Clinical Endocrinology (1992)36,325-332
Current therapy
Primary hyperparathyroidism: aggressive or conservative treat ment? M. Davies University of Manchester Bone Disease Research Centre, Department of Medicine and Metabolism, Royal Infirmary, Oxford Road, Manchester M13 9WL, UK (Received 13 May 1991; returned for revision 7 June 1991; finally revised 29 November 1991; accepted 2 January 1992)
Primary hyperparathyroidism results from an increased and inappropriate production of parathyroid hormone from the parathyroid glands. The disorder is usually due to a single benign adenoma, less often to multiple adenomas or 'primary' hyperplasia or, exceptionally, to carcinoma of the parathyroid glands. Primary hyperparathyroidism is occasionally familial when it may occur alone or in association with other endocrine tumours. The biochemical hallmark of the disease is hypercalcaemia and the clinical features of primary hyperparathyroidism are a consequence of chronic hypercalcaemia and increased parathyroid hormone activity. Parathyroid hormone elevates the serum calcium directly by increasing the renal tubular reabsorption of calcium and by its 'calcaemic' action on bone through increased bone resorption, and indirectly by stimulating the formation in the kidney of the active metabolite of vitamin D, 1,25-dihydroxyvitaminD (1 ,25(0H)2D),thereby increasing intestinal calcium absorption. All these actions tend to be enhanced in primary hyperparathyroidism to produce hypercalcaemia. Modifications to these processes, e.g. dehydration, further enhancing tubular reabsorption of calcium and reducing the filtered load of calcium, or the development of vitamin D deficiency, reducing 1,25(OH)*D levels and thus calcium absorption, may produce increments or decrements in the prevailing serum calcium concentration. The earliest description of primary hyperparathyroidism was of a rare but serious disturbance of calcium metabolism characterized by the bone disease osteitis fibrosa generalisata (von Recklinghausen, 1891). In 1925 Felix Mandl performed the first successful parathroidectomy for primary hyperparathyroidism and the patient, a Viennese street car conductor, was cured of a disease hitherto considered fatal (Mandl, 1926). The early history of hyperparathyroidism was reviewed in a most excellent narrative by Fuller Albright (Albright, 1948). In the 65 years since Mandl it has become apparent that primary hyperparathyroidism is one of the commonest endocrine disturbances with a reported incidence of between
26 and 146 cases per 100000 population per year (Boonstra & Jackson, 1965; Heath H. et al., 1980; Mundy et af., 1980; Harrop er af., 1982). It is more common in females, particularly after the menopause. The mode of presentation has changed over the years so that many patients are now found to have primary hyperparathyroidism when hypercalcaemia is discovered during the use of multichannel biochemical screening. Many of these patients have no symptoms or recognized complications of the disease and this is how the majority of patients now present. Figure 1 details the presentation of primary hyperparathyroidism at the Royal Infirmary Manchester from 1960 to 1989. The use of multichannel biochemical profiles became commonplace in the mid-1970s and with them an increasing number of patients without symptoms of primary hyperparathyroidism were discovered. In many of these cases the hypercalcaemia is mild ( < 3 mmol/l) and there has been much debate about the need for parathyroidectomy in such patients. That patients with untreated primary hyperparathyroidism live for many years is not disputed (Scholz & Purnell, 1981; Adams, 1982; Paterson et af.,1984; Posen et af.,1985;Sampson et al., 1987) but it has recently been suggested that it is time to end a conservative approach to the treatment for mild asymptomatic hyperparathyroidism (Stevenson & Lynn, 1988). Protagonists of surgical treatment argue that asymptomatic patients may have subtle physical and psychological changes which respond to surgery, that untreated patients may develop renal failure, and there is an increased loss of bone which may have devastating effects in older women. Before discussing the merits of this aggressive approach it is important to be sure that primary hyperparathyroidism has been correctly diagnosed. It is important that hypercalcaemic patients are investigated appropriately; in particular, it must be recognized that malignancy and primary hyperparathyroidim may coexist (Drezner & Lebovitz, 1978; Kambouris et ai.,1987). Also, demarcation between mild primary hyperparathyroidism and familial benign hypercalcaemia (Foley et al., 1972)is sometimes difficult. It is for such reasons that I believe that hypercalcaemic patients are better assessed by clinicians familiar with disorders of calcium metabolism and in this way unnecessary neck explorations can be reduced to a minimum. In the United Kingdom many people, particularly the elderly and Asian immigrants, have a suboptimal degree of vitamin D nutrition (Davies et al., 1986; Stephens et af., 1982). If one adopts a selective approach to the surgical management of primary hyperpara325
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69 60
r
40 ? a
20 0
1960-1969
1970-1979
1980-1989
Fig. 1 Changing pattern of presentation of patients with primary hyperparathyroidism in Manchester between 1960 and 1989. M, Stones; 0,bones; N, hyper Ca; H, accident.
D, 4000 unitdday
m I
I
Hypercalcaemicsymptoms
/
E 2
‘
2.6
thyroidism it is important that the patients with what is believed to be ‘mild disease’ are genuine and do not have ‘mild’ hyperparathyroidism because of subclinical vitamin D deficiency. It is known that some patients with primary hyperparathyroidism show significant seasonal changes in serum and urinary calcium and these changes are thought to reflect improvements in vitamin D nutrition resulting from solar exposure during the summer months (Adams, 1982). Figure 2 shows a gross example of the way in which asymptomatic vitamin D deficiency can mask the full expression of what proved to be moderate primary hyperparathyroidism. I also believe that the imposition of low calcium diets which may produce significant reductions in urinary calcium excretion should be avoided. Low calcium diets are not to be found in standard texts on primary hyperparathyroidism but are sometimes imposed by physicians to treat primary hyperparathyroidism medically. It is my opinion that the first choice treatment of primary hyperparathyroidism is either surgical or no treatment at all. Conservative management implies observation and followup. Medical treatments should be kept in reserve for patients who warrant therapy but in whom surgical treatment has failed. The expression ‘mild primary hyperparathyroidism’ refers to patients in whom the serum calcium is less than 3 mmol/l and 24-hour urinary calcium excretion below 10 mmol. It would seem sensible to expect surgical treatment in primary hyperparathyroidism to achieve at least one of the following objectives: (a) relief of symptoms, (b) prevention of symptoms, and (c) prolongation of life expectancy. Evidence that parathyroidectomy achieves some of these aims is reviewed below.
It is generally accepted that hypercalcaemic symptoms are abolished by returning the serum calcium to normal. Such symptoms, which include thirst, polyuria, constipation, nausea, and sometimes dyspepsia, are rarely reported in the literature, occurring in less than 10% of reported series,and in my view are features of the more severe forms of primary hyperparathyroidism. Physicians should be wary of advising a patient that such symptoms will be abolished by parathyroidectomy unless the serum calcium is well over 3 mmol/
/
h-m-¤
1. 1 1 1 1 1 1 1 I I
I
I
I
l
l
l
l
l
L
Treatment (days)
Fig. 2 Sequential changes in serum and urine biochemistry
following treatment of a patient with mild primary hyperparathyroidismwith vitamin D. W, Serum Ca; 0,iPTH.
Some clinicians would include symptoms such as tiredness, lethargy, fatigue and weakness as being attributable to the hypercalcaemia of primary hyperparathyroidism and this indeed may be so. However, these complaints are often symptoms of life itself and caution is required in assuming
Treatment of hyperparathyroidism
Clinical Endocrinology (1992) 36
that such symptoms will be abolished in the long term by parathyroidectomy for mild hyperparathyroidism.
