Understanding Hypoparathyroidism
By Elaine Moore
Hormones and Health
Hypoparathyroidism is a condition characterized by decreased blood levels of parathyroid hormone. Although hormones are produced in specific glands, hormones affect other bodily systems. For instance, parathyroid hormone produced by the parathyroid glands regulates calcium concentrations in cells throughout the body. The term hormone (from Greek hormaō, to set in motion or stir up) dates back to the writings of Hippocrates. In “Airs, Waters, and Places,” a volume of the Hippocratic Corpus, Hippocrates makes mention of the body’s specific requirements for hormonal and chemical balance if health is to be attained. Unfortunately, however, levels of the body’s hormones and chemicals occasionally stray outside of the desirable a normal range, a range found to be necessary for optimal health. In hypoparathyroidism, the subject of this article, levels of parathyroid hormone are deficient. This deficiency causes specific chemical imbalances. Correcting these chemical imbalances is the primary goal in treating patients with hypoparathyroidism.
Homeostasis and Reference Ranges
In 1953, Dr. Walter Cannon coined the term homeostasis. Homeostasis refers to the intricate internal mechanism in which the various bodily systems, along with the chemicals and hormones they release, work together to promote health. For example, parathyroid hormone (PTH), along with the hormones vitamin D and calcitonin, work together to regulate the body’s calcium levels, assuring that the body has sufficient circulating calcium for its needs.
By measuring the amounts of chemicals and hormones in healthy individuals, laboratories can determine the average amount of these substances required for health. From this average or mean, a reference or normal range is established. In calculating the reference range for a particular substance, 50% of the normal subjects in the study fall below the mean and 50% of the subjects fall above the mean. These normal or reference ranges serve as guidelines which aid in the diagnosis and treatment of disease. While hypoparathyroidism is diagnosed by laboratory measurements of parathyroid hormone with levels of PTH generally being low or undetectable, a low blood calcium level is often the first clue that something is wrong. In addition, serum phosphorus levels are increased in hypoparathyroidism. Phosphorus, like calcium, is involved in bone formation and resorption. Consequently, PTH also influences phosphorus excretion.
Normally, blood levels of a substance, be it a hormone or an element such as sodium, fluctuate throughout the day. However, these levels normally remain within the normal range despite the demands of the body for nutrients. The amount of calcium leached from bone, absorbed through the intestines, or excreted by the kidneys is carefully regulated by PTH, calcitonin and vitamin D. Normally, the rate at which these hormones are secreted is, in turn, exquisitely controlled by the levels of calcium present in the serum (the liquid portion of blood). The challenge of these three hormones is to maintain a constant level of calcium in the blood while simultaneously providing adequate amounts of calcium to cells, to bone, and for renal excretion. To accomplish this, this hormonal system must compensate, on an hourly basis, for changes in daily intake of calcium, bone metabolism, and kidney function.
The Normal Function of the Parathyroid Gland
Ions such as calcium and potassium travel inside and outside of cells as needed. Through a system of membrane channels and ion pumps, ions are stored in blood cells and released into the extracellular circulation as needed. Extracellular is a term that refers to the amount of calcium in the liquid portion of blood, rather than in the blood cells.
The primary function of the parathyroid gland is to regulate calcium levels in the body. All of the body’s tissues, including blood, are composed of several different types of cells, all with specific functions. For instance, the tissue that comprises the parathyroid gland is made up several different cell types. The most functionally important are the “chief” cells, which produce and store parathyroid hormone.
Each of the parathyroid gland’s “chief” cells contains a sensor or protein receptor attached to its outer surface. This sensor tells the cell how much extracellular calcium is present. If the sensors detect that there is too much or too little extracellular calcium, they order the parathyroid glands to, respectively, cut back or increase the rate of parathyroid hormone released from the parathyroid glands.
Half of the body’s extracellular supply of calcium is linked or bound to protein molecules and unable to interact with other cells. The other half is ionized or free calcium. Calcium is required for the proper functioning of many tissues, including excitation-contraction coupling in the heart and other muscles, proper transmission of impulses within the nervous system, platelet aggregation, blood coagulation, cell reproduction, and the synthesis of other hormones.
Calcium Metabolism and PTH Secretion
Calcium metabolism is remarkable in that the body’s stores of ionized calcium, which represent a small fraction of the body’s total calcium stores, are kept within a tightly regulated range despite the rapid changes in calcium utilization that are constantly occurring. When sensors in the parathyroid cells detect increased levels of ionized calcium in the blood, they order the chief cells to stop releasing PTH.
Besides calcium, there are several other substances that influence PTH secretion. High levels of magnesium may also inhibit PTH secretion. For instance, the high levels of magnesium sulfate administered to patients in premature labor cause a reduction in PTH levels. Conversely, low levels of magnesium can stimulate PTH secretion although prolonged depletion of magnesium can paralyze PTH secretion. Catecholamines, such as epinephrine and norepinephrine, also stimulate PTH secretion. As serum calcium decreases acutely, PTH secretion may rise up to five times the normal secretion rate. If the hypocalcemia is chronic, PTH secretion may approach 50 times the basal rate. A rising serum calcium will suppress PTH secretion.
