1 Department of Renal Medicine St George's Hospital Blackshaw Road London SW17 0QT2 Department of Clinical Biochemistry University of Liverpool Liverpool L69 3BX UK3 Department of Medicine University of Pennsylvania 3615 Chestnut St Philadelphia PA 19104 USA
Correspondence and offprint requests to: Dr J. B. Eastwood, Department of Renal Medicine, St. George's Hospital, Blackshaw Road, London SW17 0QT, UK. Email: jbeastwo{at}sghms.ac.uk
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Our patient's resistant hypercalcaemia was investigated and a number of hormones and cytokines involved in calcium homeostasis were measured using standard chemistry assays (Roche, Lewes, UK) and commercial immunoassays (Nichols, San Juan Capistrano, USA, R & D Systems, UK, Biomedica, GmbH): parathyroid hormone (PTH) 0.3 pmol/l (0.55.5), 25-OH-vitamin D 29 nmol/l (>50), 1,25-(OH)2-vitamin D 38 nmol/l (43144), PTH-related peptide (PTHrP) 6.3 pmol/l (<1.8), interleukin-6 (IL-6) 4.6 pg/ml (<3), receptor activator of nuclear factor-B ligand (RANKL) 1.3 pmol/l (0.71.2), osteoprotegerin (OPG) 8.3 pmol/l (2.73.2), tumour necrosis factor-
(TNF-
) 2.9 pg/ml (<15.6) and soluble TNF receptor-1 (sTNFR-1) 3787 pg/ml (5121739).
Radiographs of the sites of bony tenderness were taken (Figure 1). An isotope scan of the parathyroids was normal, and computed tomography (CT) scan of his neck, thorax and abdomen showed a non-obstructing right renal calculus but no other abnormalities.
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In view of the patient's country of origin, antibodies to human lymphotropic T-cell virus type 1 (HTLV-1) were sought; they were positive. A diagnosis of acute adult T-cell leukaemia/lymphoma (ATLL) was made; immunophenotyping (CD2+/HLA-DR+ = 85%) was diagnostic of HTLV-1 infection. Our patient's illness, therefore, was a clear example of ATLL-related humoral hypercalcaemia of malignancy (HHM).
Prognosis of patients with ATLL is poor. The median survival is 8 months, and the 4-year survival is only 12% even when treated optimally. Our patient had a particularly aggressive and resistant form of the disease and he underwent multiple regimens of chemotherapy including CHOP (cyclophosphamide, doxorubicin, vinicristine, prednisolone), PitMiCEBO (mitoxantrone, cyclophosphamide, etoposide, bleomycin, vinicristine, prednisolone), DHAP (dexamethasone, cisplatin, cytarabine) and EMI (epirubicin, etoposide, ifosfamide, mesna). He was also given CAMPATH (CD52 monoclonal antibody), and a combination of interferon- with combivir (zidovudine and lamivudine), the latter regimen having been shown to be beneficial in recent studies. Sadly, our patient failed to improve and died 3 months after presentation.
Hypercalcaemia is common in certain haematological malignancies and occurs in up to 80% of cases of ATLL, a condition closely associated with HTLV-1 infection [1]. This virus is endemic in the southern Caribbean (where our patient was born) and Japan. It can be transmitted both sexually and through blood contamination, but in our patient vertical transmission, during pregnancy or breast-feeding [2], is most likely. In patients acquiring HTLV-1 infection at an early age, there is a 24% lifetime risk of developing ATLL [3]. The fact that our patient was completely well until presentation is consistent with the known latent period of at least 20 years between infection and disease manifestation [4].
HHM is a consequence of calcium release secondary to accelerated widespread bone resorption [5]. A number of cytokines, also expressed by ATLL cells, can induce proliferation of the bone-resorbing osteoclast, but until recently it was not clear which ones were responsible for directly initiating osteoclastogenesis. Osteogenic factors previously postulated include IL-1, IL-2, IL-6, TNF-, macrophage colony-stimulating factor (M-CSF) and PTHrP [6,7]. It is now clear that the elusive osteoclastic differentiation factor is the well-known ligand, RANKL [8]. Expressed by pre-osteoblastic and stromal cells, RANKL binds to its receptor RANK on the surface of pre-osteoclast lineage cells and pre-fusion osteoclasts to initiate differentiation to osteoclasts. The process is moderated by OPG (a soluble protein secreted by osteoblasts), which acts as a decoy receptor for RANKL [9].
PTH can be low in HHM, whereas PTHrP, which has a partially identical sequence (13 amino acids) in the active domain to PTH and shares the same receptor (PTH1-R), can be significantly elevated [10]. This was the case in our patient. In vivo, PTHrP increases bone resorption and renal tubular reabsorption of calcium. In addition, cytokines such as IL-6, IL-1 and TNF have been shown to have a synergistic action with PTHrP [11,12]. However, PTHrP alone does not appear to increase the numbers of osteoclasts and it has not been shown convincingly that osteoclasts express PTH receptors; hence, direct osteoclast activation by PTHrP is unlikely.
Circulating IL-6, TNF- and PTHrP were increased in our patient, and the overall synergistic effect could explain the extreme hypercalcaemia observed. Surprisingly, for such severe hypercalcaemia, both RANKL and TNF-
levels were not significantly elevated in the presence of high OPG and sTNFR-1 levels. However, since each assay measures only the free fraction of the molecule, it is possible that the bound (unmeasured) portion of RANKL/TNF-
was high. The significance and role of sTNFR-1 in osteoclastogenesis have yet to be defined.
We did not check for the presence of tax, a viral gene product that is expressed in tumour cells transformed by HTLV-I in vivo. Tax, although it induces the expression of a wide range of host cell gene productsincluding cytokines, transcription factors and membrane proteins and receptorsis not associated with the expression of the RANKL gene [13].
Although some patients with ATLL have elevated levels of 1,25-(OH)2-vitamin D as a result of increased 1-hydroxylase activity, the majority, like our patient, have suppressed 1,25-(OH)2-vitamin D levels. Elevation of 1,25-(OH)2-vitamin D levels, therefore, is not a contributory factor in the hypercalcaemia.
This case highlights the complexity of the pathophysiology of HHM and the advances that have been made in its understanding. It should be mentioned that OPG has shown promising therapeutic effects in malignant, rheumatic and post-menopausal bone disease and also in inhibiting the apoptosis of myeloma and cancer cells in vitro.
Our patient is unusual in presenting with symptoms secondary to hypercalcaemia but with no obvious clinical features of ATLLlymphadenopathy, skin lesions or organomegaly; also, there were no constitutional symptoms of lymphoma. The important clue in making the correct diagnosis was his country of origin. This case underlines the importance of considering all aspects of a patient's history. It also illustrates the paradox of having a very long period of asymptomatic HTLV-1 infection culminating in a short fulminating final phase of acute ATLL.
Several questions are raised by this patient's case. Since HTLV-1 is sexually transmitted, should his wife be screened? Indeed, should individuals at risk, including the newborn, be screened routinely? Currently in the UK, there is no widespread screening of individuals from endemic areas. However, in August 2002, HTLV-1 screening was introduced by the National Blood Service for all donations of blood products, and for certain donor tissuecornea, skin, bone and heart valves [14,15]. Yet, for solid organs, neither the UK nor Eurotransplant tests for HTLV-1 infection. Should they not now be doing so?
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Conflict of interest statement: None declared.
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