Secondary Hyperparathyroidism

Definition, Etiology, PathogenesisTop

Secondary hyperparathyroidism refers to parathyroid hormone (PTH) hypersecretion by hypertrophic parathyroid glands. There are 3 main stimuli that have been demonstrated to affect PTH secretion. The most potent regulator of PTH synthesis and secretion is low serum calcium concentration, acting through its interaction with the calcium-sensing receptor (CaSR) on the parathyroid cell surface. Phosphate is another important PTH stimulus, as high phosphate level can stimulate PTH secretion directly at the parathyroid level as well as indirectly by lowering the serum calcium and 1,25-dihydroxycholecalciferol (1,25[OH]2D3). Vitamin D deficiency represents a third regulator of increased PTH synthesis, mainly through decreased calcium absorption. Secondary hyperparathyroidism can therefore be regarded as an adaptive response of the parathyroid gland to one or multiple stimuli excess in order to maintain the balance of calcium homeostasis.

Causes: 

Chronic kidney disease (CKD) leads to a decrease in nephron mass causing phosphate retention and decreased activation of calcitriol by renal 1-alpha-hydroxylase. High phosphate directly stimulates PTH secretion and indirectly contributes to hypocalcemia by binding calcium [Ca2+] in the serum. Decreased calcitriol contributes to reduced vitamin D–mediated gastrointestinal calcium absorption, leading to a further increase in PTH secretion.

Vitamin D deficiency due to insufficient oral intake or in association with malabsorption syndromes such as celiac disease, exocrine pancreas insufficiency, gastric bypass, or small bowel disease can lead to secondary hyperparathyroidism. Hereditary defects in the vitamin D metabolism pathway also cause vitamin D deficiency. Another cause of vitamin D deficiency can be severe liver disease, since the liver is the site of production of calcidol (25-hydroxyvitamin D [25(OH)D]). Certain drugs (eg, certain antiepileptics) can also increase the catabolism of vitamin D. Nephrotic syndrome can lead to loss of vitamin D in the urine.

Hypocalcemia leads to an appropriate rise in PTH levels and manifests as secondary hyperparathyroidism. This can occur through insufficient calcium intake through diet, following a bariatric surgery, or due to hypercalciuria, hypomagnesemia, and other causes.

Secondary hyperparathyroidism can also rarely occur in the context of PTH resistance syndromes known as pseudohypoparathyroidism.

Clinical Features and Natural HistoryTop

If due to hypocalcemia, signs and symptoms of secondary hyperparathyroidism depend on the underlying condition that caused chronic hypocalcemia, its duration, and prior treatment. These patients may show classic signs and symptoms of hypocalcemia such as neuromuscular irritability (ie, acral and perioral paresthesia) as well as muscle spasms, cramps, and weakness.

Advanced secondary hyperparathyroidism in patients with CKD may lead to the development of renal osteodystrophy associated with high bone turnover. On the contrary, aggressive treatment of secondary hyperparathyroidism in CKD may paradoxically lead to adynamic bone disease, characterized by low bone turnover (see Chronic Kidney Disease). Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have significant bone pain, deformity, and even fractures. They can develop severe osteodystrophy, soft tissue calcification, persistent pruritus and, in extreme cases,  spontaneous rupture of tendons. Calciphylaxis has been reported in a small proportion of patients with end-stage CKD, with areas of painful ischemic skin necrosis most commonly involving the lower extremities.

Vitamin D deficiency may present as rickets in children and osteomalacia in adults; patients may be referred for evaluation of osteopenia or osteoporosis in these contexts.

Clinical manifestations of malabsorption syndromes should be investigated in patients with otherwise appropriate vitamin D intake or supplementation.

Cirrhosis can be associated with vitamin D deficiency related to impaired 25-hydroxylation.

A detailed drug history is also important to see if any drugs interfere with calcium, phosphate, or vitamin D metabolism. Common medications that impair vitamin D metabolism: Table 1.

DiagnosisTop

The diagnosis of secondary hyperparathyroidism relies on a combination of clinical and biochemical findings: Table 2.

