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Thứ Hai, 9 tháng 12, 2013


Primary or tertiary hyperparathyroidism in CKD 

In this report, we described a case of a middle-aged Filipino man with severe hypercalcaemia—refractory to volume expansion, loop diuretics, bisphosphonates, calcimimetics and haemodialysis—with PTH concentrations in excess of 2400 pg/mL. Diagnostic evaluation confirmed the presence of an extremely large (2 g) parathyroid adenoma.
HPT and hypercalcaemia resolved rapidly following adenoma resection. We believe that our patient’ s findings reflect the most severe clinical manifestations of primary (in contrast to tertiary) HPT ever described in a patient with CKD.
While HPT caused by parathyroid adenoma is common, this case is novel for several reasons. First, severe hypercalcaemia is rare in primary HPT. This degree of hypercalcaemia results only when primary HPT is exceptionally severe (this case) or when tertiary HPT (autonomous PTH hypersecretion after long-standing renal insufficiency) develops. Vasoconstriction induced by severe hypercalcaemia is an important contributing cause of the acute renal failure observed in this patient. The resultant decline in glomerular filtration rate (GFR) most likely accounted for his normal to slightly elevated serum phosphorus concentrations, which are typically low–normal in primary HPT. Indeed, as the patient’ s hypercalcaemia and kidney function worsened on transfer to our institution, his hyperphosphataemia worsened as well with the serum phosphorus reaching a peak of 5.6 mg/dL on the day of surgery. In the setting of hypercalcaemia where primary or tertiary HPT is suspected, physicians should investigate other aetiologies (e.g. malignancy, thiazide or lithium use, milkalkali syndrome, hypervitaminosis D and granulomatous disease) in addition to HPT (Table 1). Iatrogenic hypercalcaemia can also result from use of high-dose oral calcium and activated vitamin D derivatives, which are commonly given to patients with end-stage renal disease but are rarely used in patients with lesser degrees of impaired kidney function.
Second, the markedly elevated PTH concentration (>2400 pg/mL) observed in this case is more typical of secondary (or tertiary) HPT. We are confident in the accuracy of these values; at our institution, PTH was measured using a non-competitive immunoassay (Immulite 2000, Siemens Medical Solutions Diagnostics, Newark, DE) with precision documented at 5% CVand linearity verified across the analytically measurable range of 3–2500 pg/ml (R2= 0.99). In a recent series of 80 patients with primary HPT from adenoma, the highest reported PTH concentration was 2578 pg/mL [11].
Third, the size of this patient’ s parathyroid adenoma was quite large. In primary HPT, adenoma size is an important determinant of disease severity, but the reason for the large variation (100-fold) in size is unknown. Two recent studies reported normal parathyroid glands weights from 62.4 ± 31.6 mg [12] and from 42.6 ± 20.3 mg [13], respectively.
The mean parathyroid adenoma weight was 553.7 ± 520.5 mg [12]. This patient’ s parathyroid adenoma weighed 2 g, making it significantly larger than most reported parathyroid adenona.

Table 1. PTH concentrations in various aetiologies of hypercalcaemia

Adenomas weighing more than 60 g have been rarely reported [14,15]. Fourth, this patient suffered acute-on-chronic renal failure, most likely due to hypercalcaemia (peaking at more than 17.0 mg/dL). Serum calcium concentrations from 12.0 to 15.0 mg/dL have been shown to decrease GFR by direct vasoconstriction and natriuresis leading to volume depletion and pre-renal azotemia [16]. Additionally,
aquaporin-2 downregulation along with tubulointerstitial injury resulting in impaired osmotic gradient formation may preclude effective urine concentrating mechanisms [17]. In addition to impaired kidney function related to hypercalcaemia-induced vasoconstriction, nephrocalcinosis and possibly acute tubular necrosis (associated with radiocontrast administration and/or hypotension) may have con-
tributed to the acute kidney injury.
Rather than an exceptional case of primary HPT, most of this patient’ s clinical features are more consistent with either tertiary HPT or parathyroid carcinoma. Parathyroid carcinoma accounted for only 0.74% of more than 22 000 cases of ‘primary HPT’ in a large retrospective study [8].
Total serum calcium concentrations were >14 mg/dL in more than two-thirds of carcinoma cases [9,18]. Nephrolithiasis, nephrocalcinosis and impaired kidney function are found in 32–80% of patients with parathyroid carcinoma compared with 4–18% in benign primary HPT [19]. In this case, there was no evidence of malignancy.
All physicians encountering patients with HPT must be familiar with the multiple aetiologies of hypercalcaemia and understand that ionized calcium is typically maintained in the normal range unless CKD is quite advanced (GFR well below 30 mL/min/1.73 m2) [20]. While uncommon, hypercalcaemia and HPT may exist concurrently from unrelated aetiologies. Malignancies, including multiple myeloma, non-Hodgkin’ s lymphoma and tumours metastatic to bone can lead to frank or relative hypercalcaemia. However, elevated PTH concentrations typically only occur with concomitant primary HPT (adenoma, carcinoma), and current assays are able to distinguish PTH from rare PTH-related peptide-secreting neoplasms [21]. Thiazide diuretics [22], oral calcium supplementation (including milk–alkali syndrome) and hypervitaminosis D can also result in iatrogenic, PTH-independent hypercalcaemia.
If HPT is confirmed, secondary HPT should be entertained. While most patients with moderate to advanced CKD and evidence of elevated PTH have normal or low serum calcium concentrations, a fraction with low bone turnover may have mild hypercalcaemia. More commonly, iatrogenic hypercalcaemia develops from overzealous management of hyperphosphataemia with calcium-based phosphate binders (calcium carbonate and acetate) and activated vitamin D derivatives. When secondary HPT is refractory to medical therapy and/or PTH fails to suppress in the presence of hypercalcaemia (as in this case), tertiary HPT should be suspected. Subtotal parathyroidectomy should be considered in patients with signs or symptoms referable to HPT, including calcific uremic arteriolopathy (calciphylaxis), fracture, bone pain, myopathy, neuropathy, recalcitrant pruritus or refractory hypertension.
While secondary HPT is the dominant disorder of parathyroid structure and function in patients with CKD, hypercalcaemia in the absence of culprit medications and/or non-suppression of PTH should direct clinicians toward ‘non-secondary’ HPT—either tertiary or, as in this case, primary. The latter may co-exist with secondary HPT and be more subtle and difficult to diagnose. This case illustrates the importance of understanding endogenous and iatrogenic aetiologies of hypercalcaemia and HPT along with an effective diagnostic approach to identify and promptly treat patients with this severe syndrome.

Sinh lý bệnh học cường tuyến cận giáp thứ phát: Suy thận ----> Giảm Ca, tăng P, giảm vitamin D3 ---> Tuyến cận giáp tăng tiết PTH ---> ảnh hưởng ngược trở lại trên thận và các xương.

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