Disorders of the Parathyroid gland-Hypoparathyrodism and Hyperparathyroidism
Usually, 4 parathyroid glands develop, although approximately 10% of people may have 2, 3, or 5 glands. The superior glands are typically located on the posterior aspect of the upper thyroid, whereas the location of the inferior glands is more variable. The inferior glands may be posterior to the inferior aspect of the thyroid or ectopically located in the thyroid gland, along the carotid sheath, or attached to the thymus. Superior glands may also be ectopic and in a retroesophageal, retrotracheal, or retropharyngeal location. Typical parathyroid glands are approximately 5 X 3 X 1 mm.
Parathyroid hormone (PTH) is secreted by the parathyroid glands. PTH and vitamin D are the principle regulators of Ca and phosphorus (P) homeostasis; their metabolic actions are interrelated. PTH promotes renal formation of the active metabolite of vitamin D. Conversely, with a deficiency of the vitamin or any resistance to its action, some of the effects of the hormone are blunted.
The most important actions of PTH are:
1) increasing the rate of bone resorption with mobilization of Ca and P from bone;
2) increasing intestinal absorption of Ca (mediated by an action on the metabolism of vitamin D);
3) stimulation of Ca resorption in the distal tubule of the kidney;
4) decreasing renal tubular reabsorption of phosphate (PO4).
These actions account for most of the important clinical manifestations of PTH excess or deficiency.
(Calcitonin is synthesized in the C cells of the thyroid gland. The major regulator of calcitonin secretion is the serum Ca concentration. In contrast to their effect on PTH, hypercalcemia stimulates and hypocalcemia suppresses calcitonin secretion. A number of gastrointestinal hormones including gastrin, glucagon, and cholecystokinin are pharmacologic secretegogues for calcitonin, but gastrin is the most potent.
- inhibiting osteoclastic bone resorption;
- decreasing renal tubular calcium reabsorption and others.)
Normal serum calcium (Ca) levels range between 2, 25 – 2,75 mmol/l (8.8 – 10.4 mg/100 ml. Approximately 40 % of the total blood Ca is bound to serum proteins while the remaining 50 % is ultrafilterable and includes ionized Ca plus Ca comlexed with phosphate and citrate. The ionized Ca fraction (about 50 % of the total blood Ca) is influenced by pH changes. Acidosis is associated with decreased protein - binding and increased ionized Ca and alkalosis with a fall of ionized Ca due to increased protein – binding. These pH – induced changes in ionized Ca occur independently of any change in total blood Ca concentration. In the laboratory determination of serum Ca, only total serum Ca is usually measured.
Maintenance of the blood Ca level is partially dependent upon dietary Ca intake (0,5 – 1,0 gm/day), gastro-intestinal absorption of Ca, and renal Ca excretion. The major factor preserving the constancy of blood Ca concentration is the bone Ca reservoir. About 99 % of body Ca is in bone, of which 1 % is freely exchangeable with ECF.
it is a disease resulting from PTH deficiency, characterized chemically by low serum calcium and high serum phosphorus levels, often associated with chronic tetany.
(Pseudohypoparathyroidism is a congenital condition in which there is tissue resistance to the effects of parathyroid hormone. It presents with skeletal abnormalities, elevated levels of serum parathyroid hormone and normal serum calcium.)
1) accidental removal of or damage to several parathyroid glands during thyroidectomy (2 %);
2) radioactive iodine therapy of the hyperthyroidism or X-ray therapy of the neck organs;
3) it is also occurs as a part of a genetic syndrome of type I (hypoparathyroidism, Addison’s disease, mucucutaneous candidiasis);
4) congenital deficiency (DiGeorge syndrome), agenesis or aplasia of parathyroid glands;
5) hemorrhages, infarctions, infections of the glands;
6) severe hypomagnesemia;
7) autoimmune processes.
