مخاطبین محترم : رزیدنتهای داخلی و فلوهای غدد
مفید و خلاصه از : UPTODATE 21.2
Diagnosis and differential diagnosis of primary hyperparathyroidism
for diagnosis of hyperparathyroidism hypercalcemia should be confirmed on a repeat sample
PTH should be measured using a two-site immunoradiometric sandwich assay.
The most common clinical presentation of primary hyperparathyroidism is asymptomatic hypercalcemia.
The diagnosis : by finding a frankly elevated PTH concentration or one that is within the normal range but inappropriately elevated given the patient’s hypercalcemia
Measurement of serum calcium —
The total serum Ca should be used for both the initial and the repeat serum calcium measurements.
One circumstance in which ionized Ca measurements may be a useful adjunct to diagnosis is in patients with normocalcemic primary hyperparathyroidism.
The presence of longstanding asymptomatic hypercalcemia is more suggestive of PHP and FHH
Measurement of PTH —
by the use of (IRMA) and immunochemiluminescent assays measure intact PTH
Approximately 80 to 90 % of patients with PHP have high serum PTH concentrations (normal range 10 to 60 pg/mL )
۱۰ to 20 % of patients : have only minimally elevated or normal serum PTH , are ranging from 35 to 65 pg/mL
These “normal” values PTH in the presence of hypercalcemia are inappropriately high;
normal subjects given IV calcium have suppressed serum PTH concentrations (<10 pg/mL) .
patients with nonparathyroid hypercalcemia virtually always have PTH < 20 to 25 pg/mL.
Rarely, a patient with proven PHP has a serum intact PTH in the lower half of the normal range or one that is undetectable.
The immunoradiometric assays -IRMA-(second generation PTH assays) that replaced older radioimmunoassays – RIA -(first generation PTH assays) for PTH were touted as measuring “intact” PTH molecule.
It is now recognized that second-generation PTH assays detect not only intact 1-84 PTH, but also large carboxyterminal fragments (such as 7-84) of PTH.
Some of these fragments may be biologically inactive, while others may inhibit osteoclastic bone resorption, inhibit the formation of mature osteoclasts, and have hypocalcemic properties
Newer third-generation assays that detect exclusively the biologically active PTH 1-84 (whole PTH or bioactive PTH) require both the extreme amino-terminal and carboxy-terminal ends of the molecule for detection.
Thus, either intact PTH (second-generation PTH assay) or PTH (1-84) assays (third generation PTH assays) can be used for diagnosis of hyperparathyroidism .
DIFFERENTIAL DIAGNOSIS —
primary hyperparathyroidism PHP
familial hypocalciuric hypercalcemia (FHH),
and secondary hyperparathyroidism
In PHP and FHH: the Ca and PTH levels are usually simultaneously elevated.
Other less common causes of hypercalcemia, including milk-alkali syndrome, granulomatous disease, and hypervitaminosis D, are associated with suppressed rather than elevated PTH concentrations.
Malignancy is often evident clinically by the time it causes hypercalcemia,
patients with hypercalcemia of malignancy have higher Ca concentrations
are more symptomatic
some patients with occult malignancy may present with mild hypercalcemia. Alternatively, patients with hyperparathyroidism can occasionally have acute onset of severe, symptomatic hypercalcemia (parathyroid crisis).
Intact PTH are generally undetectable or very low in hypercalcemia of malignancy and are elevated or high-normal in PHP.
Familial hypocalciuric hypercalcemia —
(FHH) is due to an inactivating mutation in the calcium-sensing receptor in the parathyroid glands and the kidneys
A family history of hypercalcemia, especially in young children, and the absence of symptoms and signs of hypercalcemia (such as anorexia, neuromuscular symptoms, and polyuria) are characteristic of this disorder.
۱۵ to 20 %of pt with FHH may have a mildly elevated PTH .
The major feature that distinguishes FHH from PHP is a low urine calcium excretion and Ca/Cr clearance ratio .
most patients with PHP have either normal or elevated urinary calcium excretion.
urinary magnesium is low in FHH in contrast to primary hyperparathyroidism
Two drugs: thiazide diuretics and lithium.
Thiazide diuretics reduce urinary calcium excretion and therefore can cause mild hypercalcemia (up to 11.5 mg/dL
if a patient taking a thiazide is found to be hypercalcemic, the drug should be withdrawn, if possible, and calcium and PTH assessed three months later. Persistent hypercalcemia (with elevated or high-normal PTH) after drug withdrawal suggests that the thiazide has unmasked PHP .
Lithium decreases parathyroid gland sensitivity to calcium, may also reduce urinary calcium excretion.
Some patients taking lithium develop hypercalcemia and hypocalciuria, and a subset of these individuals has high serum PTH.
Following discontinuation, Ca is more likely to normalize if the duration of lithium use had been relatively short, eg, less than a few years, but less likely if it had been longer, eg, more than 10 years
Normocalcemic PHP versus secondary PHP —
Occasionally, patients with PHP have normal total and ionized Ca (Normocalcemic PHP). These patients typically come to medical attention in the setting of an evaluation for low bone mineral density.
Secondary hyperparathyroidism —
it is characterized biochemically by elevated PTH and normal or low serum calcium concentrations.
may occur in patients with renal failure and impaired calcitriol (1,25 dihydroxyvitamin D) production, as well as in individuals with inadequate calcium intake or absorption, as can occur with vitamin D deficiency or with GI diseases causing malabsorption .
