A 31 year old white male, presented with some joint and low back pain together with generalised lethargy. Past history of kidney stones. Routine screen showed elevated blood calcium. No other symptoms noted. No hypertension, depression, peptic ulcer disease, fever, chills, nausea or vomiting. Neck supples without adenopathy, thyroid not enlarged. There was a family history of hyperparathyroidism.
The major findings are the high level of calcium, joint and low back pain, lethargy, low phosphorus, high chloride, high alkaline phosphatise, high PTH(intact) and high PTH(C-term), past history of kidney stone and family history of hyperparathyroidism.
Ionised calcium found in plasma is strictly regulated and ranges from 4.2 to 5.1mEq/L. The optimum function of physiological processes can be ensured by the precise control of ionised calcium, particularly neural function, muscular function, bone metabolism and cell signalling. Secretion of parathyroid hormone from the parathyroid glands is crucial in regulation of ionised calcium; usually found in the neck, which reacts to changes in circulating ionised calcium via the calcium-sensing receptor (CaSR) found on the surface of the chief cells. Parathyroid hormone plays a key biological role in maintaining ionised calcium and phosphate within the reference range by stimulating precise receptor-mediated responses in cells all over the body.
Figure 1. Parathyroid hormone response to decreased ionised calcium
Taking from (Taniegra, 2004)
Parathyroid hormone increases when a decline in circulating ionised calcium occurs and it has three main functions that assist to restore a normal circulating concentration (figure 1): stimulation of osteoclast re-absorption to release skeletal calcium (bone); receptor-mediated tubular re-absorption of calcium (kidney); and increasing activity of renal 1 hydroxylase, resulting in production of 1,25-dihyroxyvitamin D, this acts on the gut and increasing calcium absorption (bowel). The rise in calcium in response to these effects mediated by parathyroid hormone acts via a classic endocrine feedback loop on the CaSR, reducing secretion of parathyroid hormone.
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Components in this regulatory system can cause excessive secretion of parathyroid hormone and hyperparathyroidism. Primary hyperparathyroidism can occur when one or more parathyroid glands secrete excess parathyroid hormone; secondary hyperparathyroidism arises when increased secretion of this hormone is a response to lowered ionised calcium as a result of kidney, liver, or bowel disease; and in tertiary hyperparathyroidism, a state of autonomous secretion of parathyroid hormone usually occurs as a result of long-lasting chronic kidney disease. (Taniegra, 2004)
Pathophysiology and forms of HPT
The parathyroid glands are made up of two cellular components; the chief cells and oxyphil cells, and a stroma that is basically composed of fat cells. Most of the parathyroid hormone (PTH) is produced by the chief cell, which is an 84-amino-acid single-chain peptide. It has a plasma half-life of 3-4 min with a molecular weight of about 9500. Lesser compounds with as little as 34 amino acids next to the N-terminus of the molecule that have also been isolated from the parathyroid gland exhibit full parathyroid hormone (PTH) activity.
Primary hyperparathyroidism take place in one out of every 500 women and 1 per 2000 men above 40 years of age. This is due to autonomous secretion of PTH. Solitary parathyroid adenoma is the cause of 85% of pHPT. Hyperparathyroidism in 15% of patients is caused by hypertrophy of all four parathyroid glands (Silverberg, 2000). Parathyroid malignancies occur in less than 1% cases. The etiology of pHPT is not known, calcium nutrition and vitamin D deficiency of the population could be a risk factor (Rao, et al 2002) [16] D.S. Rao, G. Agarwal, G.B. Talpos, E.R. Phillips, F. Bandeira and S.K. Mishra et al., Role of vitamin D and calcium nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective, J. Bone Miner. Res. 17 (2002) (Suppl 2), pp. N75-N80. View Record in Scopus | Cited By in Scopus (48). Lithium therapy, thiazide diuretics and external neck irradiation can be responsible for pHPT in minority of patients (Younes, et al 2004)
Genetic predisposition cannot be ruled out as the patient had a family history of hyperparathyroidism. Though most cases of pHPT occur sporadically; genetics is a major factor in this disease. An ancestral disorder is usually considered particularly in young patients diagnosed with pHPT or patients with positive family history of HPT. Majority of these familial cases occur in association with multiple endocrine neoplasia (MEN). Multiple endocrine neoplasia type 1 (MEN-1) is the most common variant of familial HPT. About 87% to 97% of patients with MEN-1 have associated pHPT (Marx, 2000).
