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J Clin Endocrinol Metab 2002; 87: 5353-61.
Primary hyperparathyrodism (PHPT) is a common endocrine disease but the clinical presentation in 2003 is typically one characterised by minimal signs or symptoms of hypercalcaemia or parathyroid hormone excess. A group of experts convened in April 2002 to consider whether changes were needed to the 1990 consensus guidelines which defined criteria for the diagnosis and management of asymptomatic PHPT.1 I will review the revised recommendations which have been disseminated by the panel and recently published as well as provide some critical appraisal of the new diagnostic criteria.2
The panel emphasised the importance of correcting serum total calcium measurements for the prevailing serum albumin concentration. The panel quoted a widely used correction factor which adjusts the serum calcium upward by 0.2 mmol/L for every 10 g/L the albumin falls below the median of the reference interval. The only reason cited for not adopting ionised calcium as the most appropriate analyte was the lack of ready access to this investigation in the USA. This is unlikely to be a problem for most Australian laboratories and there is increasing evidence in the literature regarding the use of ionised calcium in preference to corrected total calcium in the diagnosis of PHPT.3 Consequently, within Australia, I believe the use of ionised calcium measurements should be encouraged.
The panel recognised that intact Parathyroid hormone (PTH) may be registered within the "upper range" of the reference interval whilst still being consistent with a diagnosis of PHPT (Table 1). However, most patients with PHPT have an elevated PTH. The panel did not precisely define what constitutes the "upper range" of the PTH reference interval. In our experience, this is represented by the upper half of the reference interval.4 Consequently, in the setting of ionised hypercalcaemia, the median value of the intact PTH reference interval should be used as the clinical decision limit. The new generation "whole" PTH assay, which measures only the full length PTH molecule and not N-terminal fragments, was mentioned but not currently recommended for diagnosis by the panel.
One perennial problem in the diagnosis of hypercalcaemic individuals is the problem of differentiating patients with familial hypocalciuric hyperecalcaemia (FHH) from those with PHPT. FHH is generally a benign condition that cannot be corrected with parathyroid surgery. The calcium to creatinine (Ca/Cr) clearance ratio as defined by:
is often less than 0.01 in FHH and is still advocated as the parameter to measure when contemplating this diagnosis (Table 1). The panel defined a Ca/Cr clearance ratio of greater than 0.02 as being typical of PHPT. This definition dates from the first large published studies of the biochemical features of FHH.5,6 However, ionised calcium was not measured in early studies and those subjects identified as having PHPT were not clearly defined. As the magnitude of mild PHPT became apparent, more recent case series have identified that almost 1/3 of patients with PHPT will have a Ca/Cr clearance ratio less than 0.01 and another 1/3 will have a Ca/Cr ratio less than 0.02.7,8 Consequently, the use of Ca/Cr clearance ratio is a sensitive measure of FHH but not a specific one. Therefore, some groups recommend the use of fasting urinary calcium excretion CaE as defined by:
CaE is probably an equally sensitive measure to detect suspected cases of FHH.7,8 The advantages of the use of CaE over Ca/Cr clearance ratio related to the ease of spot urine compared to 24 hour urine collections and the need for acidification of 24 hour urine collections but not spot urine samples.9 The recent panel statement did not consider the utility of CaE measurements nor did the panel emphasise the lack of specificity of Ca/Cr clearance ratio in the diagnosis of FHH.
Measurement of 25 hydroxyvitamin D (25D) was not routinely recommended by the panel (Table 1). However, in this regard, specific mention should be made regarding the entity described as "normocalcaemic" PHPT. The panel acknowledged that in mild PHPT it is not uncommon to measure serum calcium concentrations within the reference interval on some occasions, albeit within the upper half of the reference interval. The panel also acknowledged that in some cases of PHPT, only ionised calcium values maybe elevated. Furthermore, they outlined the even more unusual circumstances when neither total nor ionised hypercalcaemia may prevail. In this latter circumstance, all potential causes of secondary hyperparathyroidism should be considered and calcium deficiency due to gastrointestinal disease, renal insufficiency, hypercalciuria of renal origin and lastly vitamin D deficiency (defined by 25D < 50 nmol/L) should be excluded. However, the panel recommended treatment of vitamin D deficiency in patients with asymptomatic PHPT (see later). Taking this last issue into consideration it seems reasonable to measure 25D in all cases of PHPT.
Only two criteria were revised from the 1990 consensus statement (Table 2). Serum total corrected calcium measurements that are 0.25 mmol/L above the upper reference limit are now regarded as one criterion to consider surgery. These recommendations were revised from the 1990 criterion which advocated total corrected serum calcium values of between 0.25 and 0.4 mmol/L above the upper reference limit. Secondly, to accept uniformity of definition, bone mineral density at the lumbar spine, hip or distal radius that is more than 2.5 SD below peak bone mass (T score < −2.5) was determined as another criterion for surgery. This definition is now in alignment with WHO defined risk for osteoporotic fracture, which were adopted for use in the general population. The remaining criteria for surgical selection include a 24 hour total urinary calcium excretion greater than 10 mmol/day, reduction of creatinine clearance by 30% compared with age-matched individuals with intact renal function, patients under the age of 50 years and those individuals who dislike long-term follow-up or cannot be followed up for other reasons. These criteria remain the same as defined in the 1990 consensus statement. Lastly, neuropsychiatric symptoms, hypertension, pancreatitis or peptic ulcer disease were not recommended criteria for surgical intervention.
Surgical options were considered given the availability of minimally invasive procedures; however, conventional neck exploration was ultimately favoured. The utility of preoperative localisation techniques using ultrasound and nuclear medicine imaging were reviewed but the benefit of this approach was not endorsed. Finally, a number of areas for future research were outlined.
Medical therapeutic options with calcimimetics, raloxifene or bisphosphonates were not endorsed. However, the rationale for calcium dietary restriction was questioned and adherence to 1000–1200 mg dietary calcium intake was recommended. Furthermore, 400–600 IU/day calciferol replacement was recommended for individuals with 25D below 50 nmol/L.
Long-term monitoring for patients who do not fulfil the criteria for surgical management were recommended by the panel. The panel advocated some changes to long-term monitoring (Table 3). Radiographs or ultrasound to detect silent nephrolithiasis and measurement of 24-hour urinary calcium and creatinine clearance were recommended only at baseline but not for monitoring. For latter purposes, annual serum creatinine and estimation of creatinine clearance by use of Cockcroft-Gault analysis were now recommended.
Overall, there were minimal changes recommended to the 1990 criteria for the diagnosis, surgical and non-surgical management of asymptomatic PHPT by the panel of convened experts. However, with increasing availability of ionised calcium and 25D assays in Australia and the ease of fasting urine collections it would seem prudent to consider measurement of both the above serum analytes and CaE as a matter of routine in this country in patients suspected of asymptomatic PHPT.