Hyperparathyroidism

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TkIE KOYAL COLLEGE OF PA.THOLOGISTS

Preliminary investigations showed that the PS-TCA method at large sample volumes suffered from poor recoveries. An optimized PS-TCA method was devised whereby sample volume was minimized to ensure good recoveries and the subsequent protein-dye precipitate recovered in a small volume to preserve sensitivity. An alternative Ponceau S method (PS-PA, not otherwise reported) was developed and shown to provide good recoveries of added protein. Method distinct reference intervals were evident with the B-EPA being highest. Discrimination between the 24 normal and 165 patient urines was better by the B-EPA, CBA and PS-PA methods. Good correlations were obtained between the Ponceau S methods and the B-TCA methods, while the CBA method correlated best with that of B-EPA. Where serious discrepancies occurred, SDS-electrophoretic characterization tended to favour results by the CBA and B-EPA methods. The CBA method may be the method of choice for mild proteinuria where the B-TCA method is least useful because of its limited sensitivity. References

I . McElderry I A , .Tarbli IF, Ca~~ells-Sniith AJ. Six methods of urinary protzin compared. Clin Chcm 1982; 28: 356.60. 2. Dilena BA, Penberthy L.A, Fraser C G . Six methods for determining urinary protein compared. Clin Chem 1983; 29: 553-7.

TESTING FOR DISORDERS OF CALCIUM METABOLISM SOLOMON POSFN Department of Medicine, University of Sydney and Endocrine Unit, Royal North Shore Hospital, St. Leonards, NS W 2065 Many tests have been described for the evaluation of calcium metabolism. Like other tests of endocrine functions some are appropriate to certain clinical scenarios, others to different situations. Some lead to clinical decisions, others are only of academic interest. Three types of clinical conditions will be discussed: (a) Hypercalcemic states, (b) hypocalcemic states and (c) conditions associated with nitrogenous retention. A . Hyperculcemic States The 2 main causes of hypercalcemia - hyperparathyroidism and malignant disorders - are relatively easy to distinguish on clinical grounds. Traditional biochemical tests such as phosphate excretion, pho5phate:chloride ratios and serum alkaline phosphatase activities are not usually of diagnostic value in doubtful cases. Very low urinary calcium values ( < 2 mmo1/24 h) in hypercalcemic patients with normal renal function raise the possibility of familial hypocalciuric hypercalcemia. This condition requires a surgical approach different from that of primary hyperparathyroidism. Parathyroid hormone (PTH) immunoassays are now widely available and form an integral part of the pre-operative work-up for primary hyperparathyroidism.’ This diagnosis is suspect if serum P T H is undetectable or low in relation to the degree of hypercalcemia. Urinary cyclic A M P assays d o not differentiate between hyperparathyroidism and hypercalcemia of malignancy. PTH bioassays are at present either too cumbersome or not sufficiently sensitive for diagnostic purposes. Hypercalcemia of sarcoidosis is currently believed t o be due to the uncontrolled production of calcitriol by sarcoid tissue’ but serum calcitriol measurements are not at present sufficiently precise or specific to be used for the diagnosis of sarcoidosis. B. Hypocalcemic States Hypocalcemia occurs in association with a variety of conditions (hypoparathyroidism, hypomagnesemia, severe vitamin D deficiency) some of which may occur concurrently and reinforce each other. For this reason, parathyroid hormone assays are, in general, not very useful in distinguishing various hypocalcernic states from one another. Hypomagnesemia leads to secretory failure of parathyroid cells (as well as PTH resistance in target tissues) so that it may be impossible to predict in particular individuals whether low serum PTH values in the face of hypocalcemia are or are not due to permanent hypoparathyroidism. The various forms of hypoparathyroidism are, to some extent, distinguishable by their clinical background. A history of previous thyroid or parathyroid surgery favours a diagnosis of surgical