Hyperparathyroidism is rarely seen in MEN-2B patients but is seen in 20-30% of MEN-2A (Younes, et al 2004). A third unusual familial form of HPT not linked with MEN syndromes (non-MEN familial HPT) has been described and thought to be an expression of occult multiple endocrine neoplasia type I (Perrier, et al 2002). Another type of familial HPT is found in patients with familial benign hypocalciuric hypercalcemia (FBHH). This is typically a benign and asymptomatic disorder with an autosomal dominant mode of inheritance linked to a defect on chromosome 3 (Younes, et al 2004). Regardless of the hypercalcemia, patients that have this disease show none of the morbidity seen in hypercalcemic patients with HPT and most need no surgical treatment. (Sosa, et al 2003)
Calcium, PTH, Vitamin D, and calcitonin interaction
The skeleton, which is the principal calcium reservoir, contains as high as 99% of the total body calcium. This reservoir is readily on hand for homeostatic needs. (Kinder, et al 2002) Hypocalcaemia and hypercalcemia are life-threatening conditions. Consequently, extracellular Ca concentration should be controlled in a narrow range (4.2-5.1mEq/L). Three organs (bone, kidney and intestine) targeted by three calciotropic hormones (PTH, calcitonin and vitamin D) work in unity to achieve this goal. Intensely, slight changes (1-2% decrease) in the extracellular calcium concentration result in a quick rise in PTH secretion and restitution of extracellular fluid (ECF) calcium to normal (figure 1) (Younes,et al 2004). In the kidney, PTH blocks reabsorption of both calcium and phosphate in the proximal tubule while promoting calcium reabsorption in the ascending loop of Henle, distal tubule, and collecting tubule with an overall effect being net calcium reabsorption. Another main action of PTH at the kidney level is converting 25-hydroxyvitamin D to its most active metabolite, 1,25-(OH)2D3 by activating 1α-hydroxylase in the proximal tubules of the kidney. (Kinder, et al 2002)
In the bones, PTH binds to receptors on the osteoblasts and osteocytes to pump calcium ions from the bone fluid into the ECF. This is generally a rapid phase that results in an increase in serum calcium in minutes. Over several days, a second slow phase of bone resorption occur that results from the stimulation and proliferation of osteoclasts by cytokines released from activated osteoblasts and stromal precursors that possess PTH and vitamin D receptors (Kinder, et al 2002), (Younes, et al 2004)and (Kostenuik, et al 2001)
Vitamin D axis is the second major arm in calcium regulation. Vitamin D is synthesized in the skin from cholesterol precursor, 7-dehydrocholesterol upon exposure to ultraviolet light. It is carried to the liver via a vitamin D binding protein to be converted to 25-(OH)D3. The later is then moved to the kidney to be converted to 1,25-(OH)2D3 in the proximal tubules by the enzymes 1α-hydroxylase. This enzyme is stimulated by increased levels of PTH and low serum phosphorus levels. The levels of 1,25-(OH)2D3 are usually elevated in primary hyperparathyroidism (Kinder, et al 2002). The main action of 1,25-(OH)2D3 is the promotion of gut absorption of calcium by stimulating the formation of calcium-binding protein in the intestinal epithelial cells. Vitamin D encourages intestinal absorption of phosphate ions, and this could play a synergistic role with PTH in stimulating osteoclast proliferation and bone resorption. High concentrations of 1,25-(OH)2D3 appear to increase the turnover of bone with subsequent loss of bone mineral content (Younes, et al 2004) .
Further test that can be done to establish hypercalcemia
Calcitonin is the third arm of calcium homeostasis. This hormone is secreted by the parafollicular cells of the thyroid gland to act as an antihypercalcemic hormone. Calcitonin inhibits bone resorption and increases phosphate excretion by the kidneys (figure 2). Calcitonin secretion reduces with advancing age, and is higher in men than women and in osteoporotic females compared with aged matched controls. (Marqusee, 2007). Calcitonin deficiency or glut does not cause clear pathology. Consequently, some researchers are still sceptical about its physiologic role (Younes, et al 2004).
Figure 2 Role of Calcitonin in calcium metabolism
Taking from (http://porpax.bio.miami.edu/~cmallery/150/physiol/sf44x6.jpg)
Diagnosis of hyperparathyroidism
Clinical diagnosis
Based on the history and laboratory findings it is suggestive that the 31 year old patient could be suffering from Primary hyperparathyroidism (pHPT). It is the most common form of hyperparathyroidism. After diabetes mellitus and thyroid disease, it is the third most common endocrine disorder. In its typical form (which is becoming less common); symptomatic hyperparathyroidism patients have manifestations secondary to high serum calcium and PTH levels such as kidney stones, seen in this patient, other symptoms such as overt bone disease, and nonspecific gastrointestinal, neuromuscular and cardiovascular dysfunction can occur. (Younes, et al 2004). Currently, 75-80% of cases accounts for asymptomatic primary hyperparathyroidism. Patients in this group have minimal signs or symptoms of hypercalcemia. Signs and symptoms that may be present but are not obviously associated with pHPT include left ventricular hypertrophy, hypertension, , valvular or myocardial calcification, pancreatitis, peptic ulcer disease, gout or pseudogout, weakness, easy fatgability, normocytic normochromic anemia, anxiety, lassitude, cognitive difficulties, clinical depression and somatic complaints. (Younes, et al 2004).
