In our cohort, asymptomatic PHPT was uncommon due to various reasons, including, lack of awareness regarding the disease in the primary health care facilities, lack of routine calcium screening and prevalent vitamin D deficiency in our country. Moreover, 75% of our cohort were vitamin D insufficient. Suboptimal vitamin D nutrition stimulates parathyroid adenoma growth and calcaemic response to PTH [2]. Apart from the predominance of severe symptomatic presentations, this may also explain the earlier presentation of PHPT in our study compared to that reported in western countries.
Among symptomatic phenotypes in west, overt nephrolithiasis usually occurs in less than 20% of patients with PHPT and radiologically evident bone disease is found to be even less common [16]. Our cohort had 40% cases of nephrolithiasis and 25% cases of clinical fractures at presentation. Age and female gender were earlier found to be significant predictors of fractures in PHPT [17]. In support of this finding, all patients presenting with clinical fractures in our cohort were females and majority (80%) of them were postmenopausal. All patients who had clinical vertebral fractures at presentation (n = 5), were postmenopausal. Although trabecular bone is relatively preserved compared to the cortical bone in patients with PHPT, fracture risk is increased at both non-vertebral (predominantly cortical) and vertebral (trabecular) sites [18]. The higher prevalence of fractures (especially vertebral) in postmenopausal females can be explained by the typical postmenopausal bone loss (particularly in trabecular bone) due to estrogen deficiency.
In our study 25-OHD had a significant negative correlation with ALP, but no correlation with PTH levels was seen. This observation is in contrast to one study done among 100 Caucasian patients that found a significant correlation of lower 25-OHD levels with some (PTH, r= -0.42; 1,25-(OH)2D, r = -0.27; phosphate, r = 0.31), but not all (serum or urine calcium) indicators of PHPT severity [3]. PTH can stimulate the renal 1α-hydroxylase with subsequent reduction in 25-OHD via increased 1,25-(OH)2D biosynthesis; and increased 1,25-(OH)2D can in turn accelerate 25-OHD catabolism. Due to lack of consistently significant inverse correlation between 25-OHD and 1,25-(OH)2D in PHPT, 25-OHD deficiency has long been believed to be the reason behind increased parathyroid gland weight and higher PTH level [2]. However, adenomatous transformation following parathyroid hyperplasia may lead to increased set point of the calcium sensing receptor (CaSR) and resetting of serum calcium levels at a higher level [19]. This abnormal calcium or 1, 25-(OH)2D sensing in tumours along with autonomous PTH secretion can explain the lack of correlation between PTH and 25-OHD in our cohort. Impaired calcium sensing in parathyroid tumours was indeed observed in one subset of patients with severe bone mineral density deficit [20].
Patients with isolated bone disease phenotype in our cohort had significantly higher ALP levels (not PTH levels) and lower 25-OHD levels compared to other subgroups. In this regard, 25-OHD was found to be an independent predictor (effect not mediated by higher PTH) of cortical bone mineral density in PHPT [3]. In another study, 25-OHD deficiency was associated with lower cortical width on bone biopsy, whereas PTH levels failed to show any association [21]. Although PTH was similar between symptomatic PHPT subgroups in our study, higher ALP levels indeed suggest increased bone turnover in patients with isolated bone disease. The pulsatile secretion of intact PTH account for about 50% of its total secretion even in patients with PHPT [22]. This could explain the lack of correlation between PTH and ALP levels in our cohort. Serum ALP demonstrates a lower variability, thereby may be a more suitable marker of bone turnover.
Younger age and male gender have been found to be independently associated with presence of nephrolithiasis in previous studies [6, 9, 23]. A trend towards significant association with male gender was observed in our study. Serum calcium was significantly higher in patients with nephrolithiasis similar to previous studies [9, 24, 25]. As in our cohort of symptomatic PHPT, 25-OHD was found to be significantly higher in nephrolithiasis in one study [3]. In contrast, another study reported lower level of 25-OHD in nephrolithiasis at diagnosis than their counterparts [23]. Several other studies did not find any association between serum biochemistry and renal stones [6, 26–28].
Patients with IRF (eGFR < 60 ml/min/m2) in our cohort had significantly higher calcium, phosphate, PTH levels and nephrolithiasis rates. Reduced glomerular filtration leading to higher phosphate levels, as seen in our study, has been reported in one previous study [29]. Long standing nephrolithiasis or hypercalcemia in PHPT can lead to decrease in eGFR [8]. Few previous studies however did not find higher nephrolithiasis rates in IRF [9, 11, 30], thereby suggesting that urinary obstruction might not be common in PHPT with renal stones. With the exception of few studies [9, 30], neither calcium levels [10, 11, 29, 31] nor PTH levels [11, 29, 31] have consistently been found to be higher in IRF. It has therefore been suggested that secondary elevation of PTH might not occur at the eGFR threshold of 60 ml/min per 1.73 m2 [12]. Nonetheless, Tassone et al. observed that PTH levels increase further in PHPT only when eGFR goes below 30 ml/min per 1.73 m2 [10]. The conflicting evidence with regards to PTH elevation in IRF may be due to variable proportion of severe renal dysfunction in the IRF group. Although 35% of patients with IRF (n = 6/17) in our study had eGFR below 30 ml/min per 1.73 m2, PTH was not found to be significantly higher in these patients when compared to subgroup with eGFR 30–60 ml/min per 1.73 m2 despite a higher phosphate level (an important stimulus for PTH secretion). Underlying 25-OHD deficiency could also be an important determinant of eGFR threshold at which significant PTH elevation occurs. However, a trend towards higher 25-OHD in IRF nullifies this possibility in our study.
Thereafter we did a logistic regression analysis and showed that PTH was an independent biochemical predictor of IRF in our symptomatic PHPT cohort. Amongst several reasons of PHPT related kidney dysfunction, direct effect of PTH in accentuating endothelial injury and organ fibrosis in the kidneys with high expression of PTH receptors has also been suggested [32]. The causal effect of CaxP on renal dysfunction is difficult to establish. Nonetheless, elevated admission CaxP has previously been found to be an independent predictor of decline in renal function in hospitalized patients [33]. As phosphate levels increase with decline in eGFR in a background of persistent hypercalcemia as in PHPT, precipitation of calcium phosphate crystals is more likely to occur and that may lead to injuries in the distal tubules and collecting ducts.
Our study has certain limitations. First, there was a lack of information regarding sun exposure, hydration status, dietary calcium and vitamin D intake in majority of our patients. Second, gold standard LC-MS/MS assay for 25-OHD measurement was not available.