Abstract
Objective
The objective was to investigate factors influencing the high incidence of abnormal iron metabolism in a Tibetan population.
Methods
This was a retrospective observational study. Magnetic resonance imaging and blood analysis of 363 Tibetan patients were performed and patients divided into normal and abnormal groups based on the clinical diagnostic standard. The upper limit of normal liver iron content was 50 μmol/g. We analyzed the association between abnormal iron metabolism and blood cell indicators using the Spearman rank correlation test.
Results
In male patients, differences in mean corpuscular hemoglobin (MCH) and MCH concentration in blood between the normal and abnormal groups were significant. Abnormal iron metabolism in male patients was positively correlated with MCH and MCH concentration. In female patients, differences in erythrocytes, hemoglobin, and hematocrit levels between the two groups were significant. Erythrocyte counts and hemoglobin and hematocrit levels of female patients were positively correlated.
Conclusion
Iron overload in male patients was correlated with an increase in MCH and MCH concentration, and that in female patients was correlated with levels of erythrocytes, hemoglobin, and hematocrit. The incidence rate of iron overload was higher in males than in females and was correlated with age in this Tibetan population.
Introduction
Systemic iron overload is a disorder characterized by high levels of plasma iron with subsequent deposition in multiple organs such as liver, pancreas, heart, pituitary gland, and joints.1–3 Histologically, excess iron in the body is stored primarily in hepatocytes and macrophages. 4 Hence, abnormal iron metabolism first involves the liver and spleen. The liver is the main location for iron storage and is the earliest and most critical organ for iron deposition. 5 Excess accumulation of iron may lead to life-threatening complications, including liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. 6
The gold standard method to measure liver iron concentration is a biopsy; however, a liver biopsy is invasive and susceptible to sample variability from uneven hepatic iron concentration. 7 In recent years, radiological technologies, including computed tomography and magnetic resonance imaging (MRI), are better able to reflect the degree of organ iron overload and monitor treatment noninvasively and quantitatively.8–11 MRI has recently been favored as an initial diagnostic test for assessing iron overload via the T2* parameter, an exponential decay constant that can be calculated from a single gradient-echo sequence with multiple echo times. T2* sequences have demonstrated high sensitivity in detecting hepatic iron deposition, even in the early stages of the disease, and T2* values correlate well with liver iron concentrations derived from biopsy.12–14
At present, few etiological studies have been conducted on the high incidence of abnormal iron metabolism among plateau people. Hence, the pathogenesis of abnormal iron metabolism in Tibetan people remains unclear. The present study aimed to investigate the factors underlying the high incidence rate of abnormal iron metabolism in the Tibetan population and to conduct a preliminary study on the correlation between abdominal MRI manifestations and blood cell analysis.
Patients and methods
This study was conducted in accordance with the Declaration of Helsinki and in compliance with ethical guidelines. The study was approved by the Ethics Committee of West China Hospital, Sichuan University. Written informed consent was obtained from the participants or their guardians.
Study objective
This was a retrospective observational study. Imaging and blood cell analysis data were collected from 363 patients in Tibet who underwent middle and upper abdominal MRI examinations in our hospital from January 2014 to December 2017. The inclusion criteria were (1) Tibetan; (2) patients who underwent middle and upper abdominal MRI examinations and blood cell analysis; (3) patients who had an abnormal MRI and met the diagnostic standard for clinical abnormal iron metabolism (transferrin saturation >45% and serum ferritin >250 and >200 ng/mL for men and women, respectively).15–17 The exclusion criteria were (1) patients with serious image motion artifacts in which an analysis could not be made; (2) patients with large space-occupying lesions of the liver, spleen, or pancreas in which the excessively large focus affected assessment and analysis of MRI signal.
MRI examination
MRI examinations were performed on a 3.0 T system (Philips, Best, Netherlands) with 16-channel body phased-array coils. The patient was placed in the supine position and an MRI plain scan sequence was taken, including T1-weighted image (WI), T2WI, T2WI spectral attenuated inversion recovery (SPAIR), multi-echo T2*WI, and in/out phase sequence. We used a signal intensity ratio method based on T1 and T2* contrast imaging without gadolinium, as established by Gandon et al. at Rennes University. 18 For liver iron content (LIC) measured by MRI performance, the upper limit was set at 50 μmol/g for this study; LIC values >50 μmol/g were considered abnormal.
Statistical analysis
SPSS version 22.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. Measurement data of normally distributed data were expressed as mean ± standard deviation (SD), data of skewed distributions were expressed in medians, and enumeration data were expressed as frequencies. Continuous variables were compared between the two groups by using the two independent samples t-test. Discontinuous variables were compared by χ2 test. Associations between abnormal iron metabolism and indicators of blood cells were analyzed using the Spearman rank correlation test. P < 0.05 was considered statistically significant.
