Hyperparathyroidism
Hyperparathyroidism (HPT) is an excess of parathyroid hormone in the bloodstream due to over function of one or more of the four parathyroid glands which are usually located around the thyroid. Parathyroid hormone (PTH) helps maintain an appropriate balance of calcium in the bloodstream and in tissues that depend on calcium for proper functioning. A parathyroid gland may be normal, hyperplastic, or adenomatous. Parathyroid glands are usually very small measuring about 5 mm in size and are yellow as they are composed mostly of fat. There is only a small percentage of hormone producing cells. Hyperplastic glands are usually larger, around 10 mm in size and have a greater percentage of hormone producing cells and less fat. Adenomas are usually over 10 mm in size and are almost completely comprised of hormone producing cells. Hyperparathyroidism can occur when even one gland is abnormal in any way but can occur with multiple glands, Over production of PTH results in high levels of calcium in the blood (hypercalcemia), causing a variety of health problems.
An important consideration in addressing parathyroid pathology is the deleterious effect of overproduction of PTH on bones. When the parathyroid glands are not working properly calcium flows from the bones to the blood, resulting in weakening and thinning of the bones, leading to osteopenia and osteoporosis. Medications directed at slowing osteoporosis will not be as helpful as the underlying problem is not addressed. Moreover, the kidneys filter the calcium and are more prone to calcium stone formation. The joints, particularly the hips, ache and muscles may hurt. Some patients note abdominal pain. There can be some psychological effects as well, to include short term memory loss, attention deficits, and difficulty with calculations. Patients often report high levels of fatigue. Other than bone density scans and known nephrolithiasis by imaging, qualification of other symptoms is difficult. Often patients with neuropsychologic symptoms will have the diagnosis of fibromyalgia or chronic fatigue and pain syndromes when the parathyroid was the underlying issue all along.
The parathyroid glands embryologically are two sets of twins, which can be useful in trying to locate them. The upper parathyroid glands are located behind the thyroid to the mid to upper gland and are adjacent to the recurrent laryngeal nerves. These are the nerves that control the vocal cords. The lower parathyroid glands are usually located off the inferior pole of the thyroid.
Parathyroid glands can also be located in unusual, or ectopic, locations. These sites include the thyrothymic ligament, thymus, mediastinum, retroesophageal space, thyroid gland, carotid sheath, aortic arch, or undescended at the base of the skull. Supranumerary, or more than the standard four parathyroid glands, may also be encountered in up to 15% of patients. Recent studies suggest that that number may be higher.
Originally, it was taught that hyperparathyroidism manifested in one of two situations. The first was of a single adenoma and three normal parathyroid glands. The second was that all four glands would be hyperplastic, working together as a team. More recent observation is that each parathyroid gland can behave individually, making identification of all the glands prudent.
The diagnosis of HPT is straightforward in establishing elevated calcium levels with elevated PTH levels. Establishing hypercalciuria is important to understand if HPT could be contributing to nephrolithiasis. Correction of vitamin D deficiency is also important as this can increase the PTH level. Sometimes the calcium and PTH levels might be in the upper limit of normal. Keep in mind that the two values should be considered together. If a patient has a high calcium level, it would be expected that the PTH would be significantly suppressed under normal circumstances. Conversely, a high PTH is only normal in the situation of very low calcium. Often time extended lab ranges for what is considered normal can preclude timely diagnosis of this condition. Patients may have abnormal levels but not so abnormal that the lab will flag the result.
Once the diagnosis is established, care is taken to localize the abnormal gland if possible. It is important to note that only adenomas will be visible on imaging. Normal parathyroid glands and hyperplastic parathyroid glands contain too much fat to be images. Sometimes, ultrasound can show the exact location and size of an abnormal parathyroid gland. Success with this modality is highly operator dependent. This is usually done by qualified endocrine surgeons, specially trained endocrinologists, and radiologists who practice in a high volume endocrine institution. Ultrasound is also useful as it can show if there are any problems with the thyroid. It is useful for a patient (and surgeon) to know beforehand if there is a reason to need concurrent thyroid surgery such as large goiter or thyroid cancer.
In the event ultrasound testing does not show the location of the abnormal gland, a nuclear medicine test called Sestamibi is another option. This is an IV chemical injected into the blood which then accumulates in abnormally functioning parathyroid glands. A special camera is then used to identify any areas that light with the chemical. Again, only an adenoma will be visible on Sestamibi. This examination is particularly useful if an ectopic adenoma is suspected as the entire top half of the body is imaged, which is not possible with ultrasound.
Sometimes, testing does not reveal a specific gland most likely responsible for the HPT. Such results do not, however, rule out HPT. This can initially be frustrating to the patient as they might be told if the imaging is negative that they do not have the problem. If ultrasound is negative and Sestamibi is negative, the patient almost certainly has hyperplasia. Hyperplasia patients will typically have a calcium in the high 9 or low 10 range with PTH levels under 100. Adenoma patients will typically have higher calcium and PTH values. While the effect on the body as the same, the labs can also guide treatment decisions on imaging. For example, if a patient has a calcium level of 12, where an adenoma would be expected, a negative ultrasound might lead to additional imaging to exclude ectopic.