Hypertension
This is a well documented feature of primary hyperparathyroidism with many patients coming to diagnosis as a result of biochemical screening of hypertensive subjects. Since both conditions are common, especially in the middle aged and elderly populations, it is not surprising to find that they frequently coexist. I n view of the moderate reduction in renal function in patients with primary hyperparathyroidism, hypertension has been attributed to renal damage (Hellstrom et al., 1958) and earlier reports suggested that parathyroidectomy either improved blood pressure control or abolished hypertension in many patients (Hellstrom et al., 1958; Cope, 1960; Madhaven et al., 1970; Brinton et al., 1975). There have been many reports published describing the effects of parathyroidectomy upon blood pressure control and the bulk of the evidence indicates that hypertension alone is not an indication for parathyroidectomy (Jones et al., 1983; Posen et al., 1985; Salahudeen et al., 1989). An appreciable number of patients who are normotensive at the time of parathyroidectomy subsequently develop sustained hypertension (Jones et al., 1983). I have yet to see a patient with sustained hypertension cured by parathyroidectomy.
Renal calculi
Renal colic, dysuria and haematuria from renal stones remain the commonest symptoms attributable to primary hyperparathyroidism. Approximately half the patients with renal stones will be asymptomatic at the time of diagnosis of primary hyperparathyroidism and calculi will be discovered on either plain radiographs of the abdomen or renal ultrasound. Patients with renal stones commonly have hypercalciuria and stones appear to be commoner in men with primary hyperparathyroidism than in women; since 1960 on the medical unit of the Manchester Royal Infirmary, 55 men out of 99 have had renal stones but only 71 out of 316 women. Parathyroidectomy is recommended for patients with recurrent stone disease especially in association with hypercalciuria (24-hour urinary calcium > 10 mmol). Successful treatment does not guarantee freedom from further renal stones but data support a marked reduction in stone formation. Deaconson et al. (1987) showed a reduction of stone frequency from 0.36 stones per patient per year to 0.02, and Niederle et al. (1987) reported a cessation of stone formation in 91 %I of patients.
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Bone disease
Symptomatic bone disease is rare in primary hyperparathyroidism but histological abnormalities reflecting increased bone turnover are common (Riggs et al., 1965; Byers & Smith, 1971). Three types of bone disease may be seen in primary hyperparathyroidism: osteitis fibrosa cystica, osteomalacia and osteoporosis. Osteitis fibrosa cystica occurs in two distinct and contrasting clinical settings. Firstly it may be seen in patients with the most severe forms of the disease and is characterized radiologically by bone cysts, subperiosteal erosions, a ‘pepper-pot’ appearance of the skull and a ‘ruggerjersey’ spine. There is greatly increased alkaline phosphatase activity as well as severe hypercalcaemia. The disease heals following parathyroidectomy and treatment with vitamin D or its analogues and calcium supplements. A similar picture but with normocalcaemia or trivial hypercalcaemia is seen when primary hyperparathyroidism is complicated by vitamin D deficiency and osteomalacia. If these patients are treated surgically hypocalcaemia follows and in my opinion a more sensible approach is to treat these patients with vitamin D 1000-4000 units/day until radiology shows the bone disease to have healed and alkaline phosphatase activity has returned to normal. Vitamin D analogues have no place in this clinical situation because these patients have normal renal function and their privational vitamin D deficiency is most appropriately corrected by ergocalciferol (vitamin Dz) or cholecalciferol (vitamin D,). Successful correction of vitamin D deficiency results in an increase in the serum calcium and is not a reflection of vitamin D poisoning; one is witnessing the full expression of primary hyperparathyroidism released from the constraints of 1,25(OH)zDdeficiency and calcium malabsorption. Parathyroidectomy should be considered once the bone disease has been healed. If the patient is asymptomatic, neck exploration may not be necessary.
Osteoporosis
Through its actions on osteoclasts parathyroid hormone increases bone resorption but, by the process of coupling bone formation to resorption, it also stimulates bone formation. It is generally accepted that most women have a greatly increased loss of bone in the early post-menopausal years and this bone loss has been linked to an increase in bone resorption mediated via the effects of parathyroid hormone (Heaney, 1965). It would not be unreasonable to postulate that the existence of primary hyperparathyroidism with its known effects upon bone turnover might accelerate pre-existing imbalances in bone remodelling and play some role in the development of oesteoporosis. Parathyroid-
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ectomy might, therefore, by reducing the rate of bone loss, protect patients from osteoporosis and the risk of easy fracture. These arguments are used by those advocating an aggressive surgical approach to all patients with primary hyperparathyroidism. What then is the evidence that patients with primary hyperparathyroidism have an increased risk of fracture in the axial or appendicular skeleton?One might expect to see a disproportionate number of patients with primary hyperparathyroidism presenting with fractures to physicians and orthopaedic surgeons since primary hyperparathyroidism is such a common endocrine disturbance, especially in post-menopausal women who are at most risk from osteoporosis. This is not the clinical experience of myself or others (Adams, 1982; Heath, 1989), and I know of no definitive publication showing an increased risk of fracture in patients with mild primary hyperparathyroidism. There is an abundance of literature showing a reduction in bone mass in patients with primary hyperparathyroidism (Pak et al., 1975; Seeman et al., 1982; Mautalen et al., 1986; Richardson ei al., 1986; Silverberg ei al., 1989)but the results overestimate bone loss because of the nature of bone in primary hyperparathyroidism. Non-invasive techniques for bone mass assessment using photon absorptiometry or quantitative computerized tomography (QCT) measure the amount of bone mineral. In primary hyperparathyroidism bone turnover is accelerated and new bone formation may be increased up to fivefold (Parfitt, 1976). Since newly formed bone is less mineralized than older bone a deficit in bone mineral using these techniques is inevitable in patients with primary hyperparathyroidism but it would be reversed by parathyroidectomy. Irreversible bone loss may result from an imbalance between bone formation and bone resorption at remodelling sites, so that primary hyperparathyroidism could aggravate pre-existing risk factors for osteoporosis without necessarily being a risk factor itself. There have been several reports of an increased incidence of vertebral fractures in patients with primary hyperparathyroidism (Dauphine et al., 1975; Peacock et ul., 1984; Martinet al., 1986; Kochersbreger et al., 1987)but these have been in unselected groups of patients many of whom would be subjected to parathyroidectomy on clinical grounds. The apparently increased risk of fracture is sometimes spurious because of poor selection of control subjects. Dauphine et al. (1975) used patients with disc disease, which is associated with osteoarthrosis and a reduced incidence of osteoporosis, for their control group. In a prospective study of mild primary hyperparathyroidism in which patients with an initial forearm bone densitometry measurement 2.5 standard deviations or more below the age, sex and race adjusted mean were excluded, Wilson et al. (1988) found no increase in vertebral fractures. However, having excluded from the
Clinical Endocrinology (1992) 36
study those subjects with a reduced bone mass it is not surprising that no increase in fractures was found. Nevertheless the study does support the view that patients with mild asymptomatic primary hyperparathyroidism without a reduced bone mass can be managed conservatively without an increased risk of developing vertebral fractures. Bone histomorphometric and densitometric data (Silverberg et al., 1989; Parisien et al., 1990) have shown preferential involvement of cortical bone in primary hyperparathyroidism with preservation of cancellous bone structure (Parisien et a/., 1990). The implication of this work is that fractures may be more likely at sites rich in cortical rather than in cancellous or trabecular bone. Studies are now required to assess the risks of fracture in the appendicular skeleton before one can confidently adopt a conservative approach to asymptomatic patients with mild primary hyperparathyroidism. Hormone treatment
The biochemical parameters of primary hyperparathyroidism and indices of bone turnover return towards normal when post-menopausal women receive sex hormones. Ethinyl oestradiol 30-50 pg/day (Gallagher & Nordin, 1972; Gallagher & Wilkinson, 1973; Selby & Peacock, 1986), conjugated oestrogens 0.625-2.5 mg/day (Marcus et al., 1984; Marcus, 1989) and norethindrone 5 mg/day (Selby & Peacock, 1986) appear to be equally effective. The dose of oestrogen used in these studies has often been greater than the 10-20 gg of ethinyl oestradiol used as hormone replacement therapy (HRT) in post-menopausal women and concern has been expressed about the possible deleterious effects upon plasma lipids and cardiovascular morbidity from the prolonged use of pharmacological doses of progestogens. More studies are needed to evaluate the dose-response effects of oestrogens upon bone turnover and bone mass in primary hyperparathyroidism. HRT seems likely to offer some protection to the skeleton and could be used as a reasonable alternative in patients who are not suitable for surgery. Neuromuscular symptoms
