Pulmonary dysfunction in thalassaemia major - Wiley Online Library

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Oct 21, 2016 - pattern also had heart (T2* 14428 + 9499 ms vs. 31459 + 7443 ... together with advances in iron chelation therapy have signifi- ... and pathogenesis of this recurrent respiratory defect are still ..... Clinical Science, 42, 325–335.

research paper

Pulmonary dysfunction in thalassaemia major: is there any relationship with body iron stores?

Francesca Guidotti,1 Gioia Piatti,2 Alessia Marcon,1 Elena Cassinerio,1 Marianna Giuditta,1 Alberto Roghi,3 Valter Fasano,2 Dario Consonni4 and Maria Domenica Cappellini1,5 1

Rare Diseases Centre, Department of Medicine

and Medical Specialities, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, 2

Department of Pathophysiology and Transplan-

tation, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, University of Milan, 3CMR Unit, Department of Cardiology, Niguarda Ca’ Granda Hospital, 4Epidemiology Unit, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, and 5Department of Clinical Sciences and Community Health, Universita degli studi di Milano, Milan, Italy Received 22 June 2016; accepted for publication 11 August 2016 Correspondence: Prof. Maria Domenica Cappellini, Rare Diseases Centre – Pad. De Palo – Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Italy. E-mail: [email protected]

Summary Although pulmonary function abnormalities in thalassaemia major (TM) were described in 1980, the pathogenetic mechanism is not clear and data are contradictory, probably because of study heterogeneity and the multifactorial nature of the pathogenesis. We retrospectively analysed 73 adult TM patients to evaluate the prevalence of pulmonary dysfunction in adult TM and investigate relationships with iron load. All patients underwent body plethysmography and carbon monoxide diffusion (DLCO) was assessed in 63, in addition to blood tests, echocardiogram and T2* myocardial and liver magnetic resonance imaging. Restrictive lung disease was present in 26 (356%) patients. Serum ferritin levels were higher in patients with restrictive pattern (1526 lg/l vs. 975 lg/l, P = 005). Restrictive lung disease did not correlate with cardiac or liver iron overload. However, considering only patients with serum ferritin >2500 lg/l, those with restrictive pattern also had heart (T2* 1428  999 ms vs. 3159  743 ms) and liver iron overload (LIC 1602  844 mg vs. 502  269 mg Fe/g dry weight) compared to those without restrictive pattern. Twenty-five patients (397%) had decreased DLCO. No correlation was observed with iron parameters. In our data restrictive pattern was predominant; we observed a relationship with serum ferritin levels suggesting that iron, particularly its chronic effect, could play a role in the pathogenesis of pulmonary disease. Keywords: thalassaemia major, pulmonary function, restrictive disease, iron overload, ferritin.

Thalassaemia major (TM) is a heterogeneous inherited disorder characterized by an abnormal synthesis of haemoglobin chains causing severe transfusion-dependent anaemia through both ineffective erythropoiesis and haemolysis (Rund & Rachmilewitz, 2005). Regular blood transfusions combined with iron chelation therapy, are the main treatment for subjects affected by TM; in the last 10 years, the optimization of transfusion schedules together with advances in iron chelation therapy have significantly prolonged the life expectancy of TM patients (BorgnaPignatti & Gamberini, 2011). Hypoxia, ineffective erythropoiesis and iron overoload all contribute to the multi-organ involvement that frequently complicates TM. Liver, heart and endocrine glands are the most frequently affected organs, eventually complicating with cirrhosis, heart failure and endocrine defects, such as hypothyroidism, hyopituitarism, hypogonadism, hypoparathyroidism (Galanello & Origa, 2010). ª 2016 John Wiley & Sons Ltd British Journal of Haematology, 2017, 176, 309–314

Since 1980, lung abnormalities have also been described in TM patients (Cooper et al, 1980; Keens et al, 1980), although they are usually asymptomatic and the exact characteristics and pathogenesis of this recurrent respiratory defect are still unclear. Abnormalities of both lung mechanics and of oxygen diffusing capacity have been reported, although the literature data have been contradictory: some authors describe a restrictive pattern while others report a predominant obstructive disease, both of which can be associated with a reduced carbon monoxide diffusing capacity (DLCO) (Keens et al, 1980; Hoyt et al, 1986; Dimopoulou et al, 1999; Parakh et al, 2007). The differences among the published data may partly reflect the heterogeneity of the studies (different patient age, different iron chelation regimen) and they may also be partly caused by the multifactorial nature of the pathogenesis. Analysing the most recent studies, restrictive pattern and alveolar-capillary membrane defects seem to predominate

