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Elevated PTH levels among chronic Graft-versus- Host Disease patients and other long term survivors after allogeneic hematopoietic stem cell transplantation

Background: Chronic Graft-versus-Host disease (cGvHD) is the leading cause of late non- relapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT). Metabolic bone disease is frequently seen after alloHSCT and is related to vitamin D deficiency and to GvHD – especially corticosteroids therapy and gastrointestinal (GIT) involvement. Elevated parathyroid hormone levels (PTH>6 pmol/L) were noticed alongside vitamin D deficiency presumably causing excessive bone resorption. However, high PTH level could be also a marker of systemic inflammation in cGvHD. In this study we investigated an association of cGvHD and vitamin D with PTH levels among long-term alloHSCT survivors. Methods: Data were collected on a prospective cross-sectional study protocol in patients who underwent alloHSCT and were evaluated by the institutional multidisciplinary cGvHD team from 6/2013 to 11/2019. Laboratory tests and detailed history were obtained, and patients with cGvHD were evaluated according to NIH 2005 criteria. Exclusion criteria were active acute GvHD, and for non-cGvHD group of patients also ongoing immunosuppressive treatment. Results: Study population consisted of 89 alloHSCT survivors (46% female), median age 48 (11-72) years, median of 672 (77-9478) days after alloHSCT. 62 (69.7%) had cGvHD and were evaluated at median of 376 (0-8869) days after the diagnosis was established. Majority of cGvHD patients had severe (38.7%) or moderate (38.7%) NIH global score, 41.9% had active cGvHD by clinician impression, and 58.1% were receiving systemic immunosuppression (41.6% of them corticosteroids). Median number of organs involved by cGvHD was 3, and most frequently involved organs were skin (58.0%), eyes (53.2%), and mouth (51.6%). GIT was involved in 11.3% of the patients. There was significantly more patients with history of acute GvHD (p<0.0001), peripheral blood stem cell source (p=0.0029), higher median days from transplant to assessment (p=0.0082) and higher median age at assessment (p=0.0083) in cGvHD group. Elevated PTH was found in 25.8% of study population. Although PTH median levels were similar, (4.2 (0.2-16.05) in cGvHD vs. 3.9 (1.2-8.2) pmol/L in non-cGvHD group), elevated PTH levels were noticed in 32.3% cGvHD patients comparing to 11.1% non-cGvHD patients, but the difference did not reach statistical significance (p=0.067). Prevalence of vitamin D deficiency was 30.3% without significant difference between groups (p=0.97). PTH level has shown significant correlation with older age (r=0.44, p<0.0001) and lower calcium level (r=-0.297, p=0.0048), but not with vitamin D levels (r=0.027, p=0.8461), NIH cGvHD global score (p=0.1), organ involvement (GIT p=0.529, others not shown), current use of corticosteroids (p=0.83) and intensity of immunosuppression (p=0.267). Conclusions: Results of this study demonstrate elevated PTH levels among one in four of alloHSCT long-term survivors. Patients with cGvHD show a trend towards higher rates of elevated PTH levels than non-cGvHD patients. PTH levels correlate significantly with older age and lower calcium, but not with vitamin D levels or cGvHD severity. These results suggest other factors besides calcium metabolism driving PTH levels. The role of PTH as an inflammation marker after alloHSCT should be further investigated in larger cohort of patients.

allogeneic hematopoietic stem cell transplantation; long-term survivors; chronic Graft-versusHost disease; PTH; vitamin D

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