Approach
Secondary hyperparathyroidism (SHPT) is a diagnosis based on the clinical picture and metabolic derangements of low serum calcium and high parathyroid hormone (PTH). When phosphorus levels are also elevated, this points to chronic kidney disease (CKD) as the aetiology. If phosphorus levels are normal or low, with low serum calcium and high PTH, vitamin D levels should be measured. If vitamin D levels are low, malabsorption syndromes, inadequate sunlight exposure, and other abnormalities of vitamin D metabolism should be considered.[9]
Clinical features
Clinical features will reflect the underlying metabolic derangement itself and the underlying disease causing the derangement.
Severe vitamin D deficiency and hypocalcaemia classically presents with features of neuromuscular irritability.[32] This may manifest as numbness and paresthaesia in the fingers, toes, or periorally; muscle cramps; laryngospasm; tetany; or seizures. Chvostek's sign (tapping on the face just anterior to the ear produces twitching of muscles around the mouth) or Trousseau's sign (inflating a blood-pressure cuff above diastolic for about 3 minutes causes muscular flexion of the wrist, hyperextension of the fingers, and flexion of the thumb) may be elicited.
The inadequate calcium-phosphorus product that results from vitamin D deficiency causes the bone matrix laid down by osteoblasts to be abnormally mineralised. In children, this may lead to the development of rickets, with signs of growth retardation and skeletal deformities (e.g., bowed legs or knocked knees). In adults, inadequate bone mineralisation may lead to osteomalacia, with symptoms such as muscle weakness and diffuse bone pain (commonly affecting the pelvis, hips, legs, lower back, or ribs).[15]
CKD is a frequent cause of SHPT and is often already diagnosed. Signs and symptoms of advanced CKD include skin discoloration and bruising, pruritus, lung rales, pericardial rub, oedema, fatigue, nausea, poor concentration/memory, and myoclonus.[33][34] Diagnostic tests for CKD-mineral bone disorder (CKD-MBD) are usually reserved for when the estimated GFR is <60 mL/minute/1.73 m². Initial investigations should include PTH, calcium, phosphorus, and 25-hydroxyvitamin D.[9] Imaging for vascular or cardiac valvular calcification should be considered because patients with CKD-MBD have the highest cardiovascular risk.[1]
Malabsorption (which may lead to vitamin D deficiency and poor calcium absorption) may arise from a number of conditions, such as Crohn's disease, coeliac disease, chronic pancreatitis, or Whipple's disease, or following gastric bypass surgery.[15] Frequently these diagnoses have already been established. Patients often have a history of long-standing gastrointestinal symptoms such as abdominal pains, irregular bowel habit, and chronic diarrhoea.
Inadequate exposure to sunlight may be particularly likely in older people (who may be housebound, hospitalised, or institutionalised), heavy/habitual users of sunblock, and those who routinely wear clothing that covers their entire body. The skin of older people also has a reduced capacity to synthesise vitamin D3 under the influence of ultraviolet light.[11][23] Other factors that may lead to insufficient exposure to ultraviolet radiation include season, geographic latitude, time of day during sun exposure, degree of skin pigmentation, cloud cover, and smog.[3][12][15]
Vitamin D deficiency may also develop in people who strictly avoid dairy products in their diet or are users of drugs such as phenytoin, phenobarbital, rifampin, corticosteroids, isoniazid, or lithium.
Laboratory testing
Laboratory investigations are required to confirm the metabolic derangement of elevated PTH and hypocalcaemia, and to help establish the underlying cause. Initial investigations should include PTH, calcium, phosphorus, 25-hydroxyvitamin D, and assessment of renal function.[9]
Intact parathyroid hormone (iPTH)
Elevation of iPTH is the definitive test to establish hyperparathyroidism. iPTH should always be ordered with a paired calcium level so that the iPTH level can be properly interpreted. PTH levels vary over the course of a day, peaking at about 2 a.m.[35]
Calcium level
The relationship between the calcium level and the iPTH level is what distinguishes primary from SHPT. In SHPT, the calcium level is low, which results in a loss of negative feedback on the parathyroid glands. This causes an increase in the production of PTH in an attempt to increase calcium levels back into the normal range. Total or ionised calcium can be measured, but it is important to use the same test on every occasion in order to allow accurate comparisons and trend analysis.
25-hydroxyvitamin D
Evaluation for possible vitamin D deficiency should form part of the work-up of a patient with suspected SHPT, as it is the most common reason for PTH elevation.[11][25][36]
The level of 25-hydroxyvitamin D is the most accurate measure of the amount of vitamin D in the body. Other metabolites may be measured, but these do not reflect the total body stores of this fat-soluble vitamin as accurately as 25-hydroxyvitamin D. Thresholds for the definition of vitamin D deficiency for the general population differ between advisory bodies.[37] The normal range may vary between laboratories, but is usually 40 to 184 nanomol/L (16 to 74 nanograms/mL). Many experts hold that any value 75 nanomol/L (30 nanograms/mL) or less demonstrates vitamin D insufficiency.[3] If the PTH is elevated and the 25-hydroxyvitamin D level is low, the latter should be corrected before considering aggressive drug therapy or surgery.
In some cases, measurement of 1,25-dihydroxyvitamin D may appear normal despite significant vitamin D deficiency. Elevated PTH drives the conversion of 25-hydroxyvitamin D, thus creating the appearance that the 1,25-dihydroxy form is normal when 25-hydroxyvitamin D reserves are depleted.[21]
Renal function and phosphorus levels
Serum creatinine, urea, and calculated GFR are used to assess renal function. These laboratory tests form part of routine serum multi-analysis panels and, if elevated, suggest kidney disease, the most serious cause of SHPT.[38]
Biochemical changes of CKD-MBD increase when estimated GFR falls below 60 mL/minute/1.73 m².[9]
Measuring phosphorus levels allows an appreciation of the severity of kidney disease and may indicate the need for phosphorus reduction therapy. When phosphorus levels are elevated in addition to elevated serum creatinine and urea, this points to CKD as the aetiology of SHPT. If phosphorus levels are low, other anomalies such as vitamin D deficiency are more likely.[9]
Magnesium level
Imaging
Once the diagnosis is established and if surgical treatment is considered, ultrasound, high-resolution contrast computed tomography (CT), magnetic resonance imaging, and 99Tc-sestamibi (MIBI) nuclear medicine scans may be used to confirm parathyroid hyperplasia, and to estimate the size and location of the glands.[41][42] One meta-analysis has, however, found that planar parathyroid scintigraphy using 99Tc-MIBI did not provide adequate diagnostic accuracy in patients with SHPT and diffuse or nodular hyperplasia, and therefore should not be used as a first-line diagnostic imaging method in the presurgical detection of parathyroid gland hyperplasia.[43] 99mTc-MIBI single-photon emission computed tomography (SPECT)/CT has shown better sensitivity than 99mTc-MIBI planar scintigraphy in identifying parathyroid lesion in SHPT. 99mTc-MIBI SPECT/CT sensitivity is further improved when used in combination with ultrasound.[44]
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