Sex-dependent effects of long-term clozapine or haloperidol medication on red blood cells and liver iron metabolism in Sprague Dawley rats as a model of metabolic syndrome

Background Patients with liver diseases often have some form of anemia. Hematological dyscrasias are known side effects of antipsychotic drug medication and the occurrence of agranulocytosis under clozapine is well described. However, the sex-dependent impact of clozapine and haloperidol on erythrocytes and symptoms like anemia, and its association with hepatic iron metabolism has not yet been completely clarified. Therefore, in the present study, we investigated the effect of both antipsychotic drugs on blood parameters and iron metabolism in the liver of male and female Sprague Dawley rats. Methods After puberty, rats were treated orally with haloperidol or clozapine for 12 weeks. Blood count parameters, serum ferritin, and liver transferrin bound iron were determined by automated counter. Hemosiderin (Fe3+) was detected in liver sections by Perl’s Prussian blue staining. Liver hemoxygenase (HO-1), 5’aminolevulinate synthase (ALAS1), hepcidin, heme-regulated inhibitor (HRI), cytochrome P4501A1 (CYP1A1) and 1A2 (CYP1A2) were determined by Western blotting. Results We found anemia with decreased erythrocyte counts, associated with lower hemoglobin and hematocrit, in females with haloperidol treatment. Males with clozapine medication showed reduced hemoglobin and increased red cell distribution width (RDW) without changes in erythrocyte numbers. High levels of hepatic hemosiderin were found in the female clozapine and haloperidol medicated groups. Liver HRI was significantly elevated in male clozapine medicated rats. CYP1A2 was significantly reduced in clozapine medicated females. Conclusions The characteristics of anemia under haloperidol and clozapine medication depend on the administered antipsychotic drug and on sex. We suggest that anemia in rats under antipsychotic drug medication is a sign of an underlying liver injury induced by the drugs. Changing hepatic iron metabolism under clozapine and haloperidol may help to reduce these effects of liver diseases.

Distribution and Associated Factors of Hepatic Iron—A Population-Based Imaging Study

Hepatic iron overload can cause severe organ damage; therefore, an early diagnosis and the identification of potential risk factors is crucial. We aimed to investigate the sex-specific distribution of hepatic iron content (HIC) in a population-based cohort and identify relevant associated factors from a panel of markers. We analyzed N = 353 participants from a cross-sectional sample (KORA FF4) who underwent whole-body magnetic resonance imaging. HIC was assessed by single-voxel spectroscopy with a high-speed T2-corrected multi-echo technique. A large panel of markers, including anthropometric, genetic, and laboratory values, as well as behavioral risk factors were assessed. Relevant factors associated with HIC were identified by variable selection based on LASSO regression with bootstrap resampling. HIC in the study sample (mean age at examination: 56.0 years, 58.4% men) was significantly lower in women (mean ± SD: 39.2 ± 4.1 s−1) than in men (41.8 ± 4.7 s−1, p < 0.001). Relevant factors associated with HIC were HbA1c as well as prediabetes for men and visceral adipose tissue as well as age for women. Hepatic fat, alcohol consumption, and genetic risk score for iron levels were associated with HIC in both sexes. In conclusion, there are sex-specific associations of HIC with markers of body composition, glucose metabolism, and alcohol consumption.

Multi-echo Dixon and breath-hold T2-corrected multi-echo single-voxel MRS for quantifying hepatic iron overload in rabbits