The hallmark of pHPT is currently osteopenia, while the classic bone disease such as osteitis fibrosa cystica and pathologic fractures are infrequently seen in sHPT and severe forms of pHPT. Plain radiographs can be used to detect severe bone disease such as bone cysts of the long bones or the pelvis, salt and pepper appearance of the skull and subperiosteal bone resorption of the phalanges or the clavicle. Bone scans have demonstrated reduced bone mineral density in patients with HPT in the distal forearm and femoral neck. (Younes, et al 2004)
Patient had past history of kidney stone. The association between HPT and renal stone was first made in 1930 (Younes, et al 2004)[53] D.P. Barr and H.A. Bulger, The clinical syndrome of hyperparathyroidism, Am. J. Med. Sci. 179 (1930), pp. 471-473.. Patients with renal stones compared with patients with bone diseases have moderate hypercalcemia and PTH levels, higher 1,25(OH)2D3 concentrations, and elevated urinary calcium excretion. (Kinder, et al 2002) Younger patients in who HPT is less common have symptoms of renal stones occurring more frequently. (Younes, et al 2004)
About 80% of patients with HPT have proximal muscle atrophy and feelings of muscular weakness. Easy fatigability and weakness that are linked with HPT may or may not be linked with overt neurological findings. (Younes, et al 2004)
Biochemical diagnosis of HPT
Blood calcium
The usual clue for the diagnosis of pHPT is high serum calcium level. Patients with sHPT generally have regular or slightly low serum calcium (Kinder,et al 2002). Serum calcium is influenced by the level of serum sodium, serum proteins, and hydrogen ion concentration. The causes of hypercalcemia with a concomitant elevation in PTH level are limited. These include lithium-induced hypercalcemia and familial benign hypocalciuric hypercalcemia (FBHH). Usual level of calcium, though, may be seen in a small number of patients with hyperparathyroidism (10-20%) (Maruani,et al 2003). These patients regularly have calcium levels in the high end of the reference range (normocalcemic hyperparathyroidism). Persistent hypercalcemia and an elevated serum PTH level confirm the diagnosis of pHPT in this patient. (Hubner, et al 2006)
Serum PTH
The diagnosis of hyperparathyroidism is demonstrated by elevated parathyroid hormone levels in the setting of high serum calcium, seen in this patient's lab result. The introduction of the immunometric "sandwich" assays has greatly facilitated laboratory diagnosis of pHPT and evaluation of the severity of sHPT. These assays use two dissimilar polyclonal antibodies, which are specific for two different regions of the PTH molecule. The first antibody is specific for PTH 39-84, while the second antibody is specific for PTH 1-34 and is labelled with radioiodine or chemoluminescence. Greater sensitivity is provided by such 'sandwich" settings than either antibody alone[80] E. Blind, H. Schmidt-Gayk, S. Scharla, D. Flentje, S. Fischer and U. Gohring et al., Two-site assay of intact parathyroid hormone in the investigation of primary hyperparathyroidism and other disorders of calcium metabolism compared with a midregion assay, J. Clin. Endocrinol. Metab. 67 (1988), pp. 353-360. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (37). Modern intact-PTH assays have no cross-reactivity with parathyroid hormone-related peptide, and hypercalcemic patients with HPT are usually separated from patients with other causes of hypercalcemia by these assays. Occasionally, small cell lung carcinomas, ovarian tumours and thymoma may secrete intact PTH and consequently, elevating its serum levels. However, due to the rarity of these tumours, this cause of an elevated serum level of PTH may in effect be disregarded in the clinical routine demonstrated by the presence of large non-(1-84) PTH fragment that was not excluded by the "intact" IRMA assay. Subsequently, a second generation of new IRMA assay has been developed, that is specific for the full-length molecule; PTH. (Younes, et al 2004)
Serum phosphorus, chloride, alkaline phosphatise, creatinine
Serum phosphate or phosphorus usually ranges between 2.5 to 5 mg/dl in adults. Patient had hypophosphatemia (PO4<2.5 mg/dl) is a general sequelae of hyperparathyroidism because parathyroid hormone inhibit phosphate reabsorption from the kidney. The alliance between hypophosphatemia and hypercalcemia is suggestive of pHPT or humoral hypercalcemia of malignancy (HHM) (Kinder, et al 2002). About 50% of patients with pHPT exhibit low serum phosphorus level (<2.5 mg/dl) while around 30% have their serum phosphorus in the low normal range. Severe hypercalcemia arising from whatever cause could lower phosphorus level by interfering with the renal handling of phosphate. With every decrease in glomerular filtration in patients with renal failure, there is a little rise in serum level of phosphorus which is generally accompanied by a slow reduction in serum calcium inducing a subsequent increase in PTH secretion. (Younes, et al 2004)
Patient had hyperchloremia (Chloride>109 mEq/l) this occurs in around 40% of patients with HPT, and when found in a hypercalcemic patient it's suggestive that the patient has pHPT. A further 40% of patients with pHPT have serum chloride level in the high normal range. The absorption of bicarbonate in the kidney is decreased by PTH resulting in hyperchloremic acidosis. On the other hand, metabolic alkalosis when present in a hypercalcemic patient, suggests sarcoidosis, malignancy, vitamin D intoxication or milk alkali syndrome.