1. Congenital hypoparathyroidism (aplasia of parathyroid glands).
2. Idiopathic hypoparathyroidism (autoimmune): isolated or type I autoimmune polyglandular syndrome.
3. Post operative hypoparathyroidism.
4. Secondary hypoparathyroidism due to:
- irradiation; X-ray therapy; treatment of the thyroid gland by radioactive iodine;
- infectious damaging of the glands;
- hemochromatosis, granulomatous disease of parathyroids;
- disturbances of the innervation or vascularization.
Due to duration:
1. Manifest hypoparathyroidism (acute and chronic).
2. Latent hypoparathyroidism.
Patients may be asymptomatic
1. The most characteristic syndrome is tetany, resulting from severe hypocalcemia or a reduction in the serum ionized Ca fraction without marked hypocalcemia (e.g., in respiratory or metabolic alkalosis).
Tetany is characterized by:
1) sensory symptoms consisting of paresthesias of the lips, tongue, fingers and feet:
2) carpopedal spasm (the hands incarpal spasm adopt a characteristic position, the metacarpophalangeal joints are flexed, the interphalangeal joints of fingers & thumb are extended and there is opposition of the thumb), which may be prolonged or painful;
3) generalized muscle aching;
4) spasm of facial musculature;
5) laryngeal stridor.
Tetany may be overt (spontaneous symptoms) or latent. In latent tetany the neuromuscular instability frequently is brought out by provocative tests. Trousseau’s sign is carpopedal spasm caused by reduction of the blood supply to the hand when a tourniquet or blood pressure cuff above systolic pressure is applied to the forearm for 3 min. Chvostek’s sign is contraction of the facial muscles, elicited by a light tapping of the facial nerve. Erba’s sign is dyspnea which develops after hyperventilation.
2. Changes of other organs and systems.
1. The clinical manifestations of hypocalcemia may be primarily neurologic. Slowly developing, insidious hypocalcemia may produce mild, diffuse encephalopathy and thus should be suspected in any patient with unexplained dementia, depression, or psychosis.
2. Trophic changes:
- papilledema occasionally may be present and cataracts may develop after prolonged hypocalcemia:
- changes of the skin and hair.
3. Respiratory system:
4. Cardiovascular system:
- pain in the region of the heart like angina;
- the ECG typically shows prolongation of the Q – T.
5. Gastrointestinal tract:
- spastic constipation or diarrhea.
1. The level of total Ca < 2,2 mmol/l, ionized Ca , 1,0 mmol/l.
2. High serum PO4.
3. Low or absent urinary Ca.
have to be made with other causes of hypocalcemia:
1) increased phosphate (chronic renal failure; phosphate therapy);
2) drugs (calcitonin; diphosphanates);
3) acute pancreatitis; citrated blood in massive transfusion;
4) pseudohypoparathyroidism (resistance to PTH);
5) deficiency or resistance to vitamin D;
1) infectious diseases (tetanus);
2) alkalosis (repeated vomiting of gastric juice; hyperventilation).
Acute severe hypocalcemic tetany.
1. It is treated initially with IV infusion of Ca salts. 10 – 50 ml of 10 % solution of Ca gluconate or Ca chloride may be given IV over 15 – 30 min, but the effect lasts for only a few hours. (side effects: thrombophlebitis, IM injection can cause local necrosis).
Pict. Calcium extravasation in the right
2. Magnesium repletion.
3. Parathyroidin 1 – 2 ml IM 2 times a day.
4. Sedative preparations and spasmolitics.
1. Diet with increased quantity of calcium and vitamin D.
2. Preparations of Ca and vitamin D, which have to be given orally (Calcium-D3 nicomed, Calcemin).
3. Surgery (transplantation of a special bone into the muscles of the abdomen or back. The efficacy is about 8 – 12 month).
References and sources
1. The Merck Manual of Diagnosis and Therapy (fourteenth Edition)/ Robert Berkow and others. – published by Merck Sharp & Donhme Research Laboratories, 1982. – P. , 997 – 1001. 1006 – 1010.
2. Manual of Endocrinology and Metabolism (Second Edition)/ Norman Lavin. – Little, Brown and Company.- Boston-New York-Toronto-London, 1994. - P. 357 - 380.
3. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 68 – 100. 316 - 376.
