Lack of correlation between heart, liver and pancreas <scp>MRI</scp>‐<scp>R</scp>2*: Results from long‐term follow‐up in a cohort of adult β‐thalassemia major patients
Authors: Valeria Maria Pinto, Lorenzo Bacigalupo, Barbara Gianesin, Manuela Balocco, Lucia De Franceschi, Roberto Malagò, John Wood, Gian Luca Forni
Journal: American Journal of Hematology (2017)

The non-invasive multi-organ concurrent evaluation of iron overload by MRI-R2* has improved clinical management and care of patients with transfusion-dependent diseases, such as β-thalassemia major (TM).1 Up to now, limited data on iron accumulation and pancreatic-R2* in TM patients are available and longitudinal observations are required to better understand the risk of endocrine pancreatic dysfunction and pancreatic-R2*.2-5 We report a retrospective study of a cohort of 69 patients with TM attending our Centers who had concurrent MRI-R2* evaluations (1.5 T GE HDxt scanner) of pancreas, liver and heart, and hepatic fibrosis evaluated by transient elastometry (TE) with FibroScan in the period January 2008 to December 2016. The original dataset was composed by 74 patients, for a total of 424 MRI-R2* assessments and 315 TE evaluations. During the follow-up, three patients were lost due to job reasons and two patients died (sepsis and car accident crash, respectively). Thus, 69 patients completed the follow-up and were evaluated. The median number of follow-up years was 8 (interquartile range, 25th-75th percentile-IQR: 7–8) and the median number of observations for each patient was 6 (IQR: 5–7) for MRI-R2*and 5 (IQR: 3–6) for TE. The main characteristics of patients are presented in Figure 1A. More details for data and methods, including statistics, are reported in Supporting Information. The chart review was approved by the local Ethics Committee. All participants gave written informed consent and the research was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2008. Data were collected by WebThal, a computerized clinical record system for patients affected by hemoglobinopathies. A, TM patients characteristics: the values are expressed as counts and percentages and as median and IQR range (25th to 75th percentile). B, Observations, at the baseline (time 0 yrs), at a median value of 4 years of follow-up and at a median value of 8 years of follow-up, of: correlation of R2* values of the pancreas with the R2* values of the heart; correlation of R2* values of the pancreas with the R2* values of the liver; age distribution in different groups(*) of patients. (*) NGT: group with no pancreatic complications, PFF: group with only adipose involution of pancreas, IGT: group with a diagnosis of glucose intolerance, DIA: group with a diagnosis of diabetes mellitus. We observe that the NGT TM patients were younger than subjects with glucose metabolism dysfunction (P < .05) Fifty R2*-measurements were randomly selected from the global dataset and reassessed, in 27 cases from a different radiologist. No significant differences were found between the two evaluations for pathological R2* of heart/liver/pancreas; the intra- and inter-observer bias averaged less than 10%. At baseline the median age was 34 years (IQR: 26–38). Sixty-seven percent of patients underwent splenectomy prior to the first observation, two patients during the follow-up. Cardiomyopathy was documented in four patients: two patients with both congestive heart failure and arrhythmia, one patient with congestive heart failure (the only one with cardiac iron overload), and one with arrhythmia. Pulmonary hypertension was present only in one patient. Among endocrinopathies, 25% of patients exhibited hypothyroidism, 67% had hypogonadotropic hypogonadism, and 52% suffered from osteoporosis. Chronic hepatitis C virus (HCV) was positive in 28% of patients. Median pre-transfusion hemoglobin level was 9.3 g/dL (IQR: 9.0–9.6) and patients were on regular blood transfusion (≈10–15 mL packed red blood cell/kg body weight ≈ 3–5 mgFe/kg body weight) at 2- to 4-week intervals. All patients were receiving chelation therapy: 86% of patients received oral chelator (deferipron, DFP; deferasirox, DFX; and daily alternating DFP + DFX). The median compliance to the therapy, calculated as the percentage of drug taken in respect to that administered, was 93% (IQR: 88–96); 72% of patients started chelation within their first 10 years of life. Details on therapy are reported in Supporting Information Table 1S. At the baseline, we found a positive strong correlation between the R2* values of pancreas and both the R2* of liver (Rp = 0.68, P < .001) and of heart (Rp = 0.75, P < .001), in agreement with the literature2, 6 (Figure 1B and Supporting Information). The ROC analysis with the R2* values of pancreas and heart confirmed the value of 100 Hz for the pancreatic-R2* as the predictor of cardiac-R2* > 50 Hz.5 We observed a significant correlation of serum ferritin (SF) with the R2* of liver (Rp = 0.53, P < .001), heart (Rp = 0.24, P = .04), and pancreas (Rp = 0.35, P = .003). The ROC analysis with the SF values and the presence/absence of iron overload in liver indicated for SF a value of 882 mg/mL as predictor of iron overload in the liver (details of ROC analysis are given in Supporting Information). Glucose tolerance test data was available in 60/69 patients. A total of 10 patients had already diabetes mellitus at the baseline (9/10 with adipose involution of pancreas) and a total of 8 patients showed positive impaired glucose tolerance (7/8 with adipose involution of pancreas). Overall, a total of 50 patients had adipose involution of the pancreas at the baseline; 29 patients had adipose involution of the pancreas but no diabetes or impaired glucose tolerance. A total of 13 patients had no pancreatic abnormality (ie, no adipose involution, no