In myelodysplastic syndrome (MDS), anemia often leads to red blood cell transfusion dependency and iron overload (IOL). Serum ferritin (SF) is used as a surrogate marker for IOL. IOL can lead to liver failure. Transient elastography (TE) also known as fibroscan is an easy and noninvasive procedure for liver stiffness measurements (LSM). Methods: Sixty patients with either MDS, chronic myelomonocytic leukemia with dysplastic features, acute myeloid leukemia progressed from MDS or myelodysplastic/ myeloproliferative neoplasm, unclassifiable were included. All patients underwent a fibroscan, had their SF measured and disease duration calculated. Patients were grouped according to transfusion dependency or independency status. Results: Transfusion dependent patients had significantly higher LSM than those who were transfusion independent (p=0.003). There was no positive correlation between SF and LSM (p=0.103) or time since diagnosis and LSM (p=0.886). Patients with elevated SF did not have significantly higher LSM compared to those with normal SF (p=0.583). Conclusion: These data indicate that transfusion dependency has an impact on liver stiffness in MDS. Longitudinel studies are needed to conclude whether TE is of value in monitoring IOL in MDS.
Myelodysplastic syndrome, iron overload, transfusion, liver, fibroscan
No research funding was received for this study. Malene Risum received travel expenses from Novartis to present the provisional results of the study at The 13th international symposium on myelodysplastic syndromes April 29th - May 2nd, 2015. Toke Barfod and Klas Raaschou-Jensen have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Compliance with Ethics: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions, and informed consent was received from the patient involved in this study.
Christian Alexander Möller and Roberto Oliveri for helping perform the statistics with R statistics and SPSS respectively.
July 03, 2016 Accepted
August 11, 2016
Malene Risum, Department of Hematology, University Hospital of Copenhagen, Roskilde, Denmark. E: firstname.lastname@example.org
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
In myelodysplastic syndrome (MDS), iron overload (IOL) is the result of multiple red blood cell (RBC) transfusions and increased iron absorption. The cause for the latter is low hepcidin levels due to an ineffective erythropoiesis.1 Increased iron absorption contributes to IOL, but chronic RBC transfusions are considered the main cause of IOL.2 IOL can lead to liver fibrosis, cirrhosis and heart failure. Patients with MDS are often elderly people with pre-existing co-morbidities which can worsen the clinical symptoms of anaemia and lead to the need of RBC transfusions. Cardiac failure and liver failure have been reported in 24% and 6.7% of patients, respectively; most likely as the result of heavy transfusion dependency.3
Serum ferritin (SF) works as a surrogate marker for IOL in MDS. It is usually recommended to start iron chelation when the patient has had 20–25 units of RBC transfusions, and SF exceeds 1,000 μg/l in patients with lower risk MDS.2
SF can be affected by other conditions such as infection and cancer. To determine the stage of liver fibrosis or liver iron content a liver biopsy or magnetic resonance imaging (MRI) T2* is required. Both procedures are time-consuming, but due to the risk of bleeding, a liver biopsy is almost never performed on MDS patients.4
Transient elastography (TE), also known as FibroScan® (Echosens, Paris, France), is a noninvasive method which measures the stiffness of the liver as a surrogate for liver fibrosis. Liver stiffness is determined by the velocity of a shear wave sent through the liver using a probe. Liver stiffness measurements (LSM) are expressed in kilopascal (kPa); the higher the value the stiffer tissue.5 A normal value is approximately 5 kPa.5 TE has no side-effects or complications and is easy to perform. TE has a high reproducibility with a high inter- and intra-observer agreement.6 The failure rate of TE has been reported to 2.4–9.4%.7 The cause of failure is often obesity.7 Conditions with inflammation, extrahepatic cholestasis and congestion can also affect the result since these conditions can constitute space-occupying difficulties and interfere with LSM.5
TE originates from studies on liver fibrosis in patients with hepatitis C virus (HCV)8 and hepatitis B virus (HBV) infection,9 and has been extensively investigated in patients with HCV infection. In HCV and HBV, fibrosis is considered either absent or mild when values are ≤7 kPa.5 In haematology, TE for the detection of liver fibrosis has been investigated in patients with IOL caused by different diseases10,11 and in thalassemia12–18 and haemochromatosis exclusively.19,20 TE has also been investigated in patients undergoing stem cell transplantation (SCT) with the aim of detecting complications affecting the liver in connection to SCT.21,22
The purpose with the present study was to assess whether TE could be a useable tool in evaluating liver fibrosis caused by IOL in MDS.
Patients and methods
Patients at the Department of Hematology, University Hospital of Copenhagen, Roskilde were screened for inclusion if they had MDS or chronic myelomonocytic leukemia (CMML) with dysplastic features, acute myeloid leukemia (AML) progressed from MDS or myelodysplastic/ myeloproliferative neoplasm, unclassifiable (MDS/MPN). Patients were excluded if they had a known history of alcoholic liver disorder, a known chronic infection with HBV or HCV, or any other known liver disorder. Patients were also excluded if they had a body mass index (BMI) of 30 or higher. Patients were enrolled after written informed consent. The study was approved by the local ethics committee of Region Sjaelland, Denmark and performed according to the Declaration of Helsinki.