Results
MRI signals
Of the 363 Tibetan patients, 268 were male. The age (mean ± SD) of Tibetan patients in the normal and abnormal groups was 46.14 ± 12.99 and 52.70 ± 10.79 years, respectively (P < 0.001). The age of male patients in the normal and abnormal groups was 47.68 ± 12.64 and 51.78 ± 10.78 years, respectively (P = 0.007). The age of female patients in the normal and abnormal groups was 43.78 ± 13.30 and 56.93 ± 9.92 years, respectively (P < 0.001). Representative images from the MRI examinations are shown in Figure 1.
Normal abdominal and iron overload images by MRI: (A) T1WI normal abdominal image; (B) T2WI normal abdominal image; (C) T2WI SPAIR normal abdominal image; (D) in-phase normal abdominal image; (E) out-phase normal abdominal image; (F) T1WI iron overload image; (H) T2WI iron overload image; (I) T2WI SPAIR iron overload image; (G) in-phase iron overload image; (K) out-phase iron overload image. MRI, magnetic resonance imaging; T1WI, T1-weighted image; T2WI, T2-weighted image; SPAIR, spectral attenuated inversion recovery.
Blood cell analyses
In male patients, significant differences in mean corpuscular hemoglobin (P = 0.016) and mean corpuscular hemoglobin concentration (P = 0.006) were found in patients with normal and abnormal MRI signals. However, erythrocyte counts, hemoglobin and hematocrit levels, and mean corpuscular volume did not differ significantly between the two groups (Table 1).
Blood cell analysis of patients in the normal and abnormal MRI groups.
MRI, magnetic resonance imaging.
*P < 0.05.
In female patients with normal and abnormal MRI signals, we found significant differences in erythrocyte counts and hemoglobin and hematocrit levels (P = 0.005, P = 0.001, and P = 0.001, respectively). However, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration did not differ between normal and abnormal groups (Table 1).
Correlation of abnormal iron metabolism and blood cell indicators
In male patients, we found that abnormal iron metabolism (transferrin saturation >45% and serum ferritin >250 ng/mL) was positively correlated with mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. In male patients, the single factor correlation analysis showed that abnormal iron metabolism was positively correlated with mean corpuscular hemoglobin (r = 0.147, P = 0.016) and mean corpuscular hemoglobin concentration (r = 0.169, P = 0.006). However, the correlation coefficients were low (<0.5). Correlations of abnormal iron metabolism with erythrocyte counts, hemoglobin and hematocrit levels, and mean corpuscular volume were not significant.
In female patients, abnormal iron metabolism was positively correlated with erythrocyte count and hemoglobin and hematocrit levels. However, the correlation coefficients were low (<0.5). Correlations of abnormal iron metabolism with mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were not significant.
Discussion
The incidence rate of iron overload was high in the Tibetan population studied here. Previous studies have found that the high incidence of iron overload in Tibetan people is correlated with oxygen deficiency. 19 Because oxygen deficiency in the body requires more hemoglobin to meet the oxygen demand, the demand for erythrogenin will increase. Researchers have proposed that oxygen deficiency may promote an increase of erythrogenin by inducing the transcription factor hypoxia-inducible factor. 20 However, the pathophysiology of such an interaction remains unknown. Because plateau anoxia and drying can increase the brittleness of the erythrocyte membrane, the life span of erythrocytes is shortened, erythrocyte destruction is increased, and the metabolism product from senescent erythrocytes promotes an increase of hematopoietic and erythroid cells. 21 Previous studies have shown that anoxia can be relieved by taking iron supplements. 22 Therefore, when the body is in an oxygen-deficient environment, the oxygen deficiency would certainly increase iron absorption and utilization to meet the needs of the body. We found significant differences in erythrocyte counts and hemoglobin and hematocrit levels of female patients with normal and abnormal MRIs. However, in male patients in our study, significant differences were found in mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration between the two groups.
In addition to the effect of the oxygen-deficient environment in plateaus, iron metabolism is correlated with living habits, such as drinking and long-term meat eating. The prevalence of abnormal iron metabolism among Tibetan patients increases with increasing age, regardless of sex. This may be because the oxygen demand of the body increases with age. However, cardiopulmonary function weakens and oxygen uptake decreases with increasing age. Furthermore, slower metabolism would cause deposition of iron in the body. The incidence of abnormal iron metabolism was higher in men than in women in our study, which may be due to differences in the secretion level of estrogen and androgen in men and women. 23 In addition, abnormal iron metabolism is correlated with cardiopulmonary function, the endurance capacity of oxygen deficiency, and living habits. This needs to be proven through further studies.
Although Tibetan people living on the plateau for long periods suffer from abnormal iron metabolism because of the chronic oxygen-deficient environment and have abnormal organ MRI manifestations, the male patients in our group mainly showed an increase in mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, whereas female patients manifested changes in erythrocyte counts and levels of hemoglobin and hematocrit. At present, there are few studies on iron metabolism among people living on the Tibetan plateau, and the specific factors influencing the high incidence of abnormal iron metabolism in Tibetans have been rarely reported.
Conclusion
Iron overload in Tibetan men was correlated with increases in mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, whereas iron overload in Tibetan women was correlated with erythrocyte counts and levels of hemoglobin and hematocrit. The incidence of iron overload was higher in men than in women and was correlated with age.