Proximal muscle weakness in association with osteitis fibrosa cystica or osteomalacia is common and improves with parathyroidectomy or correction of privational vitamin D deficiency. A specific neuromyopathic disorder has been reported by Patten et al. (1974), apparently unrelated to that described above, in which there is subjective evidence of proximal muscle weakness and type I1 muscle fibre atrophy is present on muscle biopsy. Improvement follows parathyroidectomy. Other workers have reported improvements
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in isokinetic muscle strength following parathyroidectomy (Hedman et al., 1984; Joborn et al., 1988). Joborn et af.were able to show a weak but significant correlation between muscle strength improvement and preoperative serum calcium so that patients with only slightly raised serum calcium values did not complain of neuromuscular symptoms and did not show any improvement in muscle strength postoperatively. Patients who complain of muscle weakness and in whom there is objective evidence of proximal muscle weakness should be offered parathyroidectomy and may be expected to show symptomatic and objective improvement. Where these symptoms are present without objective evidence and where there is only mild hypercalcaemia then one should be circumspect in offering parathyroidectomy to abolish symptoms. Neuropsychiatric symptoms
A variety of psychiatric changes can occur in primary
hyperparathyroidism and severe hypercalcaemia may be accompanied by stupor, confusion, clouding of consciousness with electroencephalographic changes of a metabolic encephalopathy. Parathyroidectomy is always beneficial to these patients. In my experience, patients’ psychiatric symptoms, including psychoses in the presence of mild hypercalcaemia, are not helped by parathyroidectomy. Serious psychiatric illness can be managed appropriately in the presence of mild hyperparathyroidism which should be assessed out of context of the underlying psychiatric disorder. These patients should not be subjected to parathyroidectomy in the belief that there will be an improvement in their mental state. Brown et al. (1987) showed that neurobehavioural symptoms in mild primary hyperparathyroidism were unaffected by parathyroidectomy but Joborn et al. (1 989) reported an improvement in self-rated psychiatric symptoms in a group of 30 patients with mild to moderate hyperparathyroidism treated surgically. Patients with mild hypercalcaemia detected during health screening also had significantly more psychiatric symptoms compared with controls, but fewer symptoms than patients subjected to parathyroidectomy. Unfortunately there was no assessment of age and sex matched patients undergoing elective surgery for other conditions. No evidence has been presented to show that patients with primary hyperparathyroidism suffer more from neuropsychiatric symptoms than other patients with chronic, but relatively benign conditions necessitating hospital follow-up. Such a study may prove difficult to perform but should answer the question whether neuropsychiatric symptoms are or are not a feature ofmild hyperparathyroidism. Heath D.A. et al. (1980) reported an improvement in the
mental state of six demented elderly patients with primary hyperparathyroidism, sufficient to allow three institutionalized patients subsequently to be managed at home. Joborn et al. (1985) had similar experience of improvement in the mental state of eight of 13 elderly patients with organic brain syndrome. These reports indicate that parathyroidectomy should be considered for elderly patients with primary hyperparathyroidism who are dementing. Life expectancy
Perhaps the most significant study of untreated presumed primary hyperparathyroidism has come from Sweden where Palmer et al. (1987b) followed 172 persons with mild to moderate hypercalcaemia for 14 years. Their survival was compared with an age and sex matched group of normocalcaemic subjects. There was no difference in the survival of individuals aged 70 years and over at the time the hypercalcaemia was discovered. Under 70 years of age there was an excess of deaths from circulatory disorders in the hypercalcaemic group (56out of 172 as opposed to 39 in the control group). The lower survival was related to the degree of hypercalcaemia and this held true in multivariate analysis when systolic and diastolic blood pressure, serum glucose, uric acid and serum cholesterol were taken into account. No person with normal renal function at the start of the study had a more than marginally elevated serum creatinine at follow-up. A 23-year follow-up of 441 patients operated upon for primary hyperparathyroidism (Palmer et al., 1987a) showed a significantly greater mortality rate than expected for age and sex matched controls but after the fifth to eighth post-operative years the increased risk of death began to decrease. The increased risk of death in this group correlated with rising blood pressure and the presence of diabetes mellitus. There was no recorded increase in deaths from malignant disease in this study but a more comprehensive review by the same workers (Palmer et al., 1988) showed that patients with treated primary hyperparathyroidism had an increased incidence of malignancy compared with the background population (relative risk 1.6). Patients with primary hyperparathyroidism appear to show some reduction of life expectancy if the diagnosis is made before 70 years of age. There are however no firm data to show that surgically curing hyperparathyroidism reduces the risk of premature death. Conclusion
In my view there is insufficient evidence to abandon a conservative approach to the management of mild asymptomatic primary hyperparathyroidism. Indeed, in patients over
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Table 1 Guidlines for treating primary
Indications for parathyroidectomy
Possible indications for parathyroidectomy
No indication for parathyroidectomy
Serum calcium > 3 mmol/l Urine calcium > 10 mmo1/24h
Intellectual decline in the elderly
Renal stones
Presentation < 50 years of Hypertension age Declining renal function Chondrocalcinosis
Bone mass > 2 SD below mean for age/sex
hyperparathyroidism
Serum calcium < 3 mmol/l Urine calcium < 10 mmo1/24 h
Asymptomatic patient year of age
50
Pancreatitis Neuromuscular syndrome
Neuropsychiatric symptoms
70 years of age there is no evidence that continuing hyperparathyroidism is harmful in the absence of symptoms. Patients should be assessed individually and a decision to operate should be based upon the patient’s general health and the severity of the hyperparathyroidism assessed from both symptomatic and biochemical aspects. In general the younger the patient at diagnosis the more inclined one should be towards surgery provided the diagnosis is secure. Occasionally even in young patients ( i50 years of age) with mild hypercalcaemia (serum calcium < 3 mmol) and with normal 24-hour urinary calcium excretion (urine calcium < 10 mmol) I adopt a conservative approach and especially when patients are reluctant to have surgery. This philosophy of offering conservative management to patients with mild hyperparathyroidism is borne out by analysis of the 41 5 cases reviewed since 1960. Only 17 of 148 patients with a serum calcium > 3 mmol/l were not treated surgically, whilst 157 of 267 patients with a serum calcium of < 3 mmol/l have been managed conservatively. Sometimes patients in whom a policy of observation and follow-up is adopted develop symptoms or complications and require parathyroidectomy. This is not a common occurrence and is usually due to the development of kidney stones or an inappropriately rapid loss of bone mass. The success of surgery depends upon the experience of the surgeon. Parathyroidectomy is best performed by an experienced parathyroid surgeon, who will have a success rate over 90%. Of 217 parathyroid explorations at this hospital, 11 (4.8 %) have failed. This success rate falls when parathyroidectomy is undertaken by non-specialist surgeons where morbidity from inappropriate surgery rises. Even in experienced centres mishaps may occur (Gough et al., 1971). Table 1 lists the main indications for parathyroidectomy in both symptomatic and asymptomatic cases. Medical follow-up should be every 6 months when serum
calcium and creatinine should be measured. Initially, 24hour urines should be collected in summer and winter to establish the degree of calciuria, and an abdominal radiograph performed periodically. Once the stable nature of the condition has been established annual follow-up is recommended. Because hypertension is common in these patients blood pressure should be checked regularly and any sustained hypertension treated, preferably without the use of thiazide diuretics. If facilities for bone mass measurement are available then cortical bone mass should be measured every 2 years. If there is evidence for increasing hypercalcaemia, deteriorating renal function, development of renal stone, or declining bone mass within age and sex matched norms, then parathyroidectomy is necessary. There is a need to continue to evaluate the appropriateness of medical follow-up of primary hyperparathyroidism and studies of the kind done by the Swedish workers (Palmer et al., 1987a, b, 1988) need to be repeated in the United Kingdom and the United States.