Besides controlling how much PTH is secreted by the parathyroid glands, calcium regulates the amount of PTH produced or synthesized by the parathyroid glands. This is important because the stores of PTH contained in the gland normally must remain sufficient to maintain maximal rates of secretion for no more than one and a half hours. PTH synthesis is also regulated by vitamin D. High levels of vitamin D inhibit PTH synthesis. This is one of the ways in which PTH and vitamin D work together to regulate calcium levels. This synchronicity is relied on in the treatment of parathyroid gland disorders. Vitamin D derivatives can be used to prevent secondary hyperparathyroidism in dialysis patients with renal osteodystrophy, a type of mineral imbalance and bone deterioration caused by impaired kidney function.
In both hypoparathyroidism and pseduodhypoparathyroidism, plasma calcium levels are usually < 7.0 mg/dl while plasma calcium levels are usually > 6.2 mg/dl. The degree of phosphorus elevation is less marked in pseudohypoparathyroidism and in adults with hypoparathyroidism. The plasma PTH is low or undetectable in hypoparathyroidism, although the PTH level may be elevated in pseudohypoparathyroidism.
Hypoparathyroid Disorders
Despite the body’s tendency towards homeostasis, certain systems can go awry. In hypoparathyroidism, the parathyroid glands fail to secrete sufficient parathyroid hormone for the body’s needs. In a similar condition, pseudohypoparathyroidism, levels of parathyroid hormone are adequate, but the body’s cells fail to respond to it.
The most common cause of hypoparathyroidism is surgery, usually thyroid gland surgery (either total or partial thyroidectomy). One of more of the parathyroid glands may also be diseased, excreting excess parathyroid hormone and causing symptoms of hyperparathyroidism. In hyperparathyroidism, the parathyroid gland or glands may need to be surgically removed. Because of their close proximity to the lobes of the thyroid gland, the parathyroid glands may be damaged, as mentioned, during thyroid surgery. The parathyroid and thyroid glands share the same blood supply. On occasion, surgical intervention interferes with this blood supply, causing transient or sporadic symptoms of hypoparathyroidism, which persist for several weeks after surgery. Once the blood vessels in this area recover, parathyroid function may be restored.
Ionizing radiation (I 131) used to destroy thyroid cells in patients with thyroid cancer or hyperthyroid disorders may also damage the parathyroid glands. In one study, researchers observed a 58 % incidence of diminished parathyroid reserve among 53 patients given high doses of I 131.[i][i] Hypoparathyroidism typically develops within 4 to 18 months after treatment with radioiodine.
In familial or autoimmune (idiopathic) hypoparathyroidism, autoantibodies to parathyroid cells develop in genetically susceptible individuals. These autoantibodies damage parathyroid cells and interfere with the production and release of parathyroid hormone. The age at onset of idiopathic hypoparathyroidism is usually 2-10 years, and there is a preponderance of female cases. Circulating parathyroid antibodies are common with up to one-third of patients having antibodies that recognize the parathyroid calcium sensor.
Idiopathic hypoparathyroidism may also occur in combination with other autoimmune endocrine disorders in a condition known as autoimmune polyglandular syndrome, type 1. In this condition, patients usually develop candidiasis and yeast infections at a very early age followed by hypoparathyroidism between ages 5-9. This is followed by the development of adrenal insufficiency or Addison’s disease.
Resistance to PTH or pseudohypoparathyroidism can result from renal insufficiency due to aberrations in mineral balance. It can also be caused by medications that block osteoclastic bone resorption, including plicamycin, calcitonin, gallium nitrate, oral phosphates and bisphosphonates.[ii][ii]
Hypoparathyroidism has also been associated with sepsis (infection). Furthermore, progressive systemic sclerosis may cause fibrosis of the parathyroid glands causing clinical symptoms of hypoparathyroidism.
Causes of Hypocalcemia
Because the three hormones vitamin D, calcitonin, and PTH work together to regulate calcium, an imbalance of any of these hormones affects the others. PTH, along with dietary phosphorus and calcium, normally stimulates the kidneys to produce sufficient vitamin D. By regulating vitamin D synthesis, PTH also regulates the intestinal absorption of calcium.
Reduced levels of ionized calcium, or hypocalcemia, are considered failures of the adaptive response. That is, chronic hypocalcemia can result from a failure to secrete PTH, a failure to respond to PTH, a deficiency of vitamin D or a failure to respond to vitamin D.
Besides the drugs mentioned in the preceding section, hypocalcemia may also result from aminoglycoside antibiotics such as amikacin, vancomycin and gentamycin. Some chemotherapeutic agents such as asparaginase used for leukemia are reported to cause hypocalcemia and hypoparathyroidism.[iii][iii]
Clinical Symptoms of Hypocalcemia
Most of the symptoms and signs of hypocalcemia occur as a result of increased neuromuscular excitability (tetany, paresthesia, seizures, organic brain syndrome) or because of deposition of calcium in soft tissues (cataract, calcification of basal ganglia).
