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Chrystal Dueno
PTH and hypocalcemia can both stimulate the conversion of the inert metabolite of vitamin D, 25-hydroxyvitamin D [25(OH)D], to the active moiety 1,25-dihydroxyvitamin D [1,25(OH)2D] (7), which in turn will enhance intestinal calcium absorption, and to a lesser extent phosphate reabsorption. 1,25(OH)2D can stimulate the production of the hormone fibroblast growth factor 23 (FGF23) from osteocytes in bone and the released FGF23 can inhibit phosphate transport in the renal proximal tubule and therefore cause phosphaturia and hypophosphatemia. PTH can also increase bone resorption and liberate both calcium and phosphate from the skeleton. The net effect of the increased reabsorption of renal calcium, the increased absorption of calcium from the gut, and the mobilization of calcium from bone, is to restore the ECF calcium to normal and to inhibit further production of PTH and 1,25(OH)2D. FGF23 elevation will also reduce 1,25(OH)2D production. The opposite sequence of events i.e., diminished PTH and 1,25(OH)2D secretion should occur when the ECF calcium is raised above the normal range and the effect of suppressing the release of these hormones should diminish skeletal calcium release, intestinal calcium absorption, and renal calcium reabsorption and restore the elevated ECF calcium to normal. Consequently, decreased levels of PTH and decreased levels of 1,25(OH)2D should accompany hypercalcemia unless the PTH or 1,25(OH)2D is the cause of the hypercalcemia.
A change in ECF calcium will also produce a change in PTH metabolism in the parathyroid cell however this response is somewhat slower than the secretory response. Thus, a rise in calcium will promote enhanced PTH degradation and the release of bioinert mid-region and COOH fragments and a fall in calcium will decrease intracellular degradation so that more intact bioactive PTH is secreted (10-12). Bioinactive PTH fragments, which can also be generated in the liver, are cleared by the kidney (13). With sustained low ECF calcium there is a change in PTH biosynthesis which represents an even slower response. Thus, low ECF calcium, acting via CaSR leads to increased transcription of the gene encoding PTH and enhanced stability of PTH mRNA (14,15). Finally, sustained hypocalcemia can eventually lead to parathyroid cell proliferation (16) and an increased total secretory capacity of the parathyroid gland. Although sustained hypercalcemia can conversely reduce parathyroid gland size, hypercalcemia appears less effective in diminishing parathyroid chief cells once a prolonged stimulus to hyperplasia has occurred.
For those patients with PHPT who meet guidelines for surgery but are unable or unwilling to undergo parathyroidectomy, medical therapy may be considered. Calcium intake should be 800 mg/day for women 70 years old (corresponding to the U.S. Institute of Medicine nutritional guidelines). If necessary, vitamin D should be supplemented to achieve levels of 25OHD which are >30 ng/mL (70mmol/L) but less than the upper limit of normal for the laboratory reference range. The calcimimetic agent cinacalcet (146) (that mimics or potentiates the action of calcium at the CaSR) may be used be used in patients with PHPT with severe chronic hypercalcemia who are not surgical candidates, in order to reduce the serum calcium concentration into the normal range. Bisphosphonates, e.g., alendronate (147), or denosumab, can be employed to increase bone density if there are no contraindications. Bisphosphonates or denosumab in combination with cinacalcet can be considered to lower the serum calcium and to increase BMD.
It has been estimated that hypercalcemia can occur in up to 10% of malignancies. Malignancy-associated hypercalcemia (MAH) can occur in the presence or the absence of elevated PTHrP production. Using two-site immunoradiometric assays for PTHrP several groups have confirmed that 50-90% of patients with solid tumors and hypercalcemia and 20-60% of patients with hematologic malignancies and hypercalcemia have elevated circulating PTHrP. MAH both with and without elevated serum PTHrP concentrations will therefore be discussed.