References Adams, P.H. (1982) Conservative management of primary hyperparathyroidism. Journal of the Royal College of Physicians of London, 16,184-190. Albright, F. (1948) A page out of the history of hyperparathyroidism. Journal of Clinical Endocrinology, 8,637-657. Boonstrd, C.E. & Jackson, C.E. (1965) Hyperparathyroidism detected by routine serum calcium analysis. Annals of Internal Medicine, 63,468-474. Brinton, G.S., Jubiz, W. & Lagerquist, L.D. (1975). Hypertension in primary hyperparathyroidism. The role of the renin-angiotensin system. Journal of Clinical Endocrinology and Metabolism, 41, 1025-1 029. Brown, G.G., Preisman, R.C. & Kleerekoper, M. (1987) Neurobehavioral symptoms in mild primary hyperparathyroidism: Related to hypercalcemia but not improved by parathyroidectomy. Henry Ford Hospital Medical Journal, 35,211-215.
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Byers, P.D. & Smith, R. (1971) Quantitative histology of bone in hyperparathyroidism: its relation to clinical features, X-ray and biochemistry. Quarterly Journal of Medicine, N.S., 40,471486. Cope, 0.(1960) Hyperparathyroidism: diagnosis and management. American Journal of Surgery, 99,394-403. Dauphine, R.T., Riggs, B.L. & Scholz, D.A. (1975) Back pain and vertebral crush fractures. An unemphasized mode of presentation for primary hyperparathyroidism. Annals of Internal Medicine, 83,365-367. Davies, M., Mawer, E.B., Hann. J.T. & Taylor, J.L. (1986) Seasonal changes in the biochemical indices of vitamin D deficiency in the elderly. A comparison of people in residential homes, long stay wards, and attending a day hospital. Age and Ageing, 15, 77-83. Deaconson. T.F.. Wilson, S.D. & Lemann Jr, J. (1987). The effect of parathyroidectomy on the recurrence of nephrolithiasis. Surgery, 102,910-913. Drezner, M.K. & Lebovitz, H.E. (1978) Primary hyperparathyroidism in paraneoplastic hypercalcaemia. Lancet, i, 1004-1006. Foley, T.P.. Harrison, H.C.. Arnaud, C.D. & Harrison, H.E. (1 972) Familial benign hypercalcemia. Journal of Pediatrics, 81, 10601067. Gallagher, J.C. & Nordin, B.E.C. (1972)Treatment with oestrogens of primary hyperparathyroidism in post-menopausal women. Lancet, i, 503-507. Gallagher, J.C. & Wilkinson. R. (1973) The effect of ethinyloestradiol on calcium and phosphorus metabolism of post-menopausal women with primary hyperparathyroidism. Clinical Science and Molecular Medicine, 45, 785-802. Cough, M.H.. Smith, R. & Bishop, M.C. (1971) Parathyroidectomy for symptomlesshyperparathyroidism: a surgial dilemma. Lancet, i, 1178. Harrop. J.E.. Bailey, J.E. & Woodhead, J.S. (1982) Incidence of hypercalcaemia and primary hyperparathyroidism in relation to the biochemcdl profile. Journalof Clinical Pathology, 35,395-400. Heaney, R.P. (1965) A unified concept of osteoporosis. American Journril of Medicine. 39, 877-880. Heath, D.A. (1 989) Primary hyperparathyroidism. Clinical presentation and factors influencing clinical management. Endocrinology and Melaholism Clinics of North America, 18, 631-646. Heath, D.A., Wright, A.D.. Barnes, A.D., Coates, G.D. & Dorricott, N.J. (1980) Surgical treatment of primary hyperparathyroidism in Ihe elderly. Brifish Medical Journal, 280, 1406-1408. Heath, H., Hodgson, S.F. & Kennedy, M.A. (1980) Primary hyperparathyroidism. Incidence. morbidity and potential economic impact in a community. New England Journal of Medicine, 302, 189-193. He’dman. I., Grimby, G . & Tisell, L.E. (1984) Improvement of muscle strength after treatment for hyperparathyroidism. Acta Chirurgica Scandinavica, 150, 52 1-524. Hellstrom, J., Birke, G. & Edvall C.A. (1958) Hypertension in hyperparathyroidism. Britlth Journal of Urology, 30, 13-24. Joborn, C., Hetta, J., Frisk, P., Palmer, M., Akerstrom, G . & Ljunghall, S.( 1986) Primary hyperparathyroidism in patients with organic brain syndrome. Acta Medica Scandinavica, 219,91-98. Joborn, C., Hetta, J., Lind, L., Rastad, J., Akerstrom, G. & Ljunghall. S. ( I 989) Self-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long standing mild hypercalcaemia. Surgery, 105, 72-78. Joborn, C.. Joborn, H., Rastad, J., Akerstrom, G. & Ljunghall, S. (1988) Maximal isokinetic muscle strength in patients with
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primary hyperparathyroidism before and after parathyroid surgery. British Journal of Surgery, 75, 77-80. Jones, D.B., Lucas, P.A., Jones, J.H., Wilkins, W.E., Lloyd, H.J. & Walker, D.A. (1983) Changes in blood pressure and renal function after parathyroidectomy in primary hyperparathyroidism. Post-Graduate Medical Journal, 59,350-353. Kambouris, A.A., Ansari, M.R. & Talpos, G.B. (1987) Primary hyperparathyroidism and associated neoplasms. Henry Ford Hospital Medical Journal, 35, 207-2 10. Kochersberger, G., Buckley, N.J., Leight, G.S., Martinez, S., Studenski, S., Vogler, J. & Lyles, K.W. (1987) What is the clinical signifianceof bone loss in primary hyperparathyroidism? Archives on Internal Medicine, 147, 1951-1953. Madhavan, T., Frame, B. &Block, M.A. (1970) Influence of surgical correction of primary hyperparathyroidism on associated hypertension. Archiiles of Surgery, 100, 212-214. Mandl, F. (1926) Klinisches und Experimentelles zur Frage der lokalisierten und generalisierten Ostitis fibrosa (unter besonderer Berucksichtigung der Therapie der letzteren). Archivfir Klinische Chirurgie, 143,245-284. Marcus, T. (1989) Estrogens and progestins in the management of primary hyperparathyroidism. Endocrinology and Metabolism Clinics of North America, 18, 715-722. Marcus, R., Madvig, P., Crim, M., Pont, A. & Kosek, J. (1984) Conjugated