impaired glucose tolerance, and no diabetes). Supporting Information Table 2S reports the median and IQR range of the R2* of the heart, the liver, and the pancreas for all patients and for the four sub-groups: with normal glucose tolerance and no pancreatic fat fraction (NGT), with pancreatic fat fraction (PFF), with impaired glucose tolerance (IGT) and with diabetes (DIA). We found a significant difference between the R2* values of the heart between NGT in respect to group IGT merged with DIA (P = .025): the median value of cardiac-R2* was 35 Hz (IQR: 25–69 Hz) for IGT/DIA patients and 25 Hz (IQR: 22–31 Hz) in NGT group (Supporting Information Table 2S). When patients were clustered according to splenectomy, the percentage of PFF was greater in splenectomized patients (P = .028), who were also the older one (P < .001). No correlation was found between the degree of liver fibrosis detected by TE and pancreatic-R2*. No difference in distribution of liver fibrosis was found between splenectomized and not splenectomized patients. At the follow-up, four patients had developed hypothyroidism (17/69), one patient started iron chelation therapy at 6 years of age due to the unavailability of iron chelators, three patients had a poor compliance during puberty and five patients had developed osteoporosis (41/69). No correlation was found between the appearance of the new cases of endocrinopathies and R2* of heart, liver, and pancreas. Eight HCV positive patients were treated with direct-acting antiviral drugs achieving sustained virological response, reducing the HCV positive population to 11/69. During the follow-up, R2* values significantly decreased in liver (P = .0012), in heart (P = .017), and pancreas (P = .018). Pancreatic-R2* still but weakly correlates with R2* of heart (Rp = 0.25) and liver (Rp = 0.42) (Figure 1B). The decrease in SF showed a linear correlation with R2* changes and the same trend was also observed clustering the patients according to splenectomy. We observed two new cases of diabetes mellitus (for a total number of 12) and three new cases of impaired glucose tolerance (for a total number of 11) whereas 5 of 8 normalized. The incidence rate of diabetes in the period of observation was 3% and that of impaired glucose tolerance 19%. All patients with diabetes and impaired glucose tolerance had adipose involution of the pancreas. Overall, a total of 52 patients had adipose involution of the pancreas; 26/52 patients had adipose involution of the pancreas but no diabetes or impaired glucose tolerance. A total of 12 patients had no abnormality of the pancreas (Supporting Information Table 3S). When patients were clustered according to splenectomy, the adipose involution of the pancreas was more significantly represented in splenectomized group (P = .035). We noted that NGT patients were younger than subjects with glucose metabolism dysfunction (Figure 1B). The percentage of patients with iron overload in the pancreas was lower (P = .0024) in NGT (42%—5/12) with respect to the other groups (respectively 23/26 in PFF; 11/11 in IGT; 9/12 in DIA). During the follow-up, the number of cases of iron overload decreased in both liver (from 11 to 0) and heart (from 14 to 2) but number of patients with pancreatic-R2* > 100 Hz (from 27 to 23) remained almost the same. The predictive power of pancreatic-R2* for cardic-R2* > 50 Hz was weaker at the follow-up: at baseline the number of false positive predicted by the rule was 52% (14/27) and increases to 91% (21/23) at follow-up (Supporting Information 3S). No significant difference in hepatic, cardiac, and pancreatic R2* was found between patients on monotherapy with either DFX or DFP. No correlation was found between TE and pancreatic-R2* and no difference in distribution of TE was found between splenectomized and not splenectomized patients. No clinical symptoms of exocrine pancreatic deficiency were recorded. In conclusion, we show a limited effect of chelation therapy on pancreatic iron overload in long-term follow-up TM patients despite a significant reduction of SF and iron accumulation in liver and heart. Pancreatic-R2* becomes a weaker predictor of heart iron overload depending on age and patient chelation history. Thus, pancreatic-R2* might remain a good prognostic parameter in children and young adults, where pancreatic volume is preserved and fatty infiltration is less severe. In TM patients, splenectomy seems also to be a risk factor for development of pancreatic adipose infiltration. Aging and fatty infiltration resulted in the strong predictors for development of IGT or DIA despite the optimal chelation therapy. In adult TM patients, SF trend and R2* are reliable tools to follow-up iron status over time. SF has a predictive power for iron overload in liver. Our study shows delay in pancreas iron overload mobilization in TM patients under standard chelation therapy compared to liver and heart. In TM subjects, the adipose pancreatic involution correlates with pancreatic iron accumulation, which might contribute to pancreatic beta cell dysfunction and insulin resistance as observed in other metabolic diseases. Our data provide a rationale to design large clinical trial combining iron chelators acting as intracellular iron mobilizators, such as minihepcidin and/or eltrombopag (ELT), with clinically available chelators. Additional references are available in Supporting Information. Dr. Forni has received research funding from Novartis, Celgene and Shire. Consults from Roche and served an DSMB panel for Apopharma. Dr. Wood consults for Shire, ApoPharma, and BioMed Informatics and received funding from Shire, speaker fees fromNovartis, and served on an advisory panel to ApoPharma. Other authors have no relationships to disclose. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.