Liver Iron Overload Research Articles

The value of magnetic resonance imaging in evaluation of myocardial and liver iron overload in a thalassaemia endemic population: a report from Northeastern Thailand

PurposePatients with chronic haemolytic anaemia, such as in thalassaemia, require repeated blood transfusions, which leads to iron overload and cellular damage, especially in the heart and liver. Classically, serum ferritin and liver biopsy have been used to monitor patient response to chelation therapy. Magnetic resonance imaging (MRI) has proven to be effective in detecting and quantifying iron in the heart and liver. The aim of the paper is to evaluate the accuracy of the MRI T2* procedure in the assessment of liver iron concentration and myocardial iron overload.Material and methodsIn 210 cases of monthly transfused patients, hepatic and myocardial iron overload was measured by multi-breath-hold MRI T2* and compared to serum ferritin (a traditional marker of iron overload).ResultsNo significant correlation was observed between serum ferritin level and cardiac T2* MRI (p = 0.68, r = 0.06). However, a significant correlation was observed between serum ferritin and liver iron concentration evaluated by MRI (p = 0.04, r = 0.68).ConclusionRoutine evaluation of liver and heart iron content using MRI T2* is suggested to better evaluate the haemosiderosis status in thalassaemic patients.

Brain iron content in systemic iron overload: A beta-thalassemia quantitative MRI study.

Multisystem iron poisoning is a major concern for long-term beta-thalassemia management. Quantitative MRI-based techniques routinely show iron overload in heart, liver, endocrine glands and kidneys. However, data on the brain are conflicting and monitoring of brain iron content is still matter of debate. This 3T-MRI study applied a well validated high-resolution whole-brain quantitative MRI assessment of iron content on 47 transfusion-dependent (mean-age: 36.9 ± 10.3 years, 63% females), 23 non-transfusion dependent (mean-age: 29.2 ± 11.7 years, 56% females) and 57 healthy controls (mean-age: 33.9 ± 10.8 years, 65% females). Clinical data, Wechsler Adult Intelligence Scale scores and treatment regimens were recorded. Beside whole-brain R2* analyses, regional R2*-values were extracted in putamen, globus pallidum, caudate nucleus, thalamus and red nucleus; hippocampal volumes were also determined. Regional analyses yielded no significant differences between patients and controls, except in those treated with deferiprone that showed lower R2*-values (p<0.05). Whole-brain analyses of R2*-maps revealed strong age-R2* correlations (r2=0.51) in both groups and clusters of significantly increased R2*-values in beta-thalassemia patients in the hippocampal formations and around the Luschka foramina; transfusion treatment was associated with additional R2* increase in dorsal thalami. Hippocampal formation R2*-values did not correlate with hippocampal volume; hippocampal volume did not differ between patients and controls. All regions with increased R2*-values shared a strict anatomical contiguity with choroid plexuses suggesting a blooming effect as the likely cause of R2* increase, in agreement with the available histopathologic literature evidence. According to our MRI findings and the available histopathologic literature evidence, concerns about neural tissue iron overload in beta-thalassemia appear to be unjustified.

Hyporegenerative anemia and other complications of rhesus hemolytic disease: to treat or not to treat is the question

Rhesus hemolytic disease of the newborn is rarely found after the implementation of anti-D immunoglobulin prophylaxis. However, it may lead to cholestasis, elevated liver transaminases, iron overload and late hyporegenerative anemia when it occurs. Etiology of this type of anemia is not defined yet and treatment is controversial. It is typically recognized after two weeks of life which is characterized by low hemoglobin and reticulocyte count. We have reported a case of a neonate with Rh hemolytic disease with late hyporegenerative anemia that was noted at day 18 of life. We treated this anemia by erythropoietin (EPO) 250 U/kg three times per week. Two weeks after initiation of erythropoietin treatment, a stable hemoglobin was noted along with an increased reticulocyte count. The patient required one further blood transfusion in the third week of therapy. Other associated findings were self-limited. A year of follow-up showed an appropriate development for age.

Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries.