The finding of low or low normal calcium with elevated PTH levels suggests secondary hyperparathyroidism. Completing the biochemical profile with creatinine, 25(OH)D, and urine calcium and phosphate levels will reveal the underlying pathology leading to secondary hyperparathyroidism.

TreatmentTop

Treatment is largely dependent on the underlying defect causing secondary hyperparathyroidism.

1. Vitamin D deficiency/insufficiency states should be treated with vitamin D3 (cholecalciferol) or D2 (ergocalciferol), and any contributing malabsorption syndromes should be addressed. Note that the doses suggested by the Institute of Medicine are for the general population and aim to prevent vitamin D insufficiency, therefore larger doses could be needed to replete vitamin D stores, and a loading regimen 50,000 IU of vitamin D2 weekly for 8 weeks has been proposed. If D2 is unavailable, replacement with vitamin D3 can be done. Vitamin D3 is significantly more potent than vitamin D2; if used as a substitute for D2, we recommend 30,000 IU of vitamin D3 weekly for 8 weeks. After the 8-week period, if the target vitamin D3 level has been reached (75-125 nmol/L), patients can be switched to a maintenance dose of 1000 to 2000 IU of vitamin D3 daily and undergo repeat vitamin D3 testing in 3 months, with further adjustment to vitamin D3 as needed to reach the target range. Data on the relationship between calcium supplementation and cardiovascular disease risk are conflicting. Efforts should be made to obtain the recommended daily intake of calcium naturally through the patient’s diet. If the total daily calcium intake is unmet through the diet, calcium supplements should be used judiciously.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Huo X, Clarke R, Halsey J, et al; Calcium Supplements Treatment Trialists’ Collaboration. Calcium Supplements and Risk of CVD: A Meta-Analysis of Randomized Trials. Curr Dev Nutr. 2023 Feb 15;7(3):100046. doi: 10.1016/j.cdnut.2023.100046. PMID: 37181938; PMCID: PMC10111600.

2. Correction of hyperphosphatemia (see Hyperphosphatemia). Prevention of hyperphosphatemia is a cornerstone of treatment in CKD and could be achieved by adherence to a low-phosphate diet as well as by the use of phosphate binders as needed. As per the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, 25(OH)D should be maintained at ~75 nmol/L in CKD stages 3 to 4. Such evidence of benefit is lacking in stage 5 disease in patients undergoing dialysis. In end-stage CKD, if PTH levels remain elevated despite the correction of vitamin D deficiency, adequate calcium supplementation, and control of phosphorous level with diet and/or phosphate binders, consideration should be given to introduce active vitamin D metabolites such as calcitriol or alfacalcidol. As these agents promote the absorption of both phosphate and calcium from the gut, they should be avoided in patients with high phosphate level to avoid the potential for ectopic calcification.

3. Correction of hypocalcemia (see Hypocalcemia) and hypomagnesemia (the latter is an important cause of hypoparathyroidism that can lead to hypocalcemia).

4. If the above treatment is ineffective in lowering PTH levels, calcimimetics may be used: cinacalcet 30 to 90 mg/d (unless the patient has hypocalcemia). Cinacalcet acts on the parathyroid gland CaSR and increases its sensitivity to calcium, therefore decreasing PTH secretion.

5. Surgical treatment of secondary hyperparathyroidism may be required when failure of the above measures results in persistent elevation of PTH levels and ongoing or worsening symptoms. However, there is no universally accepted PTH threshold for surgery in asymptomatic individuals. In such cases, parathyroidectomy is considered in the presence of refractory biochemical abnormalities (eg, hyperphosphatemia, markedly elevated PTH levels) or a high risk of complications that cannot be addressed with medical therapy. Despite advances in medical treatment, it is estimated that surgery will be required in ~15% of patients in 10 years and in 38% of patients in 20 years after the initiation of dialysis. That is tailored to renal disease and the likelihood of kidney transplant: subtotal parathyroidectomy is preferred in patients in whom kidney transplant is anticipated, and total parathyroidectomy with parathyroid transplant is preferred in those with no immediate plan for kidney transplant. The decision to proceed with parathyroidectomy is highly individualized, taking into account disease severity, treatment response, and patient-specific factors.

Management of secondary hyperparathyroidism in patients with CKD: see Chronic Kidney Disease.

TablesTop