First published online 21 October 2016 doi: 10.1111/bjh.14396

F. Guidotti et al with a prevalence ranging from 138% to 769% and from 27% to 857% respectively (Table I). Our group published a longitudinal study of 18 adult TM patients whose pulmonary function tests (PFT) were evaluated at baseline and after 7 years: results showed that PFT abnormalities did not increase with time and that they improved when optimal iron chelation was performed (Piatti et al, 2006). The aims of the present study are: (i) to determine, after 10 years of follow-up, the prevalence of lung abnormalities in a cohort of adult patients affected by TM without pulmonary hypertension or heart failure, (ii) to describe the nature of these alterations, (iii) to explore the presence of any relationship with iron overload in order to confirm its possible pathogenetic role, and (iv) to describe temporal evolution of this dysfunction.

Methods We retrospectively analysed data from 73 adult TM patients followed at the Rare Disease Centre at the Policlinico Hospital in Milan, who underwent PFT between January 2012 and December 2014. If a patient had undergone more than one set of PFT (11 cases) we reviewed all the charts and excluded those that showed technical defects. The protocol was approved by the Ethical Committee of Policlinico Hospital (24/3/2011). A previous evaluation of pulmonary function, performed in 2003, was available for 30 patients (41%). These are included in the longitudinal part of the study in order to describe temporal evolution of lung abnormalities. All TM patients were on regular blood transfusions every 2–4 weeks and were receiving adequate iron chelation

therapy (subcutaneous desferoxamine, oral deferasirox or deferiprone). Complete history was collected and all patients underwent a physical examination. No patient showed clinical signs of pneumopathy. An Echocardiography was performed and no patient displayed echo evidence of pulmonary hypertension or heart failure [pulmonary arterial pressure 50%]. All patients underwent PFT via body plethysmography and spirography (Werner Gut, Basel, Switzerland) with electronic body temperature and pressure saturated water vapour (BTPS) compensation at a constant volume of 850 l. The test was performed 1 or 2 days before the scheduled transfusion. The main parameters of lung function measured were forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), the derived Tiffenau index (FVC/FEV1), total lung capacity (TLC) and residual volume (RV). Threshold for detection of any abnormalities was below 80% of the predicted value. For 63 of the 73 TM patients, DLCO was evaluated through the single breath method. The values obtained were corrected for the measured haemoglobin level according to Cotes et al (1972) as the examination was usually performed 1 or 2 days before the transfusion. Values below 80% of those predicted were considered pathological (Blakemore et al, 1957). We also performed complete blood tests and T2* magnetic resonance imaging (MRI) to assess myocardial and liver iron load: this was performed at the Cardiovascular Magnetic Resonance Unit, Department of Cardiology, “A. De Gasperis” at Niguarda Ca’ Granda Hospital in Milan, using a 15 Tesla magnetic resonance scanner (Avanto Siemens, Erlangen, Germany). All T2* images were analysed using post-processing software [CMRtools, Cardiovascular Imaging Solutions, Imperial College, London (cmrtools.com)]. Myocardial T2*

Table I. Literature data about pulmonary dysfunction in TM patients.

Cooper et al (1980) Keens et al (1980) Hoyt et al (1986) Factor et al (1994) Tai et al (1996) Dimopoulou et al (1999) Kanj et al (2000) Filosa et al (2001) Li et al (2002) Piatti et al (2006) Parakh et al (2007) Abu-Ekteish et al (2007) Sohn et al (2011) Dimitriadou et al (2011) Noori et al (2012) Bourli et al (2012)


Mean age  SD (years)

Restrictive pattern

Obstructive pattern

Decreased DLCO

17 12 19 29 14 21 36 48 29 18 31 40 76 39 26 52

Paediatric 184  26 (10–29) 198  85 15  4 25  5 18  9 *133 (8–23) *142 (106–165) 2944  289 1356  430 125  35 256  88 2169  613 148  292 2133  624

7 – – 21 4 15 11 16 4 7 5 14 12 14 20 20

– 5 15 0 1 2 2 0 4 0 1 6 24 0 4 2

– 5 3 – 12 5 – 14 15 5 13 10 2 23 – 32


(79%) (286%) (71%) (306%) (333%) (138%) (388%) (161%) (35%) (16%) (359%) (769%) (3846%)

(417%) (789%) (71%) (9%) (56%) (138%) (32%) (15%) (32%) (154%) (384%)

(417%) (158%) (857%) (24%) (292%) (517%) (278%) (412%) (25%) (27%) (59%) (625%)

N, number of patients included in the study; DLCO, carbon monoxide diffusion; SD, standard deviation. *Median (range).