Background: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. Aims of the study: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. Results: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with β- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other “general medical and non-medical conditions”. Conclusions: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care. (www.actabiomedica.it)

The liver injury in patients with B-thalassemia major secondary to iron over load in Thalassemia center of Diwaniyah maternity and children teaching Hospital . A clinical study in Thalassemia center of Diwaniyah maternity and children teaching Hospital

Background:liver iron concentration assessed by MRI T2* is the better indicator of total-body iron depositions and should be checked in frequent blood transfused patients. MRI T2* can be detect iron overload before iron toxicity becomes clinically apparent.Aim of study: to prevalence of liver injury among patients with B- thalassemia major secondary to iron over load in Thalassemia center of Diwaniyah maternity and children teaching Hospital.Methods: This a cross – sectional study was carried out on 58 patients (34 males and 24 females ) diagnosed ?-thalassemia major on the base of the blood investigations (peripheral blood counts and hemoglobin electrophoresis), their age range from 9 years to 36 years. The study was conducted in Thalassemia center of Diwaniyah maternity and children teaching hospital in Al- Diwaniyah Governorate, Republic of Iraq. The Data collection was carried out during the period from the 30th of December 2015 to 11th of August 2016. They were studied for prevalence of liver injury among patients with thalassemia major secondary to iron over load. Results: Total numbers of B- thalassemia major patients are 58 patient. The numbers of patients with ages less than 10 years are 3 (5.2%), patients with ages(10-18)years are 39 (67.2%), patients with ages(19-25)years are 12(20.7%). statistically significant correlation was found between liver function test (LFT) abnormality ( ALT, AST) and numbers of blood transfusion per year (P=0.001) and also LFT abnormality ( ALT, AST) and ferritin levels (P=0.01). In our study reported that liver iron concentration was presented normal in 23 patients (39.7%), mild iron concentration in 29 patients (50.0%) and moderate iron concentration in 6 patients (10.3%). There was a significant association between serum ferritin level and the liver iron concentration assess by liver MRI T2* (P=0.002).Conclusion: These results showed that correlation between ferritin, LFT abnormality and liver iron storage detected by MRI T2 in patients with ?-thalassemia major. MRI T2* has become the clinical standard to estimate liver iron overload.

Quantification of liver iron overload disease with laser ablation inductively coupled plasma mass spectrometry

BackgroundHereditary hemochromatosis is the most frequent, identified, genetic disorder in Caucasians affecting about 1 in 1000 people of Northern European ancestry, where the associated genetic defect (homozygosity for the p.Cys282Tyr polymorphism in the HFE gene) has a prevalence of approximately 1:200. The disorder is characterized by excess iron stores in the body. Due to the incomplete disease penetrance of disease-associated genotype, genetic testing and accurate quantification of hepatic iron content by histological grading of stainable iron, quantitative chemical determination of iron, or imaging procedures are important in the evaluation and staging of hereditary hemochromatosis.MethodsWe here established novel laser ablation inductively coupled plasma mass spectrometry protocols for hepatic metal bio-imaging for diagnosis of iron overload.ResultsWe demonstrate that these protocols are a significant asset in the diagnosis of iron overload allowing iron measurements and simultaneous determination of various other metals and metalloids with high sensitivity, spatial resolution, and quantification ability.ConclusionsThe simultaneous measurement of various metals and metalloids offers unique opportunities for deeper understanding of metal imbalances. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a highly powerful and sensitive technique for the analysis of a variety of solid samples with high spatial resolution. We conclude that this method is an important add-on to routine diagnosis of iron overload and associated hepatic metal dysbalances resulting thereof.

Clinical-Pathological Features of Non-Transfusion Dependent Thalassemia in Adults — a Single Center Study in Hong Kong