Background Three-dimensional (3D) multi-echo-Dixon (ME-Dixon) and breath-hold T2-corrected multi-echo single-voxel MR spectroscopy (HISTO) can simultaneously quantify liver fat and liver iron. However, their diagnostic efficacy and application scope for quantitative iron in co-existing fatty liver have not been adequately evaluated. Purpose To evaluate the accuracy of ME-Dixon and HISTO for quantitative analysis of hepatic iron in rabbits with iron deposition and fatty liver using liver–iron concentration (LIC) as a reference standard. Material and Methods ME-Dixon, HISTO, and conventional two-dimensional multi-echo gradient echo (GRE) sequences were performed on 42 rabbits. The following parameters were calculated: R2* from ME-Dixon and GRE; proton density fat fraction (PDFF) from the ME-Dixon, HISTO (normal TE range), and HISTO-H (extended TE range); and R2_water from HISTO and HISTO-H. The LIC and liver–fat concentration (LFC) were measured through chemical analysis, and their relationship with the MRI parameters were assessed. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to evaluate the diagnostic efficiency. Results LIC was significantly correlated with R2_HISTO-H, R2*_Dixon, and R2*_GRE ( r = 0.858, 0.910, 0.931, respectively; P < 0.001) and weakly with R2_HISTO ( r = 0.424; P = 0.008). A strong correlation was also observed between the LFC and PDFF obtained from HISTO, HISTO-H, and ME-Dixon ( r = 0.776, 0.811, 0.888, respectively; P < 0.001). ME-Dixon showed the best performance with moderate iron overload (AUC = 0.983). Conclusion 3D ME-Dixon is useful for quantifying the LIC, especially with co-existing fatty liver. Its diagnostic performance is also superior to that of the HISTO sequence.

The impact of magnetic resonance imaging in the assessment of iron overload in heart and liver in transfusion-dependent thalassemic children: Minia experience

Background Thalassemia is the most prevalent single-gene disorder. Myocardial and hepatic iron depositions lead to complications and eventually death. We aimed to assess the diagnostic efficacy of magnetic resonance imaging T2* (MRI T2*) in quantifying iron overload in liver and heart in transfusion-dependent B-thalassemia major (TDT) children. Methods Prospective clinical study was carried on sixty children diagnosed with TDT. All of them underwent laboratory investigations, including CBC, serum iron, and ferritin levels. MRI T2* of the heart and liver was carried out to measure the iron overload and estimate the left ventricular ejection fraction (LVEF). Results Thirty-eight males and 22 females with TDT with a mean age of 13.23 years were included. Twenty cases (33.3%) had severe liver iron overload, while 36 (60%) had normal cardiac iron. There was a moderate significant negative association between hepatic and cardiac iron deposition (P = 0.03). All cases with severe cardiac iron overload had impaired LVEF below 56%. A non-significant positive association was noticed between cardiac iron deposition and LVEF in T2* (P = 0.08). A moderate negative significant association was detected between hepatic iron deposition and serum ferritin, while a fair negative significant association was found between serum ferritin and cardiac iron deposition with P values of 0.04 and 0.02, respectively. Conclusion MRI T2* is the gold standard for monitoring and follow-up of iron overload in the heart and liver. It should be routinely performed in all TDT children as liver iron, and serum ferritin do not reflect cardiac iron overload.

Distribution and associated factors of hepatic iron — a population–based imaging study

Context: Hepatic iron overload can cause severe organ damage. Therefore, an early diagnosis is crucial, and identification of modifiable risk factors could help to prevent manifestations of iron-driven complications. Objective: To investigate the sex–specific distribution of hepatic iron content (HIC) in a population-based sample, and to identify relevant associated factors from a panel of markers. Methods: We analysed N=353 participants from a cross–sectional, population–based cohort in Southern Germany (KORA FF4) who underwent whole–body magnetic resonance imaging. HIC was assessed by single–voxel spectroscopy with a high–speed T2–corrected multi–echo technique. A large panel of markers, including anthropometric, genetic and laboratory values as well as behavioural risk factors were assessed. Relevant factors associated with HIC were identified by variable selection based on LASSO regression with bootstrap resampling. Results: HIC in the study sample (mean age at examination was 56.0 years, 58.4% were men) was significantly lower in women (mean±SD: 39.2±4.1 s−1) than in men (41.8±4.7 s−1, p<0.001). Relevant factors associated with HIC were HbA1c and prediabetes for men, and visceral adipose tissue and age for women. Hepatic fat, alcohol consumption, and a genetic risk score for iron levels were associated with HIC in both sexes. Conclusion: There are sex–specific associations of HIC with markers of body composition, glucose metabolism and alcohol consumption.