These results demonstrate that chronically transfused patients with TM or SCD have significant deficiencies in both fat and water soluble nutrients which are potentially clinically relevant. For example, the levels of Vitamin A found in these patients have been shown to be related to poorer health outcomes in children with and without SCD [10
]. In addition, Vitamin D levels lower than 20 ng/ml have been associated with multiple problems in the general population [14
] and with iron cardiomyopathy in TM [15
Potential contributors to observed deficiencies are illustrated in , including hemolysis, iron toxicity, ineffective erythropoiesis, inflammation, anemia, diet, and absorption. SCD patients exhibit greater hemolysis and inflammation than TM patients, while TM patients have greater iron toxicity and ineffective erythropoiesis. Despite these phenotypic differences, the spectrum of nutritional deficiencies was remarkably similar between the two diseases (). Intravascular hemolysis, although a potent predictor of vascular disease in SCD, was not correlated with any nutritional deficiencies in both SCD and TM. Inflammation is important to the pathophysiology of SCD [16
] and markers such as Vitamin A levels decrease in the presence of inflammation while copper levels rise [10
]. We found that hs-CRP was positively correlated with copper and negatively correlated with Vitamin A in our study (see ). Despite these findings, we were unable to demonstrate a correlation between other nutrient deficiencies and inflammation in our patients.
Figure 2 Schematic representing potential contributors to vitamin and mineral deficiencies in chronically transfused TM and SCD patients, including hemolysis, iron toxicity, ineffective erythropoiesis, inflammation, chronic anemia, diet, and malabsorption. Left–right (more ...)
HIC and ferritin values were greater in the SCD than the TM patients, suggesting decreased chelation compliance in this population. Chronically transfused SCD patients have a lower prevalence of iron-mediated endocrine and cardiac mediated dysfunction [19
]. Regardless, iron overload offered little overall predictive value for antioxidant status other than mild elevations in γ-tocopherol. The negative relationship between HIC and vitamin D25-OH levels has been previously described in hereditary hemochromatosis, and is thought to reflect inhibition of hepatic 25-hydroxylation by excess iron [20
Despite their many pathophysiologic differences, SCD and TM share some common phenotypes. All patients in this study were chronically anemic. Chronically, anemic patients maintain increased cardiac output to maintain oxygen delivery [21
]. This produces a mildly hypercatabolic state, increased resting energy expenditure, and chronic oxidative stress [22
]. These findings could contribute to increased consumption of nutrients. Malabsorption could also play a role in our findings. Both SCD and TM patients develop siderosis of the exocrine pancreas. In TM pancreatic iron negatively correlates with circulating pancreatic trypsin levels [26
] and TM patients have been documented to have significant decreases in stool elastase [27
]. While these observations could clearly contribute to malabsorption of fat soluble vitamins, it does not explain the low levels of water soluble vitamins found in these patients.
Most prior work in SCD has focused on nontransfused SCD patients, with deficiencies in both water and fat-soluble vitamins. Although thiamine deficiency has not been reported, deficiencies in riboflavin and pyridoxine have been noted in SCD [28
] as well as decreases in serum pyridoxal 5-phosphate concentration [29
]. Homocysteine levels are increased in SCD disease [30
]. In addition deficiencies in vitamins A, D, and E have been reported in this group [31
]. Vitamin D deficiency is associated with decreased bone density in SCD patients [35
]. Vitamin A deficiency has been linked to increased hospitalization, poor growth and lower Hgb [10
Dietary intake has been documented in several studies to be inadequate in SCD patients and to decline further as patients age [36
]. This is particularly important for folate, which is a nutrient required by patients with increased red cell turnover and which is routinely supplemented in SCD patients despite supplementation in the US diet. As our patients have high red cell turnover, we measured serum folate. This value does not assess long term folate status. Nevertheless we also found nearly one third of our patients were folate deficient. Although we prescribe folic acid to our patients, we did not assess compliance. Thus, the low folate levels seen in this study may be due to non compliance in addition to other factors such as poor diet or malabsorption.
Only one study has examined antioxidant defenses in chronically transfused SCD patients. Alpha-tocopherol levels were lower in transfused than in nontransfused patients and were negatively correlated with number of units transfused [38
]. MDA levels, a marker of cellular oxidant damage, was found to be increased 1.8-fold in TM patients compared to controls, but not in SCD patients. MDA levels were positively correlated with HIC, but not NTBI [4
In contrast with SCD, prior work in thalassemia primarily reflects chronically transfused patients. TM patients have been shown to have low levels of Vitamins E and A as well as decreased RBC superoxide dismutase; these deficiencies were correlated with increased levels of lipid peroxidation [39
]. Similar findings were reported in Italian patients where vitamin E and A deficiencies were inversely correlated with liver enzyme levels, suggesting that liver damage may play a role in the extent of depletion of these lipid soluble antioxidants [40
]. Vitamin D deficiency has also been reported in several thalassemia cohorts [41
There are a number of limitations to the present study. We did not have a control group, such as non affected siblings in the same household or non transfused SCD patients. We did not measure dietary intake which could play a role in these findings. In addition, because we do not have age-specific norms in our study, it is possible that our results are artificially skewed. We did not use trace metal free tubes when measuring trace elements such as Zn, Se, and Cu. Nevertheless, only Cu was elevated in this study and was well correlated with ceruloplasmin levels indicating it was not a spurious finding. Finally, because almost all of our patients were on Deferasirox for chelation, we could not meaningfully assess whether the type of chelation had an effect on the findings.
Nevertheless, the breadth and depth of these deficiencies are striking. For example, many authors now consider vitamin D25-OH levels less than 30 ng/ml insufficient for proper bone mineralization and muscle function [14
]. Serum PTH and bone density data was incomplete in this study population and further work will be necessary to characterize their relationship to vitamin D stores. Thus, this study is also limited by a lack of measurable functional outcomes which prevent us from determining the degree of harm these deficiencies pose for the patients.
In summary, chronically transfused SCD and TM have broad spectrum nutritional deficiencies of both water and fat soluble nutrients. The precise mechanism of the abnormalities is unclear and is probably multifactorial. In contrast to our underlying hypothesis, iron overload, hemolysis, and inflammatory stress appear to play relative minor roles in these deficiencies. Careful nutritional studies will need to be performed to determine contributions of diet and malabsorption. Regardless of the underlying etiology, these results suggest that all patients with TM and SCD who are chronically transfused should have periodic nutritional evaluation and supplementation as necessary. Further studies of the consequences of these deficiencies are also warranted.