Introduction: Non-transfusion dependent thalassemia (NTDT) includes HbH disease, β-thalassemia intermedia (β-TI) and HbE/β-thalassemia. The transfusion requirements of patients with NTDT are variable and they are all at risk of developing iron overload and other complications. The prevalent genetic changes in thalassemia are different across geographical territories, accounting largely for the diverse clinical outcomes. The complication profile of NTDT in Southern China is less well studied than other areas. Data on age-related complications is sparse. The present study aims to describe the clinical-pathological features of adult NTDT patients in Hong Kong, and to evaluate the risk factors associated with complications.Method: A single-center observational study was performed during Jan 2017 to Jun 2018. Data collection included review of medical records for demographics; globin genotypes; hepatitis B and C status; transfusion requirement; splenectomy; iron chelation therapy; complications including gallstone disease, hypothyroidism or hypogonadism, diabetes mellitus (DM), extramedullary hematopoiesis (EMH), leg ulcer, venous thrombosis and cerebral ischemia. During the study period, steady state hemoglobin (Hb) and serum ferritin levels in the recent year were obtained; organ iron deposition assessed using liver and cardiac T2* at 1.5T MRI; liver stiffness measured by Fibroscan; and presence of pulmonary arterial hypertension (PAH) evaluated by echocardiography. The disease profile and prevalence of complications were described with descriptive statistics. Factors impacting clinical parameters and development of complication were studied with univariate regressions. Age and sex adjusted β-coefficients or odd ratios were then determined with multivariable regression analysis.Results: A total of 96 Chinese patients were recruited (mean age 50±15 years; 31% patients >60 years; females 66%). There were 63 (65%) patients having deletional HbH disease, 20 (21%) with non-deletional HbH disease (ND-HbHD), and 13 (14%) with β-TI. The mean Hb was 8.9±1.1 g/dL. Transfusion requirement was never in 39 (41%), occasional in 50 (52%), and regular in 7 (7%) patients. Ten (10%) patients were splenectomized. Iron chelation was given to 21 (21%) patients and the median duration of therapy was 3 (range 1-21) years. Respectively 4 (4%) and 2 (2%) patients were hepatitis B and C carriers. The median serum ferritin was 473 [IQR 217-1029] ng/mL. The median liver iron concentration (LIC) estimated by MRI T2* was 3.6 [IQR 1.7-7.1] mg Fe/g with 26% of patients having moderate to severe liver iron overload (≥7.1 Fe mg/g). In the study population, the prevalence of liver fibrosis (liver stiffness ≥7.1kPa) was 26%, gallstones 50%, hypo-thyroidism/-gonadism 8%, DM 16%, EMH 5%, leg ulcer 1%, thrombotic events 2%, cardiac iron overload 1%. No patients had PAH (Table 1).In multivariable regression, advanced age (>60 years) was associated with lower Hb (p=0.03), higher risk of liver fibrosis (p=0.04) and DM (p<0.01). β-TI was associated with higher transfusion requirement (p<0.01), higher serum ferritin (p<0.01) and higher risk of hypo-thyroidism/-gonadism(p=0.01). Both ND-HbHD and β-TI were associated with higher LIC (p<0.01). Patients requiring regular transfusions had higher serum ferritin (p<0.01) and LIC (p<0.01). Occasionally transfused (p=0.01) and female patients (p=0.01) had higher risk of developing gallstones. Splenectomy was associated with higher serum ferritin level (p=0.03). Patients with moderate to severe liver iron overload had increased risk of liver fibrosis (p=0.01) (Table 2).Conclusions: The present study including 1/3 of elderly patients illustrates the heterogeneous clinical features of NTDT in Hong Kong in terms of transfusion requirement and body iron store. HbH disease is the most frequent type of NTDT. Liver iron overload, liver fibrosis, gallstones and DM were the most common complications. Advancing age, β-TI, ND-HbHD were associated with higher risk of developing complications. A low prevalence of EMH, cardiac iron overload, PAH, thrombosis and leg ulcer was observed. Larger prospective study is needed to confirm the prevalence of complications in NTDT in Chinese, which may be different from other ethnic groups, and at the same time to provide more insight to the pathophysiology of NTDT and facilitate establishment of future local management strategies. DisclosuresNo relevant conflicts of interest to declare.

Iron Overload in Patients with Paroxysmal Nocturnal Hemoglobinuria

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal bone marrow disorder caused by a somatic mutation in PIGA that leads to a marked deficiency or absence of the complement regulatory proteins CD55 and CD59. The disease manifests with intravascular hemolysis, anemia and thrombosis. PNH is characterized by diverse changes in iron metabolism. Chronic hemolysis leads to the massive iron loss due to hemoglobinuria and hemosiderinuria, whereas frequent transfusions in severely anemic, transfusion-dependent patients might cause the development of iron overload.Aim: to assess iron metabolism in PNH patients based on both laboratory parameters and MRI data.Methods: the study group included 28 PNH patients (pts) followed up in our Center between 2015 and 2017. Laboratory parameters including hemoglobin (Hb), reticulocytes (RET), erythrocyte and granulocyte PNH clone sizes and LDH levels were analyzed. Iron metabolism was characterized by measurement of serum ferritin (SF), transferrin, iron concentration, total iron binding capacity (TIBC), transferrin saturation (TS). Multiecho gradient-echo T2* magnetic resonance imaging (T2* MRI) was performed to assess both liver and kidney iron load. All pts were divided into 3 cohorts: №1 - pts on treatment with eculizumab, №2 - pts who received eculizumab in the past and №3 - eculizumab naïve pts.Results:Сohort №1 included 2 pts (2 women) aged 39 and 64 yrs. Hb level was 9,3 and 9,9 g/dl, RET count - 9,6 and 10%, LDH level - 570 and 650 U/l. Erythrocyte PNH clone size was 99 and 72%, and granulocyte PNH clone size was 99 and 87%.Cohort №2 consisted of 6 pts (2 men and 4 women, median age 39 yrs (31 - 53)) which had a history of eculizumab treatment. The median duration of eculizumab treatment in these pts was 23 months, the median time of treatment cessation (due to administrative reasons) was 6 months before study assessments. The medians of laboratory parameters were as follows: Hb = 7,7 g/dl, RET count = 6,6%, LDH level = 3296 U/l (1580 - 7444), erythrocyte PNH clone size = 36%, granulocyte PNH clone size = 98%.Cohort №3 consisted of 20 untreated pts (15 men and 5 women, median age 35 yrs (29 - 58)). The medians of laboratory parameters: Hb = 8,4 g/dl, RET count = 8,5%, LDH level = 4130 U/l (670 - 8322), erythrocyte PNH clone size = 52%, granulocyte PNH clone size = 93%.Serum iron metabolism indices in all patient cohorts are reported in Table 1. Based on the analysis of the measured serum iron metabolism indices, 3 types of iron metabolism disturbances were identified in pts of the study group (n=28): iron deficiency (14% of pts), iron overload (21% of pts) and divergent changes (65% of pts). T2* MRI was performed in 23 pts. Signs of liver iron overload were revealed in 35% pts whereas signs of kidney iron overload were detected in 91% pts. T2* MRI data was analyzed within each of the patient cohorts, results are reported in Table 1.Conclusion: the results of our pilot study demonstrate that in PNH patients laboratory parameters are not sufficient to assess iron metabolism. T2* MRI is a noninvasive and accurate technique which should be considered as a method of choice to quantify tissue iron overload. Kidney iron overload was detected in all PNH patients who did not receive eculizumab at the moment of the analysis and was absent in 2 patients on eculizumab. Thus, hemosiderin deposition in the renal cortex might play an important role in the development of renal involvement including the formation of interstitial fibrosis and chronic kidney disease. [Display omitted] DisclosuresLukina:Sanofi Genzyme: Honoraria, Other: Principal investigator in the eliglustat Phase 2, ENGAGE, ENCORE, and EDGE trials; receives travel reimbursement; member of advisory boards, Research Funding.