The most prominent symptom of severe hypocalcemia is tetany. Tetany is a condition characterized by a state of spontaneous tonic muscular contraction. Overt tetany is often preceded by tingling paresthesias in the fingers and about the mouth. However, the classic muscular component of tetany is carpopedal spasm, which causes a painful contraction of the hand. Carpopedal spasm begins with adduction of the thumb, followed by flexion of the finger joints and wrists, which produces a posture known as the main d’accoucheur posture.[iv][iv]
Although the hands are most often involved, tetany can occur in other muscle groups, including the laryngeal muscles, which can obstruct breathing. When tested electromyographically, tetany appears as repetitive motor neuron action potentials usually grouped as doublets.
Patients with hypocalcemia are also predisposed to developing focal or generalized seizures. Two distinct types of seizure activity are associated with low calcium levels. Hypocalcemia decreases the excitation threshold for pre-existing subclinical epilepsy. Here, the attacks are indistinguishable from seizures that occur in individuals with normal calcium levels. EEG findings may remain abnormal after treatment of hypocalcemia event through the number of seizures is reduced. In addition, the neuronal irritability caused by hypocalcemia may occur in the central nervous system, including brain cells.
Other central nervous system effects of hypocalcemia include pseudotumor cerebri, papilledema, and confusion, lassitude and organic brain syndrome. Twenty percent of children with chronic hypocalcemia develop mental retardation.[v][v]
Patients with long-standing hypoparathyroidism or pseudohypoparathyroidism often have calcified basal ganglia. This usually doesn’t cause symptoms, but it can result in a number of motor disorders.
Patients with hypocalcemia may also experience cardiac, ophthalmologic, and dermatologic effects. The cardiac effects are manifested as a delay in repolarization with a prolonged QT interval. Cataract is common in patients with chronic hypocalcemia, and its severity is correlated with the duration and level of hypocalcemia. Patients with hypocalcemia often have dry and flaky skin as well as brittle nails. A dermatitis known as impetigo herpetiformis or pustular psoriasis is often associated with hypocalcemia. Chronic hypocalcemia may affect the ectoderm, producing dry skin, coarse hair and brittle nails. In children, delayed dentition, dental caries and enamel hypoplasia may occur. Alopecia, a disorder characterized by patchy hair growth, may also be seen.
Psychological Manifestations of Hypoparathyroidism
The chronically low levels of calcium seen in hypoparathyroidism contribute to hyperirritability, fatigue, and anxiety. [vi][vi] Organic brain syndrome, psychosis and psychoneurosis have been associated with hypoparathyroidism, and abnormal intelligence has been noted in some children.[vii][vii]
In Neurology and General Medicine, Dr. Michael Maninoff writes that hypocalcemia produces varied alterations in mental status ranging from dementia to frank psychosis.[viii][viii]
The clinical textbook, Robbins Pathologic Basis of Disease, lists mental changes in hypothyroidism as “ranging from irritability to depression to frank psychosis.”[ix][ix]
Dr. Maninoff adds that although convulsions are well-recognized symptoms of hypocalcemia, seizures are usually generalized and patients do not develop epilepsy. Furthermore, intracranial calcifications are a common feature of hypoparathyroidism. This usually doesn’t cause symptoms, but it may cause tremor and symptoms of parkinsonism. Increased cranial pressure is also common in hypoparathyroidism.
Diagnosis
The diagnosis of hypoparathyroidism must be considered when serum calcium levels are low and phosphorus levels are high in the presence of normal serum creatinine and magnesium, and in the absence of a source of massive phosphate leakage into the circulation. Hypoparathyroidism can then be confirmed by tests for parathyroid hormone and 1,25-(OH) vitamin D. In hypoparathyroidism levels of parathyroid hormone are low or undetectable and vitamin D levels are reduced.
Response to treatment can be measured by routine measurements of calcium and vitamin D. Cholecalciferol (vitamin D3) and calcium are both routinely employed to correct the hypocalcemia, which in turn, may influence levels of parathyroid hormone.
i Glazebrook, GA, “Effect of decicurie doses of radioactive iodine 131 on parathyroid function,” American Journal of Surgery, Oct 1987;154(4);368-373.
ii Greenspan, Francis, Basic and Clinical Endocrinology, Philadelphia, W. B. Saunders, 1997, 286.
iii Fitzpatrick, Lorraine and Andrew Arnold, “Hypoparathyroidism,” in Endocrinology, 3rd Ed., Leslie DeGroot, Editor, Philadelphia, W. B. Saunders, 1995, 1126.
ivIbid.
vIbid, 287.
vi Op. cit., Fitzgerald, 1124.
viiIbid,
viiiAminoff, Michael, M. D., Neurology and General Medicine, The Neurological Aspects of Medical Disorders, 2nd Edition, New York, Chruchill Livingstone, 1994.
ixSchoen, Frederick, M.D.,Managing Editor, Robbins Pathologic Basis of Disease, 5th Ed., Philadelphia, W.B. Saunders, 1994, 1148.
