Discussion
To the best of our knowledge, this was the first cohort study assessing
the prognostic role of vitamin D in secondary HLH. We discovered that 49
(90.7%) sHLH suffered VD insufficiency (25-(OH)-D<50nmol/L).
Low 25-(OH)-D level was associated with survival of sHLH after adjusting
for other prognostic factors.
Vitamin D, one of the indispensable elements of health and disease
prevention, is mainly synthesized by the skin during sun exposure, or
ingested in daily diet. Measurement of serum 25(OH)D was capable of
represent the overall level of vitamin D in vitro 20.
According to previous research, vitamin D insufficiency is a widespread
healthy issue, more common in Asia21. A large
multi-center study (2173 healthy adults in Dalian, Beijing, Hangzhou,
Guangzhou, and Urumqi) showed that 55.9% populations had insufficient
vitamin D—serum 25(OH)D levels were less than 20 ng/ml22. In immune-related diseases, the proportion of VD
insufficiency is higher or more serious. Schundeln et
al23 reported that the incidence in hemolytic anemia
was 80.5%. 80% of patients with multiple myeloma have
25-(OH)-D<50nmol/L24. Consistent with those
studies about vitamin D in different diseases, VD insufficiency
incidence rate was over 90% in HLH and 71.1% patients were assigned to
vitamin D deficiency (<30nmol/L), suggesting vitamin D may be
the cause or rather a consequence of the disease. The result of a
meta-analysis showed circulating 25-(OH)-D contributed to the occurrence
of lung cancer, with increasing 10 nmol/L dose associated with 8%
reduction in the risk25.
The biological effects of vitamin D ranged from maintaining serum
calcium and skeletal homeostasis to modulating immune
processes26. The latter may be one of the reasons
related to the prognosis of VD in sHLH. So far, the specific mechanisms
of HLH remains no consensus, but more researches considered that
congenital and acquired immunity contributed to the occurrence and
development. The excessive activation of CD8+lymphocytes and macrophages resulted in wild secretion of pro- and
anti-inflammatory cytokines, like IFN-γ, IL-6, IL-12, IL-16, IL-18,
TNF-a, and IL-10; those in turn to trigger persistent activation and
cause the organ dysfunction characteristics27. Reichel
et al 28 showed that the biologically active
metabolite of vitamin D3 participated in modulating lymphocyte function
via suppressing IL-2 secretion and decreasing production of IFN-γ by
normal human peripheral blood lymphocytes. In addition, vitamin D is
known to exert several immunomodulatory effects on cytokines synthesis
in vitro, as it inhibits TNF-α, IL-12, and IL-17 and stimulates IL-10,
promoting a shift from a Th1 to a TH2 phenocyte29.
Furthermore, it increased the expression of regulatory T lymphocytes
with a skewing away from the Th17 phenotype. It’s noteworthy that
25-(OH)-D show a deeper immunoregulatory effect after lymphocyte
activation30. Therefore, 25-(OH)-D was considered to
exert the beneficial effect on protecting the risk of immuneregulated
diseases. In our study, a negative correlation between 25-(OH)-D and TG
levels was observed (r=-0.34, P =0.011), while the increase in TG
in sHLH was mostly attributed to IFN-γ. High levels of IFN-γ increase
very low-density lipoprotein and decrease lipase activity in the
posterior liver, leading to TG clearance defects and
hypertriglyceridemia31. 25-(OH)-D was relatively
associated with ferritin (P =0.055). Therefore,we speculated that
VD may represent the level of IFN-γ. Overall survival was shorter in low
25-(OH)-D level group than that in high level group (28 vs. 125
days P =0.041). After adjusting for hemoglobin, platelet, albumin,
TG, β2-microglobulin, ferritin, loge(sCD25), 25-(OH)-D
was proved to be an independent protective factor for overall survival
(HR=0.364, 95%CI=0.183-0.724, P=0.004). Fattizzo et al30 reviewed that vitamin D deficiency is correlated
with disease severity/activity in autoimmune cytopenias. Another
plausible pathway reasonable for the relationship between 25-(OH)-D and
HLH maybe the mediation of iNK cells. Vitamin D receptor (VDR), the
mediator of VD activity, contributed to the development of invariant
natural killer (iNK) cells, a subset of lymphoid cells which
participates in the host immune response and limits autoimmunity in
negative feedback 32.
Second HLH is triggered by various pathologies, lymphoma, infections,
autoimmune disorders16. Subgroup analysis showed that
in MHLH, vitamin D displayed remarkably ability in predicting survival
(HR=0.379, 95%CI=0.187-0.769, P =0.004). Lymphoma accounts for
98.1% of malignant tumors in this study. In diffuse large B-cell
lymphoma (DLBCL) and T-cell lymphoma (TCL), Drake et al33 found that the level of 25(OH)D and 1,25-(OH)-D was
directly predictive for OS (HR=1.99 95% CI =1.27-3.13 for DLBCL;
HR=2.38 95% CI=1.04-5.41 for TCL) and EFS (HR=1.41 95%CI=0.98-2.04 for
DLBCL; HR=1.94 95% CI=1.04-3.61 for TCL). Vitamin D can regulate
several key cellular processes, including inhibiting carcinogenesis by
inducing cell differentiation, inhibiting proliferation and
angiogenesis, and promoting apoptosis34. VD also can
inhibit the proliferation of lymphoma cell lines and induce their
differentiation in vitro experiments35. 25-(OH)-D was
proven to influence tumors microenvironment, where chemokines, chemokine
receptors, adhesion molecules interacted36. Those may
explain the prognostic role of vitamin D in HLH.
Some limitations were present in our study. First, there was a
retrospective cohort study and the sample size was small. Then, further
clinical researches with more samples are needed to confirm our result.
Second, index including proinflammatory cytokines and/or inflammation
markers were absent to allow for the assessment of severity. Sfeir et al37 conducted a study about supplying vitamin D and
found the improvement of prognosis in lymphoma patients. However, this
study did not conclude the supplement of VD and answer whether 25-(OH) D
supplement improve the therapeutic effect.