Stratification for Age in Non-Transfusion-Dependent Thalassemia: Data from a National Italian Networking

Background: Non-transfusion-dependent thalassemia (NTDT) is a term used to indicate patients who do not require lifelong regular transfusions for survival. Morbidity in NTDT patients is more common and serious than previously recognized. This study aimed to examine the association of age with the presence of iron overload assessed by Magnetic Resonance Imaging (MRI) and cardiovascular and endocrine complications in NTDT patients.Methods: We considered 170 patients with thalassemia intermedia never transfused o who received occasional transfusions consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project. Iron overload was quantified by the T2* Magnetic Resonance Imaging (MRI) technique. All complications were classified according to international guidelines.Results: Six groups of patients were identified: age<18 years (N=7), age 18-30 years (N=36), age 30-40 years (N=48), age 40-50 (N=45), age 50-60 years (N=26), and age≥60 years (N=8). The Table shows the comparison among the groups.The youngest patient showing hepatic iron (MRI liver iron concentration-LIC>3 mg/g dw) had 9 years of age and the frequency of hepatic iron did not significantly increase with age.Only one patient showed cardiac iron (global heart T2*<20 ms).Diabetes appeared only in patients with more than 50 years and showed a trend toward increasing with increasing age. Hypothyroidism and osteoporosis were not present in pediatric patients and were not associated to age. Hypogonadism was not present in patients with less than 30 years and its frequency was comparable among the age groups. No patient showed hypoparathyroidism.Only patients older than 30 years showed a cardiac complication (heart failure or arrhythmias), but the rate did not significantly increase with increasing age.Conclusions: Our data in NTDT are indicative of high rate of liver iron overload at early age and extremely rare cardiac iron overload. Endocrine or cardiac complications were not present in pediatric patients but in adult patients the frequency did not increase with advancing age. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Impact of a Ten-Year National Italian Networking on Cardiac Complications in Patients with Thalassemia Major