Several studies have indicated that elevated PTHrP correlates better with hypercalcemia than does the presence or absence of skeletal metastases (196,198,200). This appears particularly relevant to certain neoplasms such as breast cancer which is commonly associated with hypercalcemia but is even more commonly associated with osteolytic skeletal metastases. Elevated circulating PTHrP concentrations (198,199) may contribute to the development of hypercalcemia in these cases in part through augmented bone resorption and in part through increased renal calcium reabsorption. PTHrP may also contribute to the pathogenesis of local osteolytic lesions (212,213). PTHrP per se may be a supportive factor for the growth and progression of cancers by acting in paracrine, autocrine and intracrine modes to modulate tumor cell proliferation, apoptosis, survival, and anoikis, and can therefore influence cell processes which enhance the capacity for tumor dissemination and metastasis (205). In addition, tumors, such as breast tumors that are metastatic to bone, may release PTHrP in the bone microenvironment which will bind to cells of the osteoblastic lineage (including stromal cells, osteoblasts and likely osteocytes), release RANKL ligand (RANKL) and decrease osteoprotegerin (OPG), stimulate osteoclasts to resorb bone and release, in addition to calcium, growth factors such as TGFb (214), IGF-1 FGF, PDGF and BMP; released growth factors can then stimulate further PTHrP release from the tumor, thus setting up a positive feedback loop (Fig. 6, see above). PTHrP released from cancers such as osteoblasts may also release the chemokine and angiogenic factor CCL2/MCP-1 from osteoblasts which may also increase osteoclastic activity and potentially angiogenesis, and further enhance tumor proliferation (215). Consequently, the presence of skeletal metastases in association with a malignancy is not mutually exclusive with high circulating PTHrP, which can contribute to the hypercalcemia, through both osseous and renal mechanisms; at the same time, locally released PTHrP may contribute to the focal osteolysis. It is in fact uncertain whether local osteolysis per se ever effectively raises ECF calcium in the absence of some cause of reduced renal calcium excretion.
Hypercalcemic manifestations will vary depending on whether the hypercalcemia is of acute onset and severe (greater than 12 mg/dL or 3 mM) or whether it is chronic and relatively mild (Table 2). Patients may also tolerate higher serum calcium levels more readily if the onset is relatively gradual, but at concentrations above 14 mg/dL (3.5 mM) most patients are symptomatic. In both acute and chronic cases, the major manifestations affect gastrointestinal, renal, and neuromuscular function. Patients with acute hypercalcemia commonly present with anorexia, nausea, vomiting, polyuria, polydipsia, dehydration, weakness, and depression and confusion which may proceed to stupor and coma. As well the QT interval on EKG may be shortened by hypercalcemia due to the increased rate of cardiac repolarization. Arrhythmias such as bradycardia and first-degree atrioventricular block, as well as digitalis sensitivity may occur. Acute hypercalcemia, therefore, can represent a life-threatening medical emergency. Patients with chronic hypercalcemia may have a history of constipation, dyspepsia (generally not due to a true ulcer), pancreatitis, and nephrolithiasis but few other signs or symptoms.
A minute examination of the circumstances served only to make the case more complex. In the first place, no reason could be given why the young man should have fastened the door upon the inside. There was the possibility that the murderer had done this, and had afterwards escaped by the window. The drop was at least twenty feet, however, and a bed of crocuses in full bloom lay beneath. Neither the flowers nor the earth showed any sign of having been disturbed, nor were there any marks upon the narrow strip of grass which separated the house from the road. Apparently, therefore, it was the young man himself who had fastened the door. But how did he come by his death? No one could have climbed up to the window without leaving traces. Suppose a man had fired through the window, he would indeed be a remarkable shot who could with a revolver inflict so deadly a wound. Again, Park Lane is a frequented thoroughfare; there is a cab stand within a hundred yards of the house. No one had heard a shot. And yet there was the dead man and there the revolver bullet, which had mushroomed out, as soft-nosed bullets will, and so inflicted a wound which must have caused instantaneous death. Such were the circumstances of the Park Lane Mystery, which were further complicated by entire absence of motive, since, as I have said, young Adair was not known to have any enemy, and no attempt had been made to remove the money or valuables in the room.
From the years 1894 to 1901 inclusive, Mr. Sherlock Holmes was a very busy man. It is safe to say that there was no public case of any difficulty in which he was not consulted during those eight years, and there were hundreds of private cases, some of them of the most intricate and extraordinary character, in which he played a prominent part. Many startling successes and a few unavoidable failures were the outcome of this long period of continuous work. As I have preserved very full notes of all these cases, and was myself personally engaged in many of them, it may be imagined that it is no easy task to know which I should select to lay before the public. I shall, however, preserve my former rule, and give the preference to those cases which derive their interest not so much from the brutality of the crime as from the ingenuity and dramatic quality of the solution. For this reason I will now lay before the reader the facts connected with Miss Violet Smith, the solitary cyclist of Charlington, and the curious sequel of our investigation, which culminated in unexpected tragedy. It is true that the circumstance did not admit of any striking illustration of those powers for which my friend was famous, but there were some points about the case which made it stand out in those long records of crime from which I gather the material for these little narratives.
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