estrogens in the treatment of post-menopausal women with hyperparathyroidism. Annals of Internal Medicine, 100,633-640. Martin, P., Bergmann, P., Gillett, C., Fuss, M., Kinnaert, P., Corvilan, J. & von Geertruyden, J. (1986) Partially reversible osteopaenia after surgery for primary hyperparathyroidism. Archives of Internal Medicine, 146, 689-691. Mautalen, C., Reyes, H.R., Ghiringhelli, G., and Fromm, G . (1986) Cortical bone mineral content in primary hyperparathyroidism. Changes after parathyroidectomy. Acta Endocrinologica, 111, 494497. Mundy, G.R., Cove, D.H., Fisken, R., Sommers, S. & Heath, D.A. (1980) Primary hyperparathyroidism: changes in the pattern of clinical presentation. Lancet, i, 1317-1320. Niederle, B., Roka, R., Woloszczuk, W., Klaushofer, K., Kovarik, J. & Schernthaner, G. (1987) Successful parathyroidectomy in primary hyperparathyroidism: A clinical follow up study of 212 consecutive patients. Surgery, 102, 903-909. Pak, C.Y.C., Stewart, A., Kaplan, R., Bone, H., Notz, C. & Browne, R. (1975) Photon absorptiometric analysis of bone density in primary hyperparathyroidism. Lancet, ii, 7-8. Palmer, M., Adami, H-O., Bergstrom, R., Akerstrom, G. & Ljunghall, S. (l987a) Mortality after surgery for primary hyperparathyroidism: a follow-up of 441 patients operated on from 1956-1979. Surgery, 102, 1-7. Palmer, M., Adami, H-O., Bergstrom, R., Jakobsson, S., Akerstrom, G. & Ljunghall, S. (1987b) Survival and renal function in untreated hypercalcaemia. Lancet, i, 59-62. Palmer, M., Adami, H-O., Krusemo, U.B. & Ljunghall, S. (1988) Increased risk of malignant diseases after surgery for primary hyperparathyroidism. American Journal of Epidemiology, 127, 103 I - 1040. Parfitt, A.M. (1976) The action of parathyroid hormone on bone. Relation to bone remodelling and turnover, calcium homoestasis and metabolic bone disease. Part 111. Merabolism, 25, 1033-1069. Parisien, M., Silverberg, S.S., Shane, E., de la Cruz, L., Lindsay, R. Bilezikian, J.P. & Dempster, D.W. (1990) The histomorphometry
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of bone in primary hyperparathyroidism: Preservation of cancellous bone structure. Journal of Clinical Endocrinology and Mefabolism, 70,930-938. Paterson, C.R., Burns, J. & Mowat, E. (1984) Long-term follow-up of untreated primary hyperparathyroidism. British Medical Journal, 289, 1261-1263. Patten, B.M., Bilezikian, J.P., Mallette, L.E., Prince, A., Engel, W.K. & Aurbach, G.D. (1974) Neuro-muscular disease in primary hyperparathyroidism. Annals of Infernal Medicine, 80, 182- 193, Peacock, M., Horsman, A., Aaron, J.E., Marshall, D.H., Selby, P.L. & Simpson, M. (1984) The role of parathyroid hormone in bone loss. In Christiansen, C., Amaud, C.D., Nordin, B.E.C., Parfitt, A.M., Peck, W. & Riggs, B.L. Osteoporosis: Proceedings of the Copenhagen International Symposium on 0 sfeoporosis. 3-8 June 1984, Denmark, pp. 463-467. Stiftsbogtrykkeri, Aalborg. Posen, S., Clifton-Bligh, P., Reeve, T.S., Wagstaffe, C. & Wilkinson, M. (1985) Is parathyroidectomy of benefit in primary hyperparathyroidism. Quarterly Journal of Medicine. N.S., 54, 241-251. Richardson, M.L., Poui-Mucelli, R.S.,Kanter, A., Kolb, F.O., Ettinger, B. & Genant, H.K. (1986) Bone mineral changes in primary hyperparathyroidism. Skeletal Radiology, 15, 85-95. Riggs, B.L., Kelly, P.J., Jowsey, J. & Keating, F.R. (1965) Skeletal alterations in hyperparathyroidism. Determination of bone formation and morphological changes by microradiography. Journal of Clinical Endocrinology and Metabolism, 25,777-783. Salahudeen, A.K., Thomas, T.H., Sellars, L., Tapster, S., Keavey, P., Farndon, J.R., Johnston, I.D.A. & Wilkinson, R. (1989) Hypertension and renal dysfunction in primary hyperparathyroidism. effect of parathyroidectomy. Clinical Science, 76, 289-296. Sampson, M.J., Van? Hoff, W. & Bicknell, E.J. (1987) The conservative management of primary hyperparathyroidism. Quarterly Journal of Medicine (N.S.) 65, 1009-1014.
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Scholz, D.A. & Purnell, D.C. (1981) Asymptomatic primary hyperparathyroidism. 10 years prospective study. Mayo Clinic Proceedings, 56,473-478. Seeman, E., Wahner, H.W., Offord, K.P., Kumar, R., Johnson, W.J. & Riggs, B.L. (1982) Differential effects of endocrine dysfunction on the axial and appendicular skeleton. Journal of Clinical Investigation, 69, 1302-1309. Selby, P.L. & Peacock, M. (1986) Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women. New EnglandJournal of Medicine, 314,148 I 1485. Silverberg, S.S., Shane, E., De la Cruz, L., Dempster, D.W., Feldman, F.,Seldin, D., Jacobs, T.P., Siris, E.S., Cafferty, M., Parisien, M.V.. Lindsay, R., Clemens, T.L. & Bilezikian, J.P. (1989) Skeletal disease in primary hyperparathyroidism. Journal of Bone and Mineral Research, 4,283-291. Stephens, W.P., Klimiuk, P.S., Warrington, S., Taylor, J.L.. Berry, J.L. & Mawer, E.B. (1982) Observations on the natural history of vitamin D deficiency amongst Asian imigrants. Quarterly Journal of Medicine (N.S.) 51, 171-188. Stevenson, J.C. & Lynn, J.A. (1988) Time to end a conservative treatment for mild hyperparathyroidism. British Medical Journal, 296, 1016-1017. von Recklinghausen, F.D. (1891) Die Fibrose oder deformirende Ostitis, die Osteomalacie und die osteoplastische Carcinose in ihren gegenseitigen Beziehungen. In Festschrgr &r Rudorf Virchow, seinem 71 Geburlstage. Gewidmef. Berlin, pp. 1-89. Wilson, R.J., Rao, S., Ellis, B. Kleerekoper, M. & Parfitt, A h . (1988) Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Annals of Infernal Medicine, 109,959-962.