▪Introduction. The MIOT (Myocardial Iron Overload in Thalassemia) Network was a national Italian network constituted by thalassemia and magnetic resonance imaging (MRI) centers built in 2006. The main aim was to assure available, accessible homogeneous and standardized T2* MRI cardiac and liver iron overload assessments for a significant number of patients with emoglobinopathies. Moreover, the creation of a solid clinical-instrumental web based database allowed data exchange between centers and constituted a means of monitoring health care processes and outcomes. We describe the impact of this ten-year Network on cardiac complications in patients with thalassemia major (TM).Methods. Among the 2497 emoglobinopathies patients consecutively enrolled in the MIOT Network we considered the 1401 TM patients who performed an end-of-study MRI. Per protocol the MRI follow up was scheduled every 18±3 months. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2* technique. Biventricular function was quantified by cine images.Results. At the last MRI significantly higher global heart T2* values (35.5±10.7 ms vs 29.2±12.0 ms; P<0.0001) and a significant lower number of patients with global heart T2*<20 ms (26.3% vs 12.0%; P<0.0001) were detected. Four patterns of MIO were identified: no MIO (all segments with T2*≥20 ms), heterogeneous MIO and global heart T2*≥20 ms, heterogeneous MIO and global heart T2*<20 ms, and homogeneous MIO (all segments with T2*<20 ms). Figure 1 shows the frequency of the 4 patterns at both scans. At the last MRI a significant higher frequency of patients with no MIO and a significant lower frequency for the other three patterns indicating MIO were detected. An improvement in MIO, that is a transition to a better risk class, was detected in the 68.4% of patients showing MIO at the baseline (at least one pathologic segment).In patients with significant baseline MIO (global heart T2*<20 ms) a significant increase in left ventricular ejection fraction (EF) (mean difference: 3.2±8.5 %, P<0.0001) as well as in right ventricular EF (mean difference: 1.2±8.9 %, P=0.002) were detected with a concordant improvement of MIO status.Based on MRI results the 75% of the patients changed the chelation therapy. At the last MRI the percentage of patients with an excellent/good compliance was significantly higher (94.7% vs 92.7%%; P=0.034).The 13.1% of the patients had a cardiac complication (heart failure, arrhythmias, pulmonary hypertension, myocardial infarction, angina, myo/pericarditis, and peripheral vascular disease) before the enrolment in the project. During the study, the frequency of cardiac complications was 7.9 %, significantly lower (P<0.0001). In particular, the frequency of heart failure was significantly lower (5.9% vs 1.7%, P<0.0001).Conclusion. Over a period of 10 years, the continuous monitoring of cardiac iron levels and a tailored chelation therapy allowed a reduction of MIO in the 70% of patients and a consequent improvement of cardiac function and reduction of heart failure. So, a national networking as the MIOT project was effective in improving the care and reducing cardiac outcomes of TM patients. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

PO-295 Effect of resveratrol on preventing iron overload in liver of mice

Objective To investigate the mechanism of resveratrol improving iron overload in liver of mice and its effect on alleviating liver oxidative damage.&#x0D; Methods 40 male Balb/Cj mice, 2 months old, were randomly divided into 4 groups, Quiet control group (group C), sucrose iron group (group I), resveratrol group (group R), resveratrol + sucrose iron group (group IR), 10 in each group. Group IC and group IR were intraperitoneally injected with sucrose iron solution (100mg/5mL) once every two days, 75uL each time; R group and IR group were intragastrically resveratrol (Res), dissolved in 1% DMSO solution, each time 30mg / Kg; Group C and IC group were intragastrically administered with 1% DMSO solution once daily for 30 mg/Kg. After the end of the intervention for 8 weeks, the mice were dissected and taken. Perls' staining was used to observe the distribution of iron in the liver of mice; biochemical kit for serum glucose, serum iron (SI), total iron binding capacity (TIBC), liver iron, liver superoxide dismutase (T-SOD), liver malondialdehyde (MDA), total liver oxidative capacity (T-AOC); enzyme-linked immunosorbent assay (ELISA) for detection of serum ferritin (SF), octahydroxydeoxyguanosine (8-OHdG); Western blot detection of FPN1 protein expression in liver; the expression of Hepcidin in liver was detected by PCR.&#x0D; Results (1) Perls' staining results: 8 weeks of iron sucrose caused a significant increase in iron content in mouse hepatocytes, and Res decreased the amount of iron ions in hepatocytes; (2) Results of iron metabolism index: 8 weeks of sucrose iron had a significant increase in liver iron, SI, TIBC and SF (P&lt;0.01), and Res intervention reduced liver iron (P&lt;0.05) and SF (P&lt;0.01). The content of TIBC (P&lt;0.01) and SI (P&lt;0.05) increased, and the iron supplement and Res interacted with the effects of liver iron, SI and TIBC; (3) Results of glucose metabolism index: iron overload increased glucose level in mice (P&lt;0.01), Res decreased glucose level, iron overload reduced liver glycogen storage in mice (P&lt;0.05), iron supplement and Res, there is no interaction on the effects of glucose metabolism indicators; (4) Oxidation index results: 8 weeks of sucrose iron significantly inhibited liver T-SOD and T-AOC activity (P&lt;0.01), increased liver MDA and 8-OHDG activity (P&lt;0.01), and Res promoted liver T-AOC (P&lt;0.01) and T-SOD activity increased, and the liver 8-OHDG (P&lt;0.01) and liver MDA activity were decreased. The effects of iron supplement and Res on 8-OHDG and T-AOC were interactive (P&lt;0.01); (5) 8 weeks of sucrose iron inhibited the expression of FPN1 protein in the liver of mice, and the intervention of Res could enhance the expression of FPN1 protein; iron supplement promoted the expression of Hepcidin in liver (P&lt;0.01), Res inhibited Hepcidin, iron supplement and Res had no interaction with the expression of FPN1 and Hepcidin in liver.&#x0D; Conclusions 8 weeks of sucrose iron caused iron overload in the liver of mice, and increased oxidative stress in the liver. Res can alleviate iron overload, reduce oxidative stress and improve glucose metabolism. The main reason is that Res inhibits Hepcidin expression in liver and promotes FPN1 expression and promotes The liver iron is released, thereby reducing the state of iron deposition.

