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Metabolic disorders may be complex but, as these case studies show, a careful history and a few investigations can provide the information for the correct diagnosis and treatment, say Dr David Heath and Dr Neil Gittoes
There are many potential causes of hypercalcaemia, but malignancy and hyperparathyroidism are the causes in the vast majority of patients seen both in general and hospital practice. Usually, the diagnosis can be ascertained either by the context within which the hypercalcaemia occurs, or by a limited number of selected investigations, as the following cases demonstrate.
Case study 1
Mrs A, aged 78, sees her GP complaining of tiredness and an increasing difficulty to manage on her own. Her GP requests thyroid function tests, haemoglobin and a biochemical profile. These are all normal with the exception of a serum calcium of 2.80mmol/L with an albumin of 40g/L.
This is a very typical presentation of primary hyperparathyroidism. Although the textbooks still talk about renal stones and bone disease, these are now unusual presentations of hyperparathyroidism – most patients are found by chance during routine investigations.
Confirming the hypercalcaemia and showing an elevated serum PTH in a modern, two-site assay will confirm the diagnosis, and further investigations will be unnecessary.
Most patients are women over the age of 70 and up to 50 per cent will be completely asymptomatic.
Typical symptoms are tiredness and lethargy, often attributed to ageing. This has led to reassessment of the need for surgery, which was previously recommended for most patients. Surgery is now indicated in symptomatic cases, in complications such as renal stones, and in young patients (typically under 50). Asymptomatic patients over the age of 50 can be considered for conservative management.
Case study 2
Mrs B, aged 56, had a mastectomy five years ago and has remained well. At a routine follow-up, blood tests reveal a serum calcium of 3.02mmol/L, serum albumin of 38g/L with no other abnormalities.
The typical reaction is to assume that the hypercalcaemia is due to a recurrence of the breast cancer. However, with no evidence of recurrence and with the patient feeling well, this is unlikely and primary hyperparathyroidism remains the most likely diagnosis.
As with the patient in the first case study above, this merely needs an elevated PTH for confirmation. This saves the patient unnecessary bone scans, skeletal surveys and anxiety.
Case study 3
Mr C, aged 60, gives a three-month history of cough, weight loss, thirst and polyuria. He is a lifelong smoker. You arrange urgent blood tests and a chest X-ray. They reveal: a mass in the left upper lung field with enlarged glands at the left hilum; haemoglobin 10.3g/dL; ESR 78mm/h; calcium 3.80mmol/L, albumin 28g/L; alkaline phosphatase 640iu/L (N<350), and="" aspartate="" transaminase="" 80iu/l="">350),><>
This is the typical presentation of hypercalcaemia of malignancy. The patient is clearly unwell and the malignancy is usually known about before the hypercalcaemia is noticed or, as in this case, immediately obvious. This is in complete contradistinction to hyperparathyroidism in which the patient is typically well. For this patient, once malignancy is confirmed, further investigation is unnecessary. Controlling hypercalcaemia can often improve the quality of life of the patient, even though the malignancy cannot be cured.
Such a degree of hypercalcaemia could not be controlled by oral therapy, and the patient would need admission for intravenous hydration and intravenous bisphosphonates.
Case study 4
Familial benign hypercalcaemia
Mrs D is a 32-year-old divorcee. Three years earlier, at a time of severe matrimonial problems, she became depressed and routine investigations revealed a serum calcium of 2.74mmol/L. She is referred to outpatients but fails to attend. She and her husband divorce and her depression clears. She agrees to further investigation, despite being completely asymptomatic. The serum calcium is 2.70mmol/L and the serum PTH is 30ng/L(N=10-60). All other routine tests are normal.
The clues here are the young asymptomatic patient with a PTH in the middle of the normal range. This makes primary hyperparathyroidism unlikely, and excludes all obvious non-parathyroid causes of hypercalcaemia. The diagnosis to consider is familial benign hypercalcaemia – also called familial hypocalciuric hypercalcaemia, a benign condition inherited in an autosomal dominant fashion, with hypercalcaemia being present from birth.
It does not require treatment and, in particular, patients should not be considered for parathyroidectomy. Diagnosis is best confirmed by demonstrating an affected hypercalcaemic parent or child.
All asymptomatic patients thought to have hyperparathyroidism and referred for parathyroidectomy should have this condition considered and, if possible, excluded before surgery.
Case study 5
Miss E is a 34-year-old alcoholic who attends your surgery with abdominal pain. You arrange some tests which show the following: haemoglobin 12.8g/dL; MCV 104fl; creatinine 125µmol/L; calcium 3.4mmol/L; albumin 39g/L. Bilirubin, alkaline phosphatase and aspartate transaminase are normal. Because of these results, you call her back one week later to repeat the tests. Her symptoms have settled and her biochemistry completely returns to normal.
Hypercalcaemia that comes and goes over a period of one week is unusual. Clinicians usually invoke laboratory error, but in our experience this is unlikely.
More likely is that the patient has milk-alkali syndrome, which is almost exclusively restricted to patients who take large numbers of 'over-the-counter' effervescent indigestion tablets.
The investigation is to ask the right questions!
Case study 6
Rapid weight loss
Mr F is a 70-year-old who presents with a four-month history of malaise and weight loss of two stone. Examination is normal. Initial investigations reveal a normochromic, normocytic anaemia of 11g/dL with an ESR of 30mm/hr. Biochemical investigations show a serum calcium of 3.0mmol/L, albumin 32g/L, PTH 8ng/L (N=10-60). A chest X-ray, bone scan and plasma and urine electrophoresis are all normal.
This is a relatively unusual case, in which hyperparathyroidism can be completely excluded and malignancy is not obvious.
Some of the rarer non-parathyroid causes of hypercalcaemia will have to be considered, such as sarcoidosis, thyrotoxicosis and so on.
Vitamin D poisoning should be obvious as a cause, as in such cases it is very unusual for the patient not to be known to be on large doses of vitamin D or its metabolites.
Most patients, however, usually have malignancy, in particular, haematological or lymphoid types.
Careful investigations are usually required to reveal the cause.
David Heath is retired
Neil Gittoes is consultant physician, University of Birmingham NHS Trust