The Natural History of Untreated Hyperparathyroidism

Fig. 10.1
Osteitis fibrosa cystica in the pelvis [8]

In less developed countries, hyperparathyroidism more often presents as a severe, symptomatic disease [7]. OFC is characterized by overstimulation and proliferation of osteoclasts secondary to prolonged elevation of parathyroid hormone levels, which leads to increased bone resorption and thinning of the cortex. Hemorrhage into these cystic areas of resorption leads to hemosiderin deposition, giving the characteristic brown tumor appearance. Parathyroidectomy is associated with resolution and progressive reversal of this bony disease [8] (Fig. 10.2).


Fig. 10.2
Brown tumor of the bone in a patient with hyperparathyroidism [29]

A more common manifestation of hyperparathyroidism in Western countries is decreased BMD measured on DEXA scanning . PTH has a higher catabolic effect on cortical bone (distal radius and femur) compared to cancellous bone (lumbar spine). A 15-year prospective study of hyperparathyroidism treated with and without surgery demonstrated statistically significant increases in BMD loss of non-operated patients in the femoral head and the distal third of the radius, which are both primarily sites of cortical bone. In contrast, the lumbar spinal BMD, composed primarily of cancellous bone, was relatively preserved. In patients treated with parathyroidectomy, BMD increased from baseline values after 15-year follow-up [9].

Studies investigating skeletal microarchitecture in the setting of PHPT have demonstrated a loss of cortical bone with preservation of the trabecular architecture of cancellous bone. In PHPT, there is a marked increase in cortical porosity, which may lead to increased bone fragility, especially in cortical bone [10].

Vitamin D deficiency is increasingly recognized as a widely prevalent condition. Recent research suggests that the prevalence vitamin D deficiency in the USA and other Western countries is over 40% [11]. In the setting of vitamin D deficiency, the anabolic effect of elevated PTH on trabecular bone (increased number, volume, and interconnectivity of trabeculae) and its catabolic effect on cortical bone (cortical width thinning) are exacerbated [12]. Three-dimensional analysis of cancellous bone specimens suggests that PHPT helps stabilize and reduce trabecular thinning in postmenopausal women [13] (Fig. 10.3).


Fig. 10.3
Cancellous bone architecture in (a) normal premenopausal women, (b) normal postmenopausal women, (c) premenopausal PHPT women, and (d) postmenopausal PHPT women [13]

The anabolic effect of elevated PTH on trabecular bone formation does not reduce the incidence of fractures in bones with predominantly trabecular architecture (e.g., vertebral column). In a retrospective study of PHPT patients (N = 407) over a 28-year period, mild PHPT resulted in a statistically significant increased risk of vertebral fractures. In addition, this study showed that there was an increased risk of distal radius, rib, pelvic, and any-site fractures. The study did not demonstrate a statistically significant increase in hip fractures [14] (Fig. 10.4).


Fig. 10.4
PHQ-9 scores >10 (used to assess depression) at baseline, 1 month, 3 months, 6 months, and 1 year for both surgical (parathyroid and thyroid surgery) and observational groups [21]. “asterisk” indicates significant drop from baseline

Effects of Hyperparathyroidism: Renal Disease

In the kidney, PTH regulates serum calcium and phosphate at the proximal and distal convoluted tubules of the nephron. The vast majority of phosphate is reabsorbed in the proximal convoluted tubules; in the proximal tubules, PTH works to internalize the Na-PO4 transporter, thereby increasing phosphate excretion into the urine. In the distal convoluted tubules, PTH stimulates active reabsorption of calcium preventing excess calcium loss into the urine. In the setting of PHPT, prolonged hypercalciuria is a known risk factor for nephrolithiasis [15]. Between 20 and 50% of patients with hyperparathyroidism develop nephrolithiasis . The most common stone types in PHPT are calcium oxalate and calcium phosphate. PHPT can also cause nephrocalcinosis , which is a deposition of calcium-phosphate complexes in the parenchyma of the kidney itself. Current recommendations from the Fourth International Workshop on PHPT recommend imaging of the kidney of patients with asymptomatic PHPT for subclinical stone disease and nephrocalcinosis, with positive imaging constituting an indication for parathyroidectomy [4].

Hyperparathyroidism can cause metabolic derangements, such as type 2 metabolic acidosis. PTH decreases bicarbonate reabsorption in the proximal tubule. Chronic PTH elevation reduces serum bicarbonate levels and causes reactive hyperchloremia [16]. This is why chloride elevation can be a subtle marker of PHPT in cases where the classic calcium/PTH relationships are absent. The severity of metabolic acidosis can be the most severe approximately 48 h after parathyroidectomy [17].

Effects of Hyperparathyroidism: Cardiovascular Disease

In a Scandinavian study, patients with moderately severe to severe PHPT demonstrated a higher mortality when compared to patients with normal serum PTH and calcium. The elevation in mortality rate diminished over time following parathyroidectomy. The mortality of patients with mild PHPT was not statistically different compared to the age- and sex-matched control population without PHPT [18]. Vestergaard et al. evaluated a group of Danish residents (N=674) diagnosed with PHPT as defined by elevated serum calcium and serum PTH in the upper one-third of the normal range or elevated beyond the normal range. In the decade preceding parathyroidectomy, PHPT patients had a significantly higher rate of myocardial infarction (MI) compared to matched controls (relative risk 2.5). MI incidence returned to control levels approximately 1 year after the patient underwent parathyroidectomy [19]. Hypertension has frequently been associated with PHPT; yet studies have not shown clear evidence of hypertension reversal following parathyroidectomy. Other studies have shown serum calcium and PTH levels to be independent predictors of coronary heart disease.

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Aug 28, 2017 | Posted by in OTOLARYNGOLOGY | Comments Off on The Natural History of Untreated Hyperparathyroidism
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