Abnormal Liver Enzymes Due to H. pylori Infection

Case: We present a case of a 53 year-old female with no past medical history, who presented to gastroenterology clinic for abdominal pain. She was seen in the emergency department on several occasions for abdominal pain, nausea and vomiting. Her labs were notable for abnormal liver enzymes (AST 103, ALT 164, normal alkaline phosphatase and bilirubin). A CT abdomen showed a calcified granuloma within the right hepatic lobe and a distended gallbladder with no definite gallbladder wall thickening. An ultrasound abdomen did not show evidence of cholelithiasis. She continued to have persistent abdominal pain as well as AST and ALT elevations with workup revealing negative serologic testing for HAV, HBV, HCV, autoimmune liver disease, alpha-1 antitrypsin, iron overload and Wilson's disease. A liver biopsy was then done and showed mild chronic portal and lobular inflammation. She also underwent an upper endoscopy with biopsies returning positive for Helicobacter pylori (H. pylori) and pathology showing chronic H. pylori-related gastritis. She received a 2-week course of standard therapy with symptom resolution. Her liver enzymes were evaluated at 8 and 12 weeks following treatment and showed normalization of her AST and ALT levels. Discussion: H. pylori is a gram negative bacterium that has the ability to adhere to the gastric epithelium. It is the most common chronic bacterial infection in humans and is thought to infect approximately 50 percent of the world's population, with higher rates seen in developing countries. The transmission route for H. pylori remains unknown but is thought to occur through the fecal-oral route. H. pylori is typically diagnosed using a urea breath test or stool antigen. Treatment involves the use of a combination of antibiotics and a proton pump inhibitor. Reinfection with H. pylori is uncommon and occurs at an annual rate of 2 percent. Complications of H. pylori infection include gastritis, gastric ulcers, duodenal ulcers and gastric cancers. In a minority of patients, mild elevations in AST and ALT levels are seen, which normalize following eradication of H. pylori. There appears to be a temporal association between the infection and liver enzyme abnormalities, but a direct link is yet to be made. The underlying mechanism of liver injury is unclear but a genetic predisposition may be the differentiating factor between patients. Further studies are required to investigate such association and its clinical significance.

Liver iron overload and hepatic function in children with thalassemia major

Background Routine blood transfusions and increased intestinal iron absorption lead to iron accumulation in various organs, especially the liver. To date, T2-star magnetic resonance imaging (T2*MRI) is a valuable tool to evaluate iron level in organs.&#x0D; Objective To assess the degree of liver iron overload among children with thalassemia major (TM) and its possible correlations with hepatic function laboratory values.&#x0D; Methods This cross-sectional study was conducted in Cipto Mangunkusumo Hospital. The degree of liver iron overload was evaluated by T2*MRI. Assessments of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and bilirubin levels were done to evaluate liver function.&#x0D; Results A total of 291 TM children were included in this study. The mean age of subjects was 12 years. Most of the subjects were diagnosed as β-thalassemia homozygote (54.6%) and β-thalassemia/HbE (41.2%). Deferiprone (DFP) was the most commonly used iron chelator. Less than 10% of the subjects had normal liver iron deposition. The AST and ALT values increased proportionally with the severity of liver iron overload, with significant, moderately negative correlation coefficients (r=-0.388 and -0.434, respectively). However, albumin level decreased proportionally with the severity of liver iron overload, with a significant, moderately positive correlation coefficient (r=0.323). Liver T2* MRI had no significant correlations with direct, indirect, and ratio of direct/total bilirubin levels.&#x0D; Conclusion Most of the children with TM have mild to severe liver iron overload. Liver T2* MRI had significant, moderate correlations with AST, ALT, and albumin values. Bilirubin level has no correlation with T2* MRI. Our findings suggest that monitoring of AST, ALT, and albumin levels is important because they may reflect the severity of liver iron overload. However, they should not be used as the only predictors of iron overload.