Current therapy
Primary hyperparathyroidism: aggressive or conservative treat ment? M. Davies University of Manchester Bone Disease Research Centre, Department of Medicine and Metabolism, Royal Infirmary, Oxford Road, Manchester M13 9WL, UK (Received 13 May 1991; returned for revision 7 June 1991; finally revised 29 November 1991; accepted 2 January 1992)
Primary hyperparathyroidism results from an increased and inappropriate production of parathyroid hormone from the parathyroid glands. The disorder is usually due to a single benign adenoma, less often to multiple adenomas or 'primary' hyperplasia or, exceptionally, to carcinoma of the parathyroid glands. Primary hyperparathyroidism is occasionally familial when it may occur alone or in association with other endocrine tumours. The biochemical hallmark of the disease is hypercalcaemia and the clinical features of primary hyperparathyroidism are a consequence of chronic hypercalcaemia and increased parathyroid hormone activity. Parathyroid hormone elevates the serum calcium directly by increasing the renal tubular reabsorption of calcium and by its 'calcaemic' action on bone through increased bone resorption, and indirectly by stimulating the formation in the kidney of the active metabolite of vitamin D, 1,25-dihydroxyvitaminD (1 ,25(0H)2D),thereby increasing intestinal calcium absorption. All these actions tend to be enhanced in primary hyperparathyroidism to produce hypercalcaemia. Modifications to these processes, e.g. dehydration, further enhancing tubular reabsorption of calcium and reducing the filtered load of calcium, or the development of vitamin D deficiency, reducing 1,25(OH)*D levels and thus calcium absorption, may produce increments or decrements in the prevailing serum calcium concentration. The earliest description of primary hyperparathyroidism was of a rare but serious disturbance of calcium metabolism characterized by the bone disease osteitis fibrosa generalisata (von Recklinghausen, 1891). In 1925 Felix Mandl performed the first successful parathroidectomy for primary hyperparathyroidism and the patient, a Viennese street car conductor, was cured of a disease hitherto considered fatal (Mandl, 1926). The early history of hyperparathyroidism was reviewed in a most excellent narrative by Fuller Albright (Albright, 1948). In the 65 years since Mandl it has become apparent that primary hyperparathyroidism is one of the commonest endocrine disturbances with a reported incidence of between
26 and 146 cases per 100000 population per year (Boonstra & Jackson, 1965; Heath H. et al., 1980; Mundy et af., 1980; Harrop er af., 1982). It is more common in females, particularly after the menopause. The mode of presentation has changed over the years so that many patients are now found to have primary hyperparathyroidism when hypercalcaemia is discovered during the use of multichannel biochemical screening. Many of these patients have no symptoms or recognized complications of the disease and this is how the majority of patients now present. Figure 1 details the presentation of primary hyperparathyroidism at the Royal Infirmary Manchester from 1960 to 1989. The use of multichannel biochemical profiles became commonplace in the mid-1970s and with them an increasing number of patients without symptoms of primary hyperparathyroidism were discovered. In many of these cases the hypercalcaemia is mild ( < 3 mmol/l) and there has been much debate about the need for parathyroidectomy in such patients. That patients with untreated primary hyperparathyroidism live for many years is not disputed (Scholz & Purnell, 1981; Adams, 1982; Paterson et af.,1984; Posen et af.,1985;Sampson et al., 1987) but it has recently been suggested that it is time to end a conservative approach to the treatment for mild asymptomatic hyperparathyroidism (Stevenson & Lynn, 1988). Protagonists of surgical treatment argue that asymptomatic patients may have subtle physical and psychological changes which respond to surgery, that untreated patients may develop renal failure, and there is an increased loss of bone which may have devastating effects in older women. Before discussing the merits of this aggressive approach it is important to be sure that primary hyperparathyroidism has been correctly diagnosed. It is important that hypercalcaemic patients are investigated appropriately; in particular, it must be recognized that malignancy and primary hyperparathyroidim may coexist (Drezner & Lebovitz, 1978; Kambouris et ai.,1987). Also, demarcation between mild primary hyperparathyroidism and familial benign hypercalcaemia (Foley et al., 1972)is sometimes difficult. It is for such reasons that I believe that hypercalcaemic patients are better assessed by clinicians familiar with disorders of calcium metabolism and in this way unnecessary neck explorations can be reduced to a minimum. In the United Kingdom many people, particularly the elderly and Asian immigrants, have a suboptimal degree of vitamin D nutrition (Davies et al., 1986; Stephens et af., 1982). If one adopts a selective approach to the surgical management of primary hyperpara325
M. Davies
326
5
Clinical Endocrinology (1992) 36
69 60
r
40 ? a
20 0
1960-1969
1970-1979
1980-1989
Fig. 1 Changing pattern of presentation of patients with primary hyperparathyroidism in Manchester between 1960 and 1989. M, Stones; 0,bones; N, hyper Ca; H, accident.
D, 4000 unitdday
m I
I
Hypercalcaemicsymptoms
/
E 2
‘
2.6
thyroidism it is important that the patients with what is believed to be ‘mild disease’ are genuine and do not have ‘mild’ hyperparathyroidism because of subclinical vitamin D deficiency. It is known that some patients with primary hyperparathyroidism show significant seasonal changes in serum and urinary calcium and these changes are thought to reflect improvements in vitamin D nutrition resulting from solar exposure during the summer months (Adams, 1982). Figure 2 shows a gross example of the way in which asymptomatic vitamin D deficiency can mask the full expression of what proved to be moderate primary hyperparathyroidism. I also believe that the imposition of low calcium diets which may produce significant reductions in urinary calcium excretion should be avoided. Low calcium diets are not to be found in standard texts on primary hyperparathyroidism but are sometimes imposed by physicians to treat primary hyperparathyroidism medically. It is my opinion that the first choice treatment of primary hyperparathyroidism is either surgical or no treatment at all. Conservative management implies observation and followup. Medical treatments should be kept in reserve for patients who warrant therapy but in whom surgical treatment has failed. The expression ‘mild primary hyperparathyroidism’ refers to patients in whom the serum calcium is less than 3 mmol/l and 24-hour urinary calcium excretion below 10 mmol. It would seem sensible to expect surgical treatment in primary hyperparathyroidism to achieve at least one of the following objectives: (a) relief of symptoms, (b) prevention of symptoms, and (c) prolongation of life expectancy. Evidence that parathyroidectomy achieves some of these aims is reviewed below.
It is generally accepted that hypercalcaemic symptoms are abolished by returning the serum calcium to normal. Such symptoms, which include thirst, polyuria, constipation, nausea, and sometimes dyspepsia, are rarely reported in the literature, occurring in less than 10% of reported series,and in my view are features of the more severe forms of primary hyperparathyroidism. Physicians should be wary of advising a patient that such symptoms will be abolished by parathyroidectomy unless the serum calcium is well over 3 mmol/
/
h-m-¤
1. 1 1 1 1 1 1 1 I I
I
I
I
l
l
l
l
l
L
Treatment (days)
Fig. 2 Sequential changes in serum and urine biochemistry
following treatment of a patient with mild primary hyperparathyroidismwith vitamin D. W, Serum Ca; 0,iPTH.
Some clinicians would include symptoms such as tiredness, lethargy, fatigue and weakness as being attributable to the hypercalcaemia of primary hyperparathyroidism and this indeed may be so. However, these complaints are often symptoms of life itself and caution is required in assuming
Treatment of hyperparathyroidism
Clinical Endocrinology (1992) 36
that such symptoms will be abolished in the long term by parathyroidectomy for mild hyperparathyroidism.
Hypertension
This is a well documented feature of primary hyperparathyroidism with many patients coming to diagnosis as a result of biochemical screening of hypertensive subjects. Since both conditions are common, especially in the middle aged and elderly populations, it is not surprising to find that they frequently coexist. I n view of the moderate reduction in renal function in patients with primary hyperparathyroidism, hypertension has been attributed to renal damage (Hellstrom et al., 1958) and earlier reports suggested that parathyroidectomy either improved blood pressure control or abolished hypertension in many patients (Hellstrom et al., 1958; Cope, 1960; Madhaven et al., 1970; Brinton et al., 1975). There have been many reports published describing the effects of parathyroidectomy upon blood pressure control and the bulk of the evidence indicates that hypertension alone is not an indication for parathyroidectomy (Jones et al., 1983; Posen et al., 1985; Salahudeen et al., 1989). An appreciable number of patients who are normotensive at the time of parathyroidectomy subsequently develop sustained hypertension (Jones et al., 1983). I have yet to see a patient with sustained hypertension cured by parathyroidectomy.