It is a generalized disorder resulting from excessive secretion of parathyroid hormone by one or more parathyroid glands; it is usually characterized by hypercalcemia, hypophosphatemia, and abnormal bone metabolism.
In 1891, von Recklinghausen described the classic bone disease termed osteitis fibrosa cystica. In 1925, the Viennese surgeon Mandl performed the first parathyroid exploration and adenoma resection. Mandl noted improvement of the patient's severe skeletal abnormalities postoperatively, linking hyperparathyroidism with bone disease. Albright later described the clinical entity of classic primary hyperparathyroidism in the 1930s on the basis of 17 cases from his clinical practice. Historically, the disorder was marked by characteristic skeletal changes, nephrolithiasis, and neuromuscular dysfunction.
Today, primary hyperparathyroidism is a different entity. Since the advent of chemical screening with an autoanalyzer in 1960s, most cases are discovered in asymptomatic patients with hypercalcemia. Patients may also present with nonspecific complaints of back pain, or they may have osteopenia, as depicted on radiographic studies. Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient population, second only to malignancy in the inpatient population. The natural progression of disease in asymptomatic patients is unclear.
Normal parathyroid glands function to maintain appropriate serum calcium concentrations and to regulate bone metabolism by means of the production of parathyroid hormone (PTH). In the nonpathologic state, PTH secretion increases in response to low serum calcium concentrations and enhances the synthesis of 1,25-dihydroxyvitamin D. PTH and 1,25-dihydroxyvitamin D act together to increase calcium reabsorption in the gut and kidney and to promote osteoclastic resorption and the demineralization of bone.
Primary hyperparathyroidism is caused by an overproduction of PTH, in excess of the amount required by the body. In contrast, secondary hyperparathyroidism involves an increase in PTH levels to meet some bodily requirement. In 75-80% of cases of primary hyperparathyroidism, one or more adenomas account for the overproduction, whereas approximately 20% of cases are secondary to diffuse hyperplasia of all glands. Carcinoma accounts for less than 2% of all cases.
The effects of hyperparathyroidism on bone are numerous. Excess PTH results in an increase in bone breakdown by means of osteoclastic resorption with subsequent fibrous replacement and reactive osteoblastic activity. The bone may have microfractures, with subsequent hemorrhage and growth of fibrous tissue and an influx of macrophages. The resulting mass is called a brown tumor because of the brown color of the vascular elements and blood in the mass. The process of bone resorption and fibrous replacement results in the characteristic radiologic features of generalized bone demineralization, resorption, cysts, brown tumors, erosion of the dental lamina dura, and pathologic fractures.
Other effects of hypercalcemia include nephrolithiasis or nephrocalcinosis, neurologic changes, peptic ulcer disease, and pancreatitis.
Mortality/Morbidity: Evidence supports an increase in the morbidity and mortality rates in patients with hyperparathyroidism that is primarily related to cardiac disease. The topic is controversial, with the results of more recent studies refuting the increased risk. Differences in mortality data may reflect the different clinical profiles of classic primary hyperparathyroidism and the modern asymptomatic cohort of patients.
Sex: Incidence of primary hyperparathyroidism in women is 2-3 times the incidence in men.
Age: The average patient age at diagnosis is 55 years.
· The incidence peaks in those aged 40-70 years.
· The disease is rare in children.
Classification due to etiology.
1. Primary (due to parathyroid glands):
- adenoma of a single gland (80 %), multiple adenomata (5 %);
Pict. Low power view of parathyroid adenoma (left side)
compressing normal parenchyma (right side)
- hyperplasia of parathyroid glands (15 %);
- carcinoma of a gland (< 5 %);
- associated with syndromes of familial endocrine neoplasia (MEN-types I and II).
2. Secondary (due to increased physiological demand of hormone in response to low serum Ca in chronic renal failure, malabsorption, rickets and osteomalacia):
- vitamin D insufficiency.
3. Tertiary (due to development of parathyroid tumor against a background of prolonged secondary hyperparathyroidism).
Clinical forms of hyperparathyroidism.