Hemostatic abnormalities in children with thalassemia major and liver iron overload

Background Thalassemia major (TM) patients are susceptible to liver dysfunction due to iron deposition. Pediatric TM patients often present with bleeding. Blood loss necessitates transfusions, leading to increased iron absorption from the gut.&#x0D; Objective To study hemostatic abnormalities in children with TM and iron deposition in the liver.&#x0D; Methods This cross-sectional study involved 190 non-splenectomized children with TM. Liver iron deposition was evaluated using T2* MRI. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet counts were assessed from blood specimens.&#x0D; Results Most subjects were diagnosed with β-thalassemia and β-thalassemia/HbE. The majority of subjects were on deferiprone (DFP) treatment. Approximately 89.5% of subjects had liver iron overload. Prolongation of PT and aPTT, as well as thrombocytopenia were observed in 60%, 27.9%, and 19.5% of subjects, respectively. Prolonged aPTT and thrombocytopenia were observed three times more frequently in subjects with moderate - severe liver iron overload than in subjects with normal - mild liver iron overload (P=0.04 and 0.001, respectively).&#x0D; Conclusion Most TM subjects have liver iron overload ranging from mild to severe. Prothrombin time and prolongation, as well as aPTT prolongation, and thrombocytopenia are easily found in TM children. There were significantly more moderate - severe liver iron deposition patients with aPTT prolongation and thrombocytopenia than normal – mild patients with these conditions. Hence, we suggest that pediatric TM patients undergo liver iron deposition evaluations and use iron chelators in an optimal manner, in order to limit the risk of bleeding.

MRI liver fat quantification in an oncologic population: the added value of complex chemical shift-encoded MRI

IntroductionChemotherapy prolongs the survival of patients with advanced and metastatic tumors. Since the liver plays an active role in the metabolism of chemotherapy agents, hepatic injury is a common adverse effect. The purpose of this study is to compare a novel quantitative chemical shift encoded magnetic resonance imaging (CSE-MRI) method with conventional T1-weighted In and Out of phase (T1 IOP) MR for evaluating the reproducibility of the methods in an oncologic population exposed to chemotherapy. Materials and methodsThis retrospective study was approved by the institutional review board with a waiver for informed consent. The study included patients who underwent chemotherapy, no suspected liver iron overload, and underwent upper abdomen MRI. Two radiologists independently draw circular ROIsin the liver parenchyma. The fat fraction was calculated from IOP imaging and measured from IDEAL-IQ fat fraction maps. Two different equations were used to estimate fat with IOP sequences. Intra-class correlation coefficient and repeatability coefficient were estimated to evaluate agreement between two readers on iron level and fat fraction measurement. ResultsCSE-MRI showed a higher reliability in fat quantification compared with both IOP methods, with a substantially higher inter-reader agreement (0.961 vs 0.372). This has important clinical implications. ConclusionThe novel CSE-MRI method described here provides increased reproducibility and confidence in diagnosing hepatic steatosis in a oncologic clinical setting. IDEAL-IQ has been proved to be more reproducible than conventional IOP imaging.

Reference values of liver volume in Caucasian population and factors influencing liver size

PurposeTo investigate factors influencing liver size and to determine reference values of liver volume (LV) for healthy subjects. Methods2773 volunteers underwent magnetic resonance imaging (MRI) of the liver in the setting of the population based Study of Health in Pomerania. Based on measurement of maximum diameters in three orientations, LVs were calculated and correlated with demographic factors such as age, gender, and body mass index. In addition, LVs of healthy volunteers and participants with parenchymal liver diseases such as fatty liver disease, iron overload, fibrosis/cirrhosis were compared. Adjusted reference values of liver volumes were defined for the group of healthy participants. ResultsIn general, mean LV (mean ± standard deviation) was 1505 ± 385 cm3. Age, gender and body mass index correlated significantly with the liver volume (p ≤ 0.001). Parenchymal liver diseases significantly influence LV (with: 1624 ± 420 cm3, n = 1525 and without parenchymal liver diseases: 1360 ± 273 cm3; n = 1.248, p ≤ 0.001). Compared to LV of participants without liver diseases, LV was increased in volunteers with hepatic steatosis (1717 ± 419 cm3; n = 1111), liver iron overload (1558 ± 367 cm3; n = 553; p ≤ 0.001) as well as in participants with fibrosis/cirrhosis (1494 ± 459 cm3; n = 383). ConclusionsLV is influenced by age, body mass index and parenchymal liver diseases. Reference values were established to aid in the diagnosis of parenchymal liver diseases.

Predicting factors for liver iron overload at the first magnetic resonance in children with thalassaemia major.

