Family Trouble.


Neil Hilla, Akila de Silvaa, Karim Meerana, Fausto Palazzob


a. Department of Endocrinology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF

b. Department of Endocrine Surgery, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS


Abstract: In 2007 a thirty five year old lady was referred  to the endocrine clinic with  hypercalcaemia - corrected calcium of 2.68mmol/L (normal range 2.15-2.60).  She was asymptomatic with no history of renal stones or bone pain. Her past history included tuberculosis 5 years previously followed by right lung bronchiectasis. She was on no medication but had previously been treated with calcium and vitamin D but this had been  stopped one year prior to her clinic visit. Her family history revealed a mother who was being simultaneously investigated for hypercalcaemia in a nearby hospital. The routine tests for the investigation of hypercalcaemic patients were requested but she failed to have these done and did not attend clinic for 9 months. In the interim her corrected calcium was found to be 2.64mmol/L with a calcium:creatinine excretion ratio of 0.0116. At her second clinic appointment, her corrected calcium had normalised to 2.59mmol/L with a  calcium:creatinine excretion ratio of 0.0154. There are no parathyroid hormone levels available during this period.


She was again lost to follow-up for 18 months, until June 2009 when she was re-referred by her general practitioner following a miscarriage at 11 weeks in March. Her corrected calcium was 2.70mmol/L with a PTH of 14.6pmol/L (1.1-6.8), vitamin D 32nmol/L and calcium:creatinine excretion ratio of 0.0138. She was commenced on vitamin D supplements (1000iu orally, liquid form). DEXA scanning showed osteopenia at the level of the femoral neck (T score -1.8). Further information about mother's biochemical and hormone profile was requested from her GP.


Her age and the family history of probable primary hyperparathyroidism meant that an inherited cause for her hypercalcaemia was considered and she was referred to the local genetics department to screen for familial hypocalciuric hypercalcaemia (FHH) and multiple endocrine neoplasia type 1 (MEN1).


The following week she returned for routine review and was 11 weeks pregnant. She normally eats a vegetarian diet with little or no dairy produce, but since becoming pregnant has been craving milk, drinking at least a pint a day and had a corrected calcium taken after clinic was 2.87mmol/L. She was reviewed by the endocrine surgical team and subsequently has been referred to Queen Charlotte's Hospital obstetric medicine department. Her MEN1 and FHH screen was expedited.


Three weeks later, her mother had been reviewed in clinic and her calcium:creatinine ratio was 0.0331, thereby excluding FHH. The patient’s MEN1 screen was also negative, thus the diagnosis for both patient and her mother is sporadic primary hyperparathyroidism.


The commonest causes of hypercalcaemia are hyperparathyroidism and malignancy so all hypercalcaemic patients require a full history, examination and investigations to secure a diagnosis. When the patient is young  or there is a family history of hypercalcaemia it is of particular importance. The avoidance of hyperparathyroidism during pregnancy is highly desireable and excluding FHH is imperative since this does not require surgery. Although MEN1 is a possibility, sporadic hyperparathyroidism is more probable. Nevertheless in patients under the age of 30 years or where there is a family history the exclusion of MEN1 syndrome  allows the appropriate choice of surgical strategy – either minimally invasive or conventional parathyroid surgery. Pregnant women with primary hyperparathyroidism requiring surgery cannot have localization nuclear medicine scans so will typically proceed directly to open parathyroidectomy in the second trimester to avoid the risk of foetal death and profound neonatal hypocalcaemia and tetany due to neonatal hypoparathyroidism.


A calcium:creatinine excretion ratio of <0.01 was previously1 thought suggestive of familial hypercalcaemic hypercalciuria, thus in our patient, the ratio is in favour of primary hyperparathyroisim, however it has been shown that using a ratio of up to 0.02 improves sensitivity to 98%,although specificity is reduced2. Our unit has experience of at least one patient with a ratio similar to this where the diagnosis was in fact FHH. FHH is caused by a defect in the parathyroid and renal calcium-sensing receptors resulting in moderately elevated serum calcium levels. Parathyroid surgery has no effect on calcium levels in FHH and should be avoided.




1. Marx SJ. Uncertainties in distinction of typical primary hyperparathyroidism from familial hypocalciuric hypercalcemia. West J Med. 1982;136(2): 145-146

2. Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol. 2008; 69 (5): 713-720