High serum levels of alkaline phosphatise which result from osteoclastic hyperactivity is linked with severe hyperparathyroid bone disease and this could be correlated with degree of postoperative hypocalcaemia (Younes. et al 2003).There is an elevation of the serum alkaline phosphatase level in 10% of patients with pHPT and in most patients with sHPT. The diagnosis of pPHT is confirmed by the presence of hypercalcemia in association to high alkaline phosphatase in a patient with subperiosteal resorption. In the lack of subperiosteal resorption in patients with hypercalcemia and elevated serum alkaline phosphatase level, malignancy associated hypercalcemia should be considered. (Hubner,et al 2006)
Creatinine level was normal this test is performed routinely, because of the patient's past history of kidney stone. Presently, obvious renal failure is an abnormal complication of pHPT. nevertheless, higher than one-third of patients with mild hypercalcemia have reduction in creatinine clearance and urinary concentrating capacity [93] B.H. Mitlak, M. Daly, J.T. Potts Jr., D. Schoenfeld and R.M. Neer, Asymptomatic primary hyperparathyroidism, J. Bone Miner. Res. 6 (1991), pp. S103-S110. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (19). Serum creatinine measurement can give a general measure of creatinine clearance using the Cockcroft-Gault equation. It is suggested in individual patients who do not have reduced renal function at baseline assessment and are going to be monitored without surgery. More so, a high serum creatinine (Cr>2 mg/dl) when found in a hyperphosphatemic patient and low-to-normal calcium and a clinical picture of uremia suggests the diagnosis of sHPT. (Younes, et al 2004)
Differential diagnoses of hypercalcemia
Hyperparathyroidism, Primary HPT, Parathyroid hyperplasia, Solitary adenoma, Secondary/tertiary hyperparathyroidism, Malignancy-associated hypercalcemia, Lithium therapy, Familial benign hypocalciuric hypercalcemia, PTHrP-mediated, Vit D mediated, Lytic bone metastasis, Vitamin D related, Vitamin D intoxication, Sarcoidosis or other granulomatous diseases, Endocrine disorders, Thyrotoxicosis, Addison's disease, Miscellaneous(Younes, et al 2004)
Treatment
Treatment of primary hyperparathyroidism is usually by surgically removing the glands containing adenomas. This will reduce the cause of mortality and symptoms.
Patient presenting with hypercalcemia should first be hydrated followed by treatment with furosemide, however if they remain severely hypercalcemic, calcitonin, mitramysin can be used.
Calcimimetica a medicine usually used for patients with sHPT can now be used for patients with pHPT. Calcimimetics decreases the amount of parathyroid hormone released by the parathyroid glands. This can be suggested in a case where surgery is inappropriate. (Denizot, et al 2004)
Conclusion
Based on the above findings, one can definitely say that the 31 year old man had an inherited primary hyperparathyroidism which is caused by the overproduction of parathyroid hormone via the parathyroid glands causing the rise in serum calcium level (hypercalcaemia) by removing calcium from the bone causing the joint and low back pain. In order to normalize the elevated serum calcium level, the kidney excretes a huge amount of calcium in the urine leading to the formation of kidney stones. Most of the symptoms that occur with hyperparathyroidism are those caused by kidney stone such as tiredness, muscle weakness and excessive urination.