To summarize, with hyperparathyroidism, there can be varying numbers of glands, in varying locations, with varying degrees of abnormality, which may or may not show on imaging testing. Further investigations in other modalities are underway, for example 4D CT scanning, but this is often limited by patient financial constraint and institution availability.
Surgery is the most common treatment for primary HPT. The operation is called a parathyroid exploration. This does not imply that it is “exploratory” but in the case of hyperplasia, the surgeon will not know until the operation which glands will be removed. The operation is done under general anesthesia through a small incision on the neck. Usually, surgery is done as an outpatient unless there are other mitigating factors. The surgeon focuses on identification of parathyroid glands with an intraoperative assessment on the degree of abnormality. In the case of glands not identified in the expected locations, limited exploration to find ectopic glands would be expected. Major neck dissection and exploration into the chest is not the standard of care for unlocalized glands and could expose the patient to significantly increased risks and potential additional surgical complications. Sometimes parathyroid glands will be abnormally located within the thyroid, requiring removal of part of the thyroid that contains the gland.
The primary objective of a parathyroid exploration is to try to achieve balance of calcium in the body. This is done by removing the abnormal parathyroid glands and leaving normal parathyroid glands in place. Particularly where pre-operative testing has not clearly localized abnormal glands, the surgeon faces a situation where there may be unknown numbers of glands with unknown levels of abnormality in each gland. There is a fine balance between helping and hurting the patient. It is believed that a person can obtain acceptable calcium regulation so long as half of one parathyroid gland is present and functioning properly. However, that does not mean that a surgeon operating on a patient with HPT should automatically just remove all but half of one gland when some of that tissue gives every indication pre-operatively and intra-operatively of being normal.
Parathyroid glands are tiny, fragile, and can become easily disrupted. Over manipulation can cause infarct the blood supply. Therefore, just examining a gland can damage it and reduce or eliminate its ability to regulate calcium by creating hemorrhage and subsequent devascularization. Surgeons previously used to biopsy each gland to document that they were normal but this was widely discouraged as this could cause hypoparathyroidism. Therefore, prudent and skilled endocrine surgeons do pre-operative testing to try to localize abnormal glands and then intra-operatively carefully assess the size and appearance of each gland so that, hopefully, only abnormal glands are removed. This is particularly important in cases of parathyroid hyperplasia. All the glands must be identified before decision is made of which to remove. If all the glands are abnormal in the case of four gland hyperplasia, it is important to leave half of the most normal and best vascularized gland. A small inert titanium vascular clip measuring 5 mm is placed across the parathyroid gland that will stay. The top is removed with scissors. The clip is important as now that hyperplastic gland half is now visible on imaging studies. Very rarely will the half overgrow in time and need additional surgery. This is extremely rare.
In some cases, intraoperative parathyroid hormone blood testing is used to watch the PTH levels fall to normal range during the surgery. There is no validation of these metrics but I tend to use this testing when there is a localized gland to try to prove surgical cure with limited single gland dissection. The half life of PTH is 10 minutes, which means that the amount of hormone present should reduce in half in that amount of time. Medical literature suggests that a patient would be cured when the PTH falls by 50% after the abnormal parathyroid (s) are removed. I have found that the number is less important than falling into normal range. PTH is considered to be elevated (depending on the lab) when the value is less than 65. One could argue that PTH drop from 500 to 100 would be more than 50%, but the value is still too high. Intraoperative PTH testing is not as useful when exploration of all four glands is planned.
Hypoparathyroidism (inadequate PTH production) is, in my opinion, the most terrible endocrine surgery complication and for that reason, removal of any parathyroid tissue must be taken very seriously. Hypoparathyroid patients often take upwards of 60 calcium pills plus Vitamin D daily with the risk of constant muscle spasm and respiratory arrest. The FDA had authorized synthetic PTH available for daily injection carrying a black box warning of osteosarcoma. Physicians had to be certified specially as parathyroid disease to prescribe this drug secondary to the risks to the patient. I have gone through this training. However, the drug is currently off the market without a projected return.
An additional note is that parathyroid glands can be transplanted back into the body in the event they would be removed. There are some reports of people donating parathyroid glands to others but it requires the same immunosuppression required of other organ transplants, so this is highly unusual. Some surgeons, in the face of four gland hyperplasia, will remove all four of the glands and then autotransplant a half back into the muscle of the arm. The parathyroid glands can live by imbibition or absorbing nutrients through the muscle fibers blood supply. The parathyroid gland would be minced into tiny pieces and planted into the muscle. The reason to move the gland to the arm would be to minimize surgical risk if re-exploration would be required. My personal preference is not to do this but to leave the half in situ in the neck. There can be up to a 3 month period of hypoparathyroidism that can occur as the graft in the arm gains functionality. Certain types of hyperparathyroidism in dialysis patients may be the exception.
Further surgical risks are similar to thyroid surgery. Patients are watched carefully for a few hours following surgery for bruising or hematoma. The recurrent laryngeal nerves run directly medial to the upper parathyroid glands. This is useful as a tool to identify the parathyroid glands, but it also poses a small risk of nerve injury by proximity. The risk of injuring a nerve during parathyroid surgery is very small. The largest risk is not solving the initial problem of hyperparathyroidism. This is a multifaceted disease with multiple variables.