Pathogenesis of Metastatic Calcification and Acute Pancreatitis in Adult T-Cell Leukemia under Hypercalcemic State

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Hypercalcemia is common in patients with ATL. These patients rarely develop metastatic calcification and acute pancreatitis. The underlying pathogenesis of this condition is osteoclast hyperactivity with associated overproduction of parathyroid hormone-related protein, which results in hypercalcemia in association with bone demineralization. The discovery of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG), enhanced our understanding of the mechanisms of ATL-associated hypercalcemia. Macrophage inflammatory protein-1-α, tumor necrosis factor-α, interleukin-1, and interleukin-6 are important molecules that enhance the migration and differentiation of osteoclasts and the associated enhanced production of RANKL for osteoblast formation. In this paper, we focus on metastatic calcification and acute pancreatitis in ATL, highlighting recent advances in the understanding of the molecular role of the RANKL/RANK/OPG system including its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis for bone resorption in hypercalcemic ATL patients.

Hypercalcaemia in selected lympho- and myeloproliferative malignancies – – pathophysiology, diagnostic approach and treatment

“…Dotyczy to białek monoklonalnych; w tym przypadku oznaczanie stężenia wapnia w surowicy nie jest wiarygodne, mimo obliczenia stężenia wapnia skorygowanego [17]. [22]. Do rozważanych czynników rozwoju hiperkalcemii w ATLL należą także metaloproteinazy (MMP).…”

“…Zauważono wzrost produkcji przez osteoblasty MMP10 oraz MMP9, główną dla migracji prekursorów i dojrzałych osteoklastów [19]. Tak jak w przypadku szpiczaka plazmocytowego, w ATLL hiperkalcemia może również wiązać się ze zmniejszoną aktywnością osteoblastów -zauważono aktywację białka DKK1 w zainfekowanych i prawidłowych limfocytach T pod wpływem basic leucine zipper factor wirusa HTLV-1 [22].…”

A Dramatic Response to Denosumab: Protracted Hypocalcemia Related to Human T-Cell Lymphotropic virus type 1-Associated Adult T-Cell Leukemia/Lymphoma

“…Hypercalcemia in patients with ATL is partially mediated by increased secretion of parathyroid hormone-related protein (PTH-RP) by the tumor cells (4). Multiple other secreted peptides and proinflammatory cytokines have been implicated in promotion of hypercalcemia by stimulating osteoblastic and osteoclastic proliferation, and therefore a state of high bone turnover (5). We report a case in which denosumab therapy was effective in controlling hypercalcemia in a patient with ATL, but resulted in protracted hypocalcemia.…”

Multicentric B-cell Lymphoma and Disseminated Atherosclerosis in a Gelding

“…Metastatic calcification in human lymphoma was reported and commonly seen in alveolar septa and myocardium but mostly showed hypercalcemia (Senba et al, 2012). The morphologic similarities suggest a similar pathogenesis, but the initiating causes are likely different for 2 reasons.…”

“…In humans, medial artery calcification usually occurs as a degenerative process that becomes more severe with age (Teeter et al, 2010) whereas, it has been reported in horses at a relatively early age (5 years) and particularly in those with a racing background (Arroyo et al, 2008;Martínez et al, 2012). Four histologic patterns of arterial calcification in human patients have been categorized, namely atherosclerotic (fibrotic), medial artery calcification (Mönckeberg's sclerosis), cardiac valve, and vascular calciphylaxis (Teeter et al, 2010;Senba et al, 2012).…”