- mixed damaging of organs and systems
Many patients with mild hypercalcemia are asymptomatic, and the condition is discovered accidentally during routine laboratory screening.
Onset is usually gradual with bone pain or swelling, rarely sudden with fracture or renal colic.
The clinical manifestations of hypercalcemia include constipation, anorexia, nausea, vomiting with abdominal pain and ileus, weight loss.. More severe elevation of serum calcium is associated with emotional lability, confusion, delirium, psychosis, stupor and coma. Myopathy may cause prominent skeletal muscle weakness. Seizures are rare.
Reversible impairment of the renal concentrating mechanism leads to polyuria, nocturia and polydipsia. Hypercalciuria with nephrolithiasis (Video) or urolithiasis is common (is noted in 50 % of patients). Less often, prolonged and severe hypercalcemia may produce reversible acute renal failure or irreversible renal damage, due to precipitation of Ca salts within the kidney parenchyma (nephrocalcinosis). Renal damage may result in azotemia and hypertension.
Pict. Sonogram of medullary nephrocalcinosis in a patient with primary hyperparathyroidism
Peptic ulcers and pancreatitis may also be associated with hyperparathyroidism.
Hyperparathyroidism is a disease of increased bone resorption and bone formation. Subsequently, plain radiographic findings may include resorption and sclerosis and numerous sites n the skeletal system. Historically, osteitis fibrosa cystica was used to describe the advanced skeletal disease in primary hyperparathyroidism.
Osteitis fibrosa cystica, in which increased osteoclastic activity causes rarefying osteitis with fibrous degeneration, the formation of cysts, and the development of fibrous nodules in the affected bone, may develop in patients severe hyperparathyroidism. Other bony manifestations include bone pain, tenderness, fracture, deformity, swelling of mandible due to cyst formation (rarely), falling of teeth.
Cardiovascular disorders are presented as hypertension, arrhythmia, left ventricle hypertrophy.
1. Increased level of serum Ca.
2. A low serum phosphate level.
3. Elevated serum parathyroid hormone.
4. Increased alkaline phosphatase.
5. Hypercalciuria, hyperphosphaturia.
6. X-ray: cortical erosions most marked in phalanges especially radial side of middle phalanx; destructive bone lesions; Ca deposition on kidney.
7. Ultrasound and CT scan: localizing of the parathyroid tumor.
8. Technetium-99m imaging has a sensitivity of 70-95% in depicting parathyroid tumors, and it allows 3-dimensional imaging with anterior-to-posterior localization of the tumor. Studies reveal equal sensitivities of technetium-99m sestamibi imaging and MRI in the localization of abnormal glands prior to repeat surgery, with sensitivities of 82-85%. By combining the 2 modalities, the sensitivity increases to 94%.
Pict. Hyperparathyroidism, primary. Initial (A) and 3.5-hour delayed (B) technetium-99m sestamibi images demonstrate a 6-cm parathyroid adenoma
Polyarthritis, radiculitis, tumors of the bones, diabetes insipidus and others.
1. Surgery. It is indicated if the disease is symptomatic or progressive. Chances of cure depend on successful removal of all excess functioning tissue and on reversibility of renal damage; renal insufficiency may progress despite cure of the underlying disease. Abnormally functioning parathyroid glands may be found in unusual locations and experience is required to find them. Preoperative localization of abnormally functioning parathyroid tissue is possible by immunoassay of the thyroid venous drainage. When hyperparathyroidism is mild, no special postoperative precautions are required. In patients with severe osteitis fibrosa cystica, prolonged symptomatic hypocalcemia may occur and require large doses of Ca together with vitamin D, usually for 1 to 3 month.
2. Conservative treatment include (may be used in patients with hypercacemic crisis, which is medical emergency and characterized by dehydration, hypotension, abdominal pain, vomiting, fever and altered consciousness):
- rehydration 2 – 6 l of sodium chloride solution and furosemid 40 – 160 mg;
- calcitonine 1 – 4 units/kg;
- prednisolone 40 – 60 mg/day.
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