Transfusion dependency determines iron overload in thalassaemia major, with devastating complications. Significant liver iron overload has been observed from early childhood and we aimed to evaluate factors that could predict liver iron overload at the first magnetic resonance imaging (MRI). All transfusion-dependent children who underwent MRI to assess iron overload were retrospectively studied. Age, weight, height, blood requirement, chelation drug and dosage, serum ferritin and liver enzymes were evaluated at three specific steps: start of transfusion regimen, start of chelation therapy, and first MRI. Among 198 patients, 25 children met inclusion criteria. No differences were detected in all the assessed parameters at start of transfusion regimen and chelation therapy (p>0.05) between patients with good iron balance (liver iron concentration [LIC] <7 mg Fe/g dry weight [dw]) and liver iron overload (LIC >7). At the first MRI, patients with iron overload had significantly higher serum ferritin (3,080.3±1,078.5 vs 1,672.0±705.3 ng/mL; p<0.01) while patients with good iron control maintained a stable ferritin value from the start of chelation therapy but showed significantly lower height Z-score (-1.48±1.02 vs -0.36±1.55; p=0.04). Serum ferritin >1,770 ng/mL was detected as the best threshold for predicting liver iron overload at the first MRI (p=0.0003). In order to prevent liver iron overload at the first MRI, children should maintain a stable level of serum ferritin below 1,770 from the start of chelation therapy. However, strict monitoring of growth is mandatory.

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4+CD28null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4+CD28null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4+CD28null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4+CD28null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4+CD28null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4+CD28null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4+CD28null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

Hepcidin levels correlate to liver iron content, but not steatohepatitis, in non-alcoholic fatty liver disease

BackgroundOne-third of patients with non-alcoholic fatty liver disease (NAFLD) develop dysmetabolic iron overload syndrome (DIOS), the pathogenesis of which is unknown. Altered production of the iron-regulatory peptide hepcidin has been reported in NAFLD, but it is unclear if this is related to iron accumulation, lipid status or steatohepatitis.MethodsEighty-four patients with liver disease, 54 of which had iron overload, underwent liver biopsy (n = 66) and/or magnetic resonance imaging (n = 35) for liver iron content determination. Thirty-eight of the patients had NAFLD, 29 had chronic liver disease other than NAFLD, and 17 had untreated genetic hemochromatosis. Serum hepcidin was measured with ELISA in all patients and in 34 controls. Hepcidin antimicrobial peptide (HAMP) mRNA in liver tissue was determined with real-time-quantitative PCR in 36 patients.ResultsSerum hepcidin was increased similarly in NAFLD with DIOS as in the other chronic liver diseases with iron overload, except for genetic hemochromatosis. HAMP mRNA in liver tissue, and serum hepcidin, both correlated to liver iron content in NAFLD patients (r2 = 0.45, p < 0.05 and r2 = 0.27, p < 0.05 respectively) but not to body mass index, NAFLD activity score or serum lipids. There was a good correlation between HAMP mRNA in liver tissue and serum hepcidin (r2 = 0.39, p < 0.01).ConclusionsIn NAFLD with or without dysmetabolic iron overload, serum hepcidin and HAMP mRNA in liver correlate to body iron content but not to the degree of steatohepatitis or lipid status. Thus, the dysmetabolic iron overload syndrome seen in NAFLD is not caused by an altered hepcidin synthesis.

Feasibility and agreement of stiffness measurements using gradient-echo and spin-echo MR elastography sequences in unselected patients undergoing liver MRI.

To evaluate the agreement of three MR elastography (MRE) sequences in patients undergoing liver MRI for clinical care. Methods: A cross-sectional retrospective study was performed with 223 patients referred for liver MRI, including 12 patients with liver iron overload. Data obtained with spin-echo (SE) and gradient-echo (GRE) MRE sequences were compared. Multiple linear regression adjusted for the presence of liver fat was also performed to assess the correlation between fat infiltration and stiffness measurements results. Agreement between two SE sequences was assessed in patients with liver iron overload. Results: We found strong correlation between the GRE sequence and two SE sequences. Spearman's correlation coefficients between the GRE, SE, and SE-EPI MRE sequences in patients with liver R2* <75Hz were 0.74, 0.81, and 0.80. GRE-MRE failed in patients with liver R2* > 75 Hz. In this subgroup, the correlation coefficient between both SE-MRE sequences was 0.97. Liver fat did not interfere with the results. In clinical setting, there is a high correlation between the GRE and SE MRE stiffness measurements, independently of the degree of liver fat infiltration measured by PDFF. A strong correlation between SE-MRE sequences is found even in patients with iron overload. Advances in knowledge: Our study addresses liver iron and fat content simultaneously to describing the technical feasibility and correlation between different MRE sequences in consecutive unselected patients refereed for liver MRI. EPI SE-MRE should be considered an optimal alternative to assess liver fibrosis in patients in whom GRE-MRE failures, such as iron-overloaded, in pediatric, elderly, or severely ill populations.