Renal calculi
Renal colic, dysuria and haematuria from renal stones remain the commonest symptoms attributable to primary hyperparathyroidism. Approximately half the patients with renal stones will be asymptomatic at the time of diagnosis of primary hyperparathyroidism and calculi will be discovered on either plain radiographs of the abdomen or renal ultrasound. Patients with renal stones commonly have hypercalciuria and stones appear to be commoner in men with primary hyperparathyroidism than in women; since 1960 on the medical unit of the Manchester Royal Infirmary, 55 men out of 99 have had renal stones but only 71 out of 316 women. Parathyroidectomy is recommended for patients with recurrent stone disease especially in association with hypercalciuria (24-hour urinary calcium > 10 mmol). Successful treatment does not guarantee freedom from further renal stones but data support a marked reduction in stone formation. Deaconson et al. (1987) showed a reduction of stone frequency from 0.36 stones per patient per year to 0.02, and Niederle et al. (1987) reported a cessation of stone formation in 91 %I of patients.
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Bone disease
Symptomatic bone disease is rare in primary hyperparathyroidism but histological abnormalities reflecting increased bone turnover are common (Riggs et al., 1965; Byers & Smith, 1971). Three types of bone disease may be seen in primary hyperparathyroidism: osteitis fibrosa cystica, osteomalacia and osteoporosis. Osteitis fibrosa cystica occurs in two distinct and contrasting clinical settings. Firstly it may be seen in patients with the most severe forms of the disease and is characterized radiologically by bone cysts, subperiosteal erosions, a ‘pepper-pot’ appearance of the skull and a ‘ruggerjersey’ spine. There is greatly increased alkaline phosphatase activity as well as severe hypercalcaemia. The disease heals following parathyroidectomy and treatment with vitamin D or its analogues and calcium supplements. A similar picture but with normocalcaemia or trivial hypercalcaemia is seen when primary hyperparathyroidism is complicated by vitamin D deficiency and osteomalacia. If these patients are treated surgically hypocalcaemia follows and in my opinion a more sensible approach is to treat these patients with vitamin D 1000-4000 units/day until radiology shows the bone disease to have healed and alkaline phosphatase activity has returned to normal. Vitamin D analogues have no place in this clinical situation because these patients have normal renal function and their privational vitamin D deficiency is most appropriately corrected by ergocalciferol (vitamin Dz) or cholecalciferol (vitamin D,). Successful correction of vitamin D deficiency results in an increase in the serum calcium and is not a reflection of vitamin D poisoning; one is witnessing the full expression of primary hyperparathyroidism released from the constraints of 1,25(OH)zDdeficiency and calcium malabsorption. Parathyroidectomy should be considered once the bone disease has been healed. If the patient is asymptomatic, neck exploration may not be necessary.
Osteoporosis
Through its actions on osteoclasts parathyroid hormone increases bone resorption but, by the process of coupling bone formation to resorption, it also stimulates bone formation. It is generally accepted that most women have a greatly increased loss of bone in the early post-menopausal years and this bone loss has been linked to an increase in bone resorption mediated via the effects of parathyroid hormone (Heaney, 1965). It would not be unreasonable to postulate that the existence of primary hyperparathyroidism with its known effects upon bone turnover might accelerate pre-existing imbalances in bone remodelling and play some role in the development of oesteoporosis. Parathyroid-
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ectomy might, therefore, by reducing the rate of bone loss, protect patients from osteoporosis and the risk of easy fracture. These arguments are used by those advocating an aggressive surgical approach to all patients with primary hyperparathyroidism. What then is the evidence that patients with primary hyperparathyroidism have an increased risk of fracture in the axial or appendicular skeleton?One might expect to see a disproportionate number of patients with primary hyperparathyroidism presenting with fractures to physicians and orthopaedic surgeons since primary hyperparathyroidism is such a common endocrine disturbance, especially in post-menopausal women who are at most risk from osteoporosis. This is not the clinical experience of myself or others (Adams, 1982; Heath, 1989), and I know of no definitive publication showing an increased risk of fracture in patients with mild primary hyperparathyroidism. There is an abundance of literature showing a reduction in bone mass in patients with primary hyperparathyroidism (Pak et al., 1975; Seeman et al., 1982; Mautalen et al., 1986; Richardson ei al., 1986; Silverberg ei al., 1989)but the results overestimate bone loss because of the nature of bone in primary hyperparathyroidism. Non-invasive techniques for bone mass assessment using photon absorptiometry or quantitative computerized tomography (QCT) measure the amount of bone mineral. In primary hyperparathyroidism bone turnover is accelerated and new bone formation may be increased up to fivefold (Parfitt, 1976). Since newly formed bone is less mineralized than older bone a deficit in bone mineral using these techniques is inevitable in patients with primary hyperparathyroidism but it would be reversed by parathyroidectomy. Irreversible bone loss may result from an imbalance between bone formation and bone resorption at remodelling sites, so that primary hyperparathyroidism could aggravate pre-existing risk factors for osteoporosis without necessarily being a risk factor itself. There have been several reports of an increased incidence of vertebral fractures in patients with primary hyperparathyroidism (Dauphine et al., 1975; Peacock et ul., 1984; Martinet al., 1986; Kochersbreger et al., 1987)but these have been in unselected groups of patients many of whom would be subjected to parathyroidectomy on clinical grounds. The apparently increased risk of fracture is sometimes spurious because of poor selection of control subjects. Dauphine et al. (1975) used patients with disc disease, which is associated with osteoarthrosis and a reduced incidence of osteoporosis, for their control group. In a prospective study of mild primary hyperparathyroidism in which patients with an initial forearm bone densitometry measurement 2.5 standard deviations or more below the age, sex and race adjusted mean were excluded, Wilson et al. (1988) found no increase in vertebral fractures. However, having excluded from the
Clinical Endocrinology (1992) 36
study those subjects with a reduced bone mass it is not surprising that no increase in fractures was found. Nevertheless the study does support the view that patients with mild asymptomatic primary hyperparathyroidism without a reduced bone mass can be managed conservatively without an increased risk of developing vertebral fractures. Bone histomorphometric and densitometric data (Silverberg et al., 1989; Parisien et al., 1990) have shown preferential involvement of cortical bone in primary hyperparathyroidism with preservation of cancellous bone structure (Parisien et a/., 1990). The implication of this work is that fractures may be more likely at sites rich in cortical rather than in cancellous or trabecular bone. Studies are now required to assess the risks of fracture in the appendicular skeleton before one can confidently adopt a conservative approach to asymptomatic patients with mild primary hyperparathyroidism. Hormone treatment
The biochemical parameters of primary hyperparathyroidism and indices of bone turnover return towards normal when post-menopausal women receive sex hormones. Ethinyl oestradiol 30-50 pg/day (Gallagher & Nordin, 1972; Gallagher & Wilkinson, 1973; Selby & Peacock, 1986), conjugated oestrogens 0.625-2.5 mg/day (Marcus et al., 1984; Marcus, 1989) and norethindrone 5 mg/day (Selby & Peacock, 1986) appear to be equally effective. The dose of oestrogen used in these studies has often been greater than the 10-20 gg of ethinyl oestradiol used as hormone replacement therapy (HRT) in post-menopausal women and concern has been expressed about the possible deleterious effects upon plasma lipids and cardiovascular morbidity from the prolonged use of pharmacological doses of progestogens. More studies are needed to evaluate the dose-response effects of oestrogens upon bone turnover and bone mass in primary hyperparathyroidism. HRT seems likely to offer some protection to the skeleton and could be used as a reasonable alternative in patients who are not suitable for surgery. Neuromuscular symptoms
Proximal muscle weakness in association with osteitis fibrosa cystica or osteomalacia is common and improves with parathyroidectomy or correction of privational vitamin D deficiency. A specific neuromyopathic disorder has been reported by Patten et al. (1974), apparently unrelated to that described above, in which there is subjective evidence of proximal muscle weakness and type I1 muscle fibre atrophy is present on muscle biopsy. Improvement follows parathyroidectomy. Other workers have reported improvements