Assessment of renal function (serum cr), vitamin D status (25OHD), and Ca sufficiency (urinary Ca excretion) may help differentiate Normocalcemic PHP AND secondary PHP
Co-existing PHP and vit D deficiency is not uncommon : serum Ca in the PHP may be reduced (into the normal range in some cases) due to vitamin D deficiency.
Normocalcemic primary hyperparathyroidism —
a new phenotype of PHP in which PTH levels are elevated but serum Ca is normal
FOR diagnosis, all secondary causes for hyperparathyroidism must be ruled out, and ionized calcium levels should be normal.
The most common explanation : concomitant hypercalcemic PHP and vit D deficiency.
Patients without an apparent secondary cause may have a “forme fruste” of PHP . It might be expected that early in the natural history of PHP .
TESTS TO CONFIRM PHP —
PHP is suspected when the intact PTH or PTH (1-84) concentration is elevated or high-normal in the setting of hypercalcemia.
Additional tests that can distinguish PHP from the diseases described above include measurement of urinary Ca excretion and 25-OH D
Measurement of urinary calcium excretion —
Measurement of 24-hour urine calcium excretion is required for distinguishing PHP from (FHH).
Approximately 40 % of pt with php are hypercalciuric,
most of the remaining patients have normal values
If Ca excretion is low, eg, < 200 mg/day (5.0 mmol/day), FHH or PHP with concomitant vitamin D deficiency are possibilities;
about 75 % of FHH excrete < 100 mg of calcium in urine daily
A Ca/Cr clearance ratio, is calculated from 24-hour urinary Ca and Cr and total serum Ca and Cr using the following formula:
Ca/Cr clearance ratio = [24 hour Urine Ca x serum Cr] ÷ [serum Ca x 24 hour Urine Cr]
The data establishing the value of the calcium to creatinine clearance ratio in differentiating FHH from PHP are based primarily on 24 hour urine collections.
A value 0.02).
a value >0.02 essentially excluded FHH .
Due to the difficulty of differentiating FHH from PHP when the Ca/Cr clearance ratio is <0.02, some have suggested CaSR mutation analysis for such individuals
Vitamin D metabolites —
Serum concentrations of 1,25 dihydroxyvitamin D may therefore be at upper limits of normal or elevated and measurement of 1,25-dihydroxyvitamin D is not generally needed to confirm the diagnosis.
However, due to the significant prevalence of vitamin D insufficiency in individuals with PHP, measuring 25OHD in all patients with the disease and repleting those with low levels (defined as ≤۲۰ ng/mL [50 nmol/L]) prior to making any management decisions
Measurement of vitamin D metabolites is also useful in the following circumstances:
• To differentiate hypervitaminosis D from PHP , we typically measure both 1,25-dihydroxyvitamin D and 25OHD.
• To differentiate FHH from mild PHP with concomitant vit D deficiency in individuals with elevated serum PTH and calcium and normal or low 24-hour urinary calcium excretion, we typically measure 25OHD. In the latter patients, urinary calcium excretion increases with vitamin D repletion, thereby distinguishing it from FHH.
• To differentiate secondary HP due to vitamin D deficiency from normocalcemic PHP in patients with elevated PTH and normal serum Ca , we typically measure 25OHD, which is low in the former and normal in the latter.
Sometimes patients with presumed secondary hyperparathyroidism have mild PHP + vit D deficiency. In these patients, the diagnosis may not be recognized until vitamin D is repleted and hypercalcemia and/or hypercalciuria develop.
PHP + vit D deficiency may be suspected when Ca are in the upper half of the normal range and urinary Ca is normal, despite vitamin D deficiency.
Individuals with normocalcemic PHP + low 25OHD may be repleted with vitamin D. vitamin D replacement should be provided cautiously in those with suspected concurrent PHP , in particular in those with hypercalciuria, as worsening hypercalcemia and hypercalciuria may develop
In contrast, serum and urinary Ca remain normal and PTH normalizes after vit D repletion in individuals with vit D deficiency-induced secondary HP.
OTHER TESTS —
Serum phosphorus —
may be decreased but typically is in the lower range of normal.
Some patients have mild hyperchloremic acidosis
Serum creatinine —
Rather than using serum cr alone, the GFR can be estimated in patients with a stable serum cr.
An estimated GFR of 60 mL/min is the threshold of CKD
Markers of bone turnover —
Biochemical markers of bone turnover (collagen crosslinks, osteocalcin, bone-specific alkaline phosphatase) are often at the upper end of normal or mildly elevated in asymptomatic PHP .
Bone mineral density —
may have decreased (BMD), in particular at more cortical sites (forearm and hip) as compared to more cancellous sites (spine).
BMD must be measured at the spine, hip, and distal one-third forearm sites.
Renal imaging —
Patients with undiagnosed nephrocalcinosis or calcium kidney stones are regarded as having symptomatic disease, regardless of the absence of symptoms. Thus, these patients meet criteria for surgical intervention
Renal imaging should be performed if kidney stones are suspected or if there is a history of kidney stones . Ultrasound is typically the imaging modality used.
Localization studies —
Localization studies with ultrasonography, technetium-99m sestamibi, CT, or MRI scanning .
Their utility is questionable when bilateral neck exploration is planned. However, they are commonly used now, along with intraoperative PTH monitoring, to facilitate unilateral exploration and minimally invasive surgery in those with probable single gland disease.