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Volume 96, Number 3 >
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Department of Diabetes and Endocrinology, Central Middlesex Hospital,
London, UK
1 Department of Diabetes and Metabolism, The Royal London Hospital, London,
UK
Correspondence to: Dr T A Chowdhury, Barts and the London NHS Trust, Mile End Diabetes Centre, The Royal London Hospital (Mile End), Bancroft Road, London E1 4DG, UK E-mail: TahseenChowdhury{at}bartsandthelondon.nhs.uk
In hypercalcaemia, exclusion of common causes such as hyperparathyroidism or disseminated malignancy is straight-forward. Matters become more difficult when no obvious cause can be found. A rare cause of refractory hypercalcaemia is adult T-cell leukaemia/lymphoma (ATLL) induced by human T-cell leukaemia virus type-1 (HTLV-1).
CASE HISTORIES
Case 1
A 61-year-old Jamaican man was admitted with a 3-day history of generalized
weakness. His wife, also originally from Jamaica, had died from ATLL 2 years
previously. Serum calcium was 4.53 mmol/L (reference range 2.2-2.6), phosphate
1.62 mmol/L (0.8-1.5), alkaline phosphatase (ALP) 73 IU/L (40-135) and white
cell count (WCC) 6.6 x 109/L (3.9-11) with lymphocyte count
3.26 x 109/L (1-4). He was treated with intravenous fluids,
diuretics and pamidronate. Serum parathyroid hormone (PTH) was 0.2 pmol/L
(1.3-7.6), urinary Bence Jones protein negative, normal serum angiotensin
converting enzyme (ACE) level and plasma electrophoresis, and lactate
dehydrogenase (LDH) 727 U/L (110-460). Blood was sent for HTLV-1 serology. A
blood film showed ‘some abnormal lymphocytes’; bone marrow
appeared normal and was sent for phenotyping. Despite treatment with
intravenous fluids, diuretics and pamidronate his serum calcium climbed to
5.08 mmol/L. Steroids were begun and further pamidronate was administered.
These measures brought down his calcium level for one 1-week, but it again
climbed to 5.11 mmol/L. HTLV-1 serology was reported as positive, and it
emerged that his wife had been HTLV-1-positive. On the assumption that he had
HTLV-1-induced ATLL, he was started on zidovudine and 
-interferon. He
remained hypercalcaemic, and highdose chemotherapy was administered. He is
currently normocalcaemic and well.
Case 2
A Ghanaian woman of 33 attended with a 2-week history of fatigue, diffuse
abdominal pain, constipation and nausea. She had lived in the UK for 23 years
but frequently returned to Ghana. On examination she had cervical
lymphadenopathy. Serum calcium was 4.23 mmol/L, phosphate 1.38 mmol/L, ALP 86
IU/L and WCC 7.8 x 109/L with a lymphocyte count of 0.64
x 109/L. 2 weeks previously her serum calcium had been 2.7
mmol/L when checked by her general practitioner. She was treated with
intravenous fluids, diuretics and intravenous pamidronate. Further
investigations revealed a PTH of 0.44 pmol/L, negative urinary Bence Jones
protein, normal serum ACE and plasma electrophoresis and negative Mantoux
test. LDH was raised at 4990 U/L. Ultrasonography confirmed cervical and
intra-abdominal lymphadenopathy. Blood was sent for HTLV-1 serology and a
lymph node biopsy was performed. Because of deteriorating renal function and
cardiac failure the patient was admitted to intensive care. Serum calcium
remained raised despite treatment with intravenous fluids, diuretics, steroids
and further pamidronate. Examination of the lymph node revealed high-grade T
cell anaplastic lymphoma, and she was started on chemotherapy. She developed
multiorgan failure and died 26 days after admission. Her HTLV-1 serology was
reported as positive.
Case 3
A 74-year-old Jamaican woman was admitted with a 3-week history of an
enlarging right parotid swelling and fatigue but no weight loss or fevers. She
had a 6 x 4 cm parotid mass and inguinal lymphadenopathy. Serum calcium
was raised at 3.39 mmol/L, phosphate 1.68 mmol/L, ALP 184 IU/L and WCC 34.3
x 109/L with lymphocyte count 22.1 x 109/L.
Blood film showed lymphocytosis suggestive of peripheral T-cell
lymphoproliferative disease. CT of the neck and thorax revealed a mediastinal
mass consistent with lymphoma and some narrowing of the trachea, with
extensive cervical lymphadenopathy. She was treated with intravenous fluids,
diuretics, steroids and intravenous pamidronate. HTLV-1 serology was
requested. Lymph node biopsy showed ATLL. She deteriorated during
chemotherapy, developed multiorgan failure, and died 29 days after admission.
HTLV-1 serology was reported as positive.
COMMENT
ATLL was first described as a distinctive malignancy of mature CD4+ (helper) T cells, when a high prevalence was reported in south-west Japan. It was subsequently identified in West Indian immigrants in the UK, and human T-cell leukaemia virus type-1 (HTLV-1) is now known to be the causative agent of ATLL1. Some 10-20 million people world-wide are infected with HTLV-1, which is endemic to Japan, the Caribbean, Central and South America and Africa where the seroprevalence is 1-20%. The estimated lifetime risk of developing ATLL in a person positive for HTLV-1 is 2-5%, with a latency of 20-30 years.
ATLL occurs in adults, with a median age at onset of 58 years, and is
classified into four clinical subtypes—smouldering, chronic, lymphoma
and acute. Patients with the first two subtypes rarely develop hypercalcaemia.
Acute type ATLL is the commonest and both acute and lymphoma types have a much
poorer prognosis than the other two subtypes. Poor prognosis is further
indicated by raised LDH and calcium and by a high WBC, with 50% survival of
less than 6 months even with combination
chemotherapy2.
Treated with zidovudine and -interferon, a small percentage of patients
achieve longlasting
remission3.
The exact prevalence of HTLV-1 positivity is hard to assess, though the prevalence in Jamaicans over 70 has been estimated at 17.4% for women and 9.1% for men. The North London Blood Transfusion Service estimate a prevalence of 0.005% in their local blood donors, whilst a study of Afro-Caribbean blood donors suggested a prevalence of 0.1%4. The catchment area of the Central Middlesex Hospital has a high immigrant population (approximately 45% non-English origin). In a study from the Royal London Hospital, which also serves a large ethnic minority population, 12 cases of HTLV-1 associated disease were found over 5 years5.
Hypercalcaemia is a common finding in the normal population and in hospital patients6. The approach to investigation is reviewed elsewhere7. Hypercalcaemia occurs in about 50% of patients with HTLV-1 induced ATLL, and, as in the three cases presented, attempts to control calcium levels may dominate the clinical course. The mechanism of hypercalcaemia associated with ATLL seems to be stimulation of bone resorption by the production of parathyroid-hormone-related peptide (PTH-rP), with ATLL cells constitutively expressing a large amount of PTH-rP mRNA8.
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