Treatment of hyperparathyroidism 329
Clinical Endocrinology (1992) 36
in isokinetic muscle strength following parathyroidectomy (Hedman et al., 1984; Joborn et al., 1988). Joborn et af.were able to show a weak but significant correlation between muscle strength improvement and preoperative serum calcium so that patients with only slightly raised serum calcium values did not complain of neuromuscular symptoms and did not show any improvement in muscle strength postoperatively. Patients who complain of muscle weakness and in whom there is objective evidence of proximal muscle weakness should be offered parathyroidectomy and may be expected to show symptomatic and objective improvement. Where these symptoms are present without objective evidence and where there is only mild hypercalcaemia then one should be circumspect in offering parathyroidectomy to abolish symptoms. Neuropsychiatric symptoms
A variety of psychiatric changes can occur in primary
hyperparathyroidism and severe hypercalcaemia may be accompanied by stupor, confusion, clouding of consciousness with electroencephalographic changes of a metabolic encephalopathy. Parathyroidectomy is always beneficial to these patients. In my experience, patients’ psychiatric symptoms, including psychoses in the presence of mild hypercalcaemia, are not helped by parathyroidectomy. Serious psychiatric illness can be managed appropriately in the presence of mild hyperparathyroidism which should be assessed out of context of the underlying psychiatric disorder. These patients should not be subjected to parathyroidectomy in the belief that there will be an improvement in their mental state. Brown et al. (1987) showed that neurobehavioural symptoms in mild primary hyperparathyroidism were unaffected by parathyroidectomy but Joborn et al. (1 989) reported an improvement in self-rated psychiatric symptoms in a group of 30 patients with mild to moderate hyperparathyroidism treated surgically. Patients with mild hypercalcaemia detected during health screening also had significantly more psychiatric symptoms compared with controls, but fewer symptoms than patients subjected to parathyroidectomy. Unfortunately there was no assessment of age and sex matched patients undergoing elective surgery for other conditions. No evidence has been presented to show that patients with primary hyperparathyroidism suffer more from neuropsychiatric symptoms than other patients with chronic, but relatively benign conditions necessitating hospital follow-up. Such a study may prove difficult to perform but should answer the question whether neuropsychiatric symptoms are or are not a feature ofmild hyperparathyroidism. Heath D.A. et al. (1980) reported an improvement in the
mental state of six demented elderly patients with primary hyperparathyroidism, sufficient to allow three institutionalized patients subsequently to be managed at home. Joborn et al. (1985) had similar experience of improvement in the mental state of eight of 13 elderly patients with organic brain syndrome. These reports indicate that parathyroidectomy should be considered for elderly patients with primary hyperparathyroidism who are dementing. Life expectancy
Perhaps the most significant study of untreated presumed primary hyperparathyroidism has come from Sweden where Palmer et al. (1987b) followed 172 persons with mild to moderate hypercalcaemia for 14 years. Their survival was compared with an age and sex matched group of normocalcaemic subjects. There was no difference in the survival of individuals aged 70 years and over at the time the hypercalcaemia was discovered. Under 70 years of age there was an excess of deaths from circulatory disorders in the hypercalcaemic group (56out of 172 as opposed to 39 in the control group). The lower survival was related to the degree of hypercalcaemia and this held true in multivariate analysis when systolic and diastolic blood pressure, serum glucose, uric acid and serum cholesterol were taken into account. No person with normal renal function at the start of the study had a more than marginally elevated serum creatinine at follow-up. A 23-year follow-up of 441 patients operated upon for primary hyperparathyroidism (Palmer et al., 1987a) showed a significantly greater mortality rate than expected for age and sex matched controls but after the fifth to eighth post-operative years the increased risk of death began to decrease. The increased risk of death in this group correlated with rising blood pressure and the presence of diabetes mellitus. There was no recorded increase in deaths from malignant disease in this study but a more comprehensive review by the same workers (Palmer et al., 1988) showed that patients with treated primary hyperparathyroidism had an increased incidence of malignancy compared with the background population (relative risk 1.6). Patients with primary hyperparathyroidism appear to show some reduction of life expectancy if the diagnosis is made before 70 years of age. There are however no firm data to show that surgically curing hyperparathyroidism reduces the risk of premature death. Conclusion
In my view there is insufficient evidence to abandon a conservative approach to the management of mild asymptomatic primary hyperparathyroidism. Indeed, in patients over
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Table 1 Guidlines for treating primary
Indications for parathyroidectomy
Possible indications for parathyroidectomy
No indication for parathyroidectomy
Serum calcium > 3 mmol/l Urine calcium > 10 mmo1/24h
Intellectual decline in the elderly
Renal stones
Presentation < 50 years of Hypertension age Declining renal function Chondrocalcinosis
Bone mass > 2 SD below mean for age/sex
hyperparathyroidism
Serum calcium < 3 mmol/l Urine calcium < 10 mmo1/24 h
Asymptomatic patient year of age
50
Pancreatitis Neuromuscular syndrome
Neuropsychiatric symptoms
70 years of age there is no evidence that continuing hyperparathyroidism is harmful in the absence of symptoms. Patients should be assessed individually and a decision to operate should be based upon the patient’s general health and the severity of the hyperparathyroidism assessed from both symptomatic and biochemical aspects. In general the younger the patient at diagnosis the more inclined one should be towards surgery provided the diagnosis is secure. Occasionally even in young patients ( i50 years of age) with mild hypercalcaemia (serum calcium < 3 mmol) and with normal 24-hour urinary calcium excretion (urine calcium < 10 mmol) I adopt a conservative approach and especially when patients are reluctant to have surgery. This philosophy of offering conservative management to patients with mild hyperparathyroidism is borne out by analysis of the 41 5 cases reviewed since 1960. Only 17 of 148 patients with a serum calcium > 3 mmol/l were not treated surgically, whilst 157 of 267 patients with a serum calcium of < 3 mmol/l have been managed conservatively. Sometimes patients in whom a policy of observation and follow-up is adopted develop symptoms or complications and require parathyroidectomy. This is not a common occurrence and is usually due to the development of kidney stones or an inappropriately rapid loss of bone mass. The success of surgery depends upon the experience of the surgeon. Parathyroidectomy is best performed by an experienced parathyroid surgeon, who will have a success rate over 90%. Of 217 parathyroid explorations at this hospital, 11 (4.8 %) have failed. This success rate falls when parathyroidectomy is undertaken by non-specialist surgeons where morbidity from inappropriate surgery rises. Even in experienced centres mishaps may occur (Gough et al., 1971). Table 1 lists the main indications for parathyroidectomy in both symptomatic and asymptomatic cases. Medical follow-up should be every 6 months when serum
calcium and creatinine should be measured. Initially, 24hour urines should be collected in summer and winter to establish the degree of calciuria, and an abdominal radiograph performed periodically. Once the stable nature of the condition has been established annual follow-up is recommended. Because hypertension is common in these patients blood pressure should be checked regularly and any sustained hypertension treated, preferably without the use of thiazide diuretics. If facilities for bone mass measurement are available then cortical bone mass should be measured every 2 years. If there is evidence for increasing hypercalcaemia, deteriorating renal function, development of renal stone, or declining bone mass within age and sex matched norms, then parathyroidectomy is necessary. There is a need to continue to evaluate the appropriateness of medical follow-up of primary hyperparathyroidism and studies of the kind done by the Swedish workers (Palmer et al., 1987a, b, 1988) need to be repeated in the United Kingdom and the United States.
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