Pathology (1985), 17, October hypoparathyroidism. Fungal infections or failure of other endocrine glands favour “idiopathic” hypoparathyroidism while short metacarpals and metatarsals in the presence of hypocalcemia are almost diagnostic of pseudohypoparathyroidism. In addition, pseudohypoparathyroid sera contain immunoreactive PTH while sera from patients with other forms of hypoparathyroidism d o not. The distinction between pseudohypoparathyroidism and other forms of hypoparathyroidism may also be based on the infusion of human parathyroid hormone (1-34). This substance which has a biological half-life of 3 min, causes a 50 fold rise in urinary nephrogenous cyclic A M P in normal subjects, in patients with surgical hypoparathyroidism a n d in patients with “idiopathic” hypoparathyroidism. Patients with pseudohypoparathyroidism generally show a flat response. Serum 25-hydroxyvitaniin D (250HD) measurements are useful to determine compliance in patients receiving pharmacological doses of vitamin D. Serum 250HD measurements are also useful for the diagnosis of vitamin D deficiency. Measurements of serum concentrations of dihydroxylated metabolites are currently not diagnostically useful in hypocalcemic states. C. Renal Failure Patients with renal impairment develop a number of abnormalities of mineral metabolism, including phosphate retention, hyperparathyroidism, low serum values of dihydroxylated vitamin D metabolites, osteomalacia and a resistance to the hypercalcemic action of exogenous P T H . Hyperparathyroidism can be diagnosed in patients with renal failure by measurements of serum immunoreactive PTH and, less specifically, by the elevation of serum alkaline phosphatase activities. Bioactive PTH values (based on in-vitro adenylate cyclase stimulation) correlate well with immunoreactive PTH concentrations but, as in primary hyperparathyroidism, are currently not sufficiently sensitive for diagnostic purposes. Serum concentrations of dihydroxylated vitamin D metabolites are almost invariably low in patients with renal failure and particularly in patients requiring chronic hemodialysis. However, there is no significant correlation between serum 1,25(OH)*D and the prevalence or the severity of osteomalacia in renal failure. This skeletal lesion is probably unrelated to vitamin D metabolites and there are no reliable non-invasive tests for its diagnosis. In the majority of patients with uremic osteomalacia the diagnosis can only be made by means of undecalcified bone biopsies.

References I . Posen S, Kleerekoper M , lngham JP, Hirshorn JE. Br Med J 1976; I : 16-19. 2. Mason RS, Frankel YL, Chan YL et al. A n n I n t Med 1984; 100: 59-61. HYPERPARATHYROIDISM SOLOMON POSEN Department of Medicine, University of Sydney and Endocrine Unit, Royal North Shore Hospital, S t . Leonards, N.S. W . 2065 With the introduction of parathyroid hormone assays, the diagnosis of primary hyperparathyroidism has become relatively simple. Many non-specific tests have become redundant and the diagnosis now rests largely on 2 investigations - a raised serum calcium and a raised serum immunoreactive parathyroid hormone (PTH) concentration. Kits are becoming available for rapid PTH assays (results within 24 h). Some 3 % of patients with primary hyperparathyroidism suffer from one or another form of multiple endocrine neoplasia. The relevant measurements (such as serum gastrin or serum prolactin) are performed only when they are clinically indicated. Osteocalcin (also known as Gla protein) is, after collagen, the most abundant bone protein. In states of increased osteoblastic activity, increased concentrations of osteocalcin are demonstrable in serum. The role of serum osteocalcin measurements in the diagnosis of hyperparathyroidism has not yet been established. Skeletal biopsies are not performed routinely in patients suspected of suffering from primary hyperparathyroidism. However, in doubtful

ABSTRACTS OF A N N U A L M E E T I N G

cases (for example in patients with hypercalcemia out of proportion to the degree of serum PTH elevation) iliac crest trephine biopsies may show parathyroid osteopathy, unsuspected granulomas or malignant cells. Many procedures have been advocated for the preoperative localization of parathyroid lesions. With the exception of ultrasonography these procedures are not sufficiently reliable to justify their routine use. After a successful parathyroidectomy, the various biochemical parameters become normal at different rates. Bioactive serum PTH becomes undetectable after 10 min, while immunoreactive (C-terminal) PTH values become normal after 30 min. Serum calcium concentrations generally reach their nadir 48 h after surgery unless the patient has been made permanently hypoparathyroid, in which case the values may fall for a further 2 d. Serum alkaline phosphatase of skeletal origin, which has a biological half-life of 40 h (1) may remain elevated for weeks or months, presumably while osteoblasts are continuing to repair previously eroded areas. The greatest problem relating to hyperparathyroidism concerns the need of individual patients t o undergo neck exploration. In patients

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with renal stones, or serum calcium values in excess of 3.5 mmol/l and in patients with radiological bone disease, surgery is usually recommended, though even such patients may survive for many years without apparent deterioration of renal function. There is at present only circumstantial evidence that patients with mild hyperparathyroidism benefit f r o m parathyroidectomy. Hypertension and renal impairment are no more prevalent amongst unoperated than amongst operated patients. Renal stone formation depends o n the history of stones at Ihe time of presentation rather than on the decision to perform a parathyroidectomy. Forearm osteodensitometry gives lower values in unoperated than in operated patients (2), though the spinal mineral content measured by CT scans is similar in the 2 groups. I t is, therefore, current policy not to recommend surgery in elderly, symptomless, hyperparathyroid patients especially when hypercalcemia is mild (2). References 1 . Poaen S , GrunFreln H S . Clin Cliern 1982; 28: 153-4. 2. Poscn S , Clifton-Bligh P, Reeve TS et al. J Med (in p r e s )