hypocalcemia, and persistent hypercalcemia. All patients should have vocal cord function documented prior to surgery. After parathyroidectomy 20% to 30% of patients experience temporary hypocalcemia. Only in 5% of cases is this permanent. continual oral supplementation or reimplantation of cryopreserved parathyroid tissue in the manner described by Dr. wells is usually sufficient for correction of this abnormality.

In summary, truly asymptomatic hyperparathyroidism is a rare phenomenon. Most patients provide subtle clues that point to hyperparathyroidism. Once documented by serum calcium and PTH levels, bilateral exploration by an experienced neck surgeon who is familiar with all potential ectopic foci is the most important assurance of success. In the case of persistent hypercalcemia, extensive use of preoperative localization studies are indicated to prevent the necessity for sternotomy. Diligent follow-up and a close working relationship with an endocrinologist is stressed for long-term success.

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