Sixty patients were prospectively included and had their LSM measured with TE with the medium (M)-probe (FibroScan). A median LSM was considered valid when the following criteria were achieved: at least 10 valid measurements, a success rate ≥60% and interquartile range (IQR) <30%. These criteria were the same as in other studies.13,15,17,18 If the TE result was invalid, a new TE was performed until the criteria were fulfilled. BMI was calculated on the same day as the performance of TE. Patients were considered fasting if they had not ingested food for 2 hours prior to the examination. All patients had their SF and alanine aminotransferase (ALAT) measured. Most patients had their SF measured within one day of the FibroScan, but some out-patients had their SF measured up to 19 days before or after the day of the FibroScan. Patients were grouped according to the level of SF. SF was considered elevated when above 320 μg/l [17–320 μg/l] in men and 161 μg/l [5–161 μg/l] in women. ALAT was also measured and considered elevated in men when above 70 U/l [10-70 U/l] and above 45 U/l [10-45 U/l] in women. Patients were grouped according to transfusion dependency and independency.23 Time since diagnosis was calculated in number of months.
1. Temraz S, Santini V, Musallam K, Taher A, Iron overload and chelation therapy in myelodysplastic syndromes, Crit Rev Oncol Hematol, 2014;91:64–73.
2. Steensma DP, Gattermann N, When is iron overload deleterious, and when and how should iron chelation therapy be administered in myelodysplastic syndromes?, Best Pract Res Clin Haematol, 2013;26:431–44.
3. Takatoku M, Uchiyama T, Okamoto S, et al., Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality, Eur J Haematol, 2007;78:487–94 .
4. Kantarjian H, Giles F, List A, et al., The incidence and impact of thrombocytopenia in myelodysplastic syndromes, Cancer, 2007;109:1705–14.
5. Castera L, Noninvasive methods to assess liver disease in patients with hepatitis B or C, Gastroenterology, 2012;142:1293–302.
6. Fraquelli M, Rigamonti C, Casazza G, et al., Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease, Gut, 2007;56:968–73.
7. Castera L, Forns X, Alberti A, Non-invasive evaluation of liver fibrosis using transient elastography, J Hepatol, 2008;48:835–47.
8. Ziol M, Handra-Luca A, Kettaneh A, et al., Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C, Hepatology, 2005;41:48–54.
9. Marcellin P, Ziol M, Bedossa P, et al., Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B, Liver Int, 2009;29:242–7.
10. Mirault T, Lucidarme D, Turlin B, et al., Non-invasive assessment of liver fibrosis by transient elastography in post transfusional iron overload, Eur J Haematol, 2008;80:337–40.
11. Paparo F, Cevasco L, Zefiro D, et al., Diagnostic value of realtime elastography in the assessment of hepatic fibrosis in patients with liver iron overload, Eur J Radiol, 2013;82:e755–61.
12. Fraquelli M, Cassinerio E, Roghi A, et al., Transient elastography in the assessment of liver fibrosis in adult thalassemia patients, Am J Hematol, 2010;85:564–8.
13. Elalfy MS, Esmat G, Matter RM, et al., Liver fibrosis in young Egyptian beta-thalassemia major patients: relation to hepatitis C virus and compliance with chelation, Ann Hepatol, 2013;12:54–61.
14. Di Marco V, Bronte F, Cabibi D, et al., Noninvasive assessment of liver fibrosis in thalassaemia major patients by transient elastography (TE) – lack of interference by iron deposition, Br J Haematol, 2010;148:476–9.
15. Cassinerio E, Orofino N, Roghi A, et al., Combination of deferasirox and deferoxamine in clinical practice: An alternative scheme of chelation in thalassemia major patients, Blood Cells Mol Dis, 2014;53:164–7.
16. Musallam KM, Motta I, Salvatori M, et al., Longitudinal changes in serum ferritin levels correlate with measures of hepatic stiffness in transfusion-independent patients with β-thalassemia intermedia, Blood Cells Mol Dis, 2012;49:136–9.
17. El-Asrar MA, Elbarbary NS, Ismail EA, Elshenity AM, Serum YKL-40 in young patients with β-thalassemia major: Relation to hepatitis C virus infection, liver stiffness by transient elastography and cardiovascular complications, Blood Cells Mol Dis, 2016;56:1–8.
18. Poustchi H, Eslami M, Ostovaneh MR, et al., Transient elastography in hepatitis C virus-infected patients with beta-thalassemia for assessment of fibrosis,Hepatol Res, 2013;43:1276–83.
19. Legros L, Bardou-Jacquet E, Latournerie M, et al., Non-invasive assessment of liver fibrosis in C282Y homozygous HFE hemochromatosis, Liver Int, 2015;35:1731–8.
20. Adhoute X, Foucher J, Laharie D, et al., Diagnosis of liver fibrosis using fibroscan and other noninvasive methods in patients with hemochromatosis: A prospective study, Gastroenterol Clin Biol, 2008;32:180–7.
21. Auberger J, Graziadei I, Clausen J, et al., Non-invasive transient elastography for the prediction of liver toxicity following hematopoietic SCT, Bone Marrow Transplant, 2013;48:159–60.
22. Karlas T, Weber J, Nehring C, et al., Value of liver elastography and abdominal ultrasound for detection of complications of allogenic hemopoietic SCT, Bone Marrow Transplant, 2014;49:806–811.
23. Malcovati L, Germing U, Kuendgen A, et al., Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes, J Clin Oncol, 2007;25:3503–10.
24. Roy NB, Myerson S, Schuh AH, et al., Cardiac iron overload in transfusion-dependent patients with myelodysplastic syndromes, Br J Haematol, 2011;154:521–4.
25. Chacko J, Pennell DJ, Tanner MA, et al., Myocardial iron loading by magnetic resonance imaging T2* in good prognostic myelodysplastic syndrome patients on long-term blood transfusions, Br J Haematol, 2007;138:587–93.
Myelodysplastic syndrome, iron overload, transfusion, liver, fibroscan