ª 2016 John Wiley & Sons Ltd British Journal of Haematology, 2017, 176, 309–314

Pulmonary Dysfunction in Thalassaemia Major was assessed with the use of a gated gradient-echo sequence with flip angle of 20°. A single 10-mm-thick short axis mid ventricular slice of the left ventricle (LV) was acquired at 8 echo times (26–1674 ms with 202 ms increments) with standard shimming with a single breath-hold. For analysis, a full-thickness region of interest was chosen in the LV septum. MRI evaluation was performed blinded to patient clinical data and the calculation was performed by a single operator. Normal cardiac T2* was defined >20 ms; T2* 20. Cines were acquired in end-expiration breath-hold. Ventricular volumes were analysed with CMRtools and stroke volume and ejection fraction were calculated from end diastolic and end systolic ventricular volumes. Liver iron concentration (LIC) was calculated from liver T2* applying the formula [1/(T2*/1000)]900254 + 0202 (Wood et al, 2005).

Table II. Patients characteristics. Mean  SD Age (years) Sex (male/female ratio) Haemoglobin (g/l) Serum ferritin (lg/l) LIC (mg Fe/g dry weight) (Wood et al, 2005) Cardiac T2* MRI (ms) Ejection fraction (%) *

37  7 24/49 98  80 1180  1096 Median 768 (range 167–4528) 526  695 3365  1383 65  63

LIC, liver iron concentration; MRI, magnetic resonance imaging; SD, standard deviation. *Ejection fraction was derived from cardiovascular MRI. Table III. Pulmonary function parameters of the 73 patients with thalassaemia major. Mean  SD FVC (% predicted) FEV1 (% predicted) FEV1/FVC (% predicted) TLC (% predicted) RV (% predicted) DLCO (corrected % predicted)*

83 81 102 81 81 78


1291 13 664 1255 2497 1339

DLCO, carbon monoxide diffusion; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, residual volume; SD, standard deviation; TLC, total lung capacity. *63 patients.

Statistical analysis For continuous variables results are reported as means  standard deviation (SD). The ferritin level, which had a right-skewed distribution, is presented as median (range). In parameters with normal distribution, mean values were compared using unpaired Student t-test. P < 005 were considered statistically significant.

Results Overall population Overall, 73 TM patients (24 males, 49 females) underwent PFT. Mean age was 37  7 years. Body mass index was within normal limits (185–249) in all patients. Some patients had abnormalities of chest conformation, especially due to flattening of the vertebral bodies with a platyspondyly appearance; this was mainly observed in those patients who received intensive chelation with desferoxamine during childhood. None of the patients had intrathoracic masses due to extramedullary haematopoiesis. The general characteristics of the patients are reported in Table II while pulmonary function testing results are described in Table III. ª 2016 John Wiley & Sons Ltd British Journal of Haematology, 2017, 176, 309–314

Figure 1. Overall population: distribution of pulmonary abnormalities. DLCO, carbon monoxide diffusion; restrictive, restrictive pattern of lung disease.

Twenty-nine patients (40%) had a normal pulmonary function whereas the remaining 44 (60%) presented abnormalities by PFT: 26 (35%) had a restrictive pulmonary pattern, none had a pure obstructive disease, whereas 25 patients (34%) had a reduced DLCO (Fig 1). Three patients had a PFT suggestive of mixed disease but were considered as only restrictive as it was the predominant feature.

Comparison between patients with restrictive pattern and those without a restrictive pattern (Table IV) No significant differences were observed between patients with restrictive pattern and those with normal spirometry


F. Guidotti et al Table IV. Comparison between thalassaemia major patients with and without a restrictive pattern.

Age (years) Hb (g/l) Serum ferritin (lg/l) LIC (mg Fe/g dry weight) Cardiac T2* MRI (ms) TLC (% predicted) DLCO (corrected, % predicted)

Restrictive (n = 26)

Non restrictive (n = 47)

36  65 977  97 1526  1437 Median 1142 (267–4528) 605  699 3205  1552 6796  507 73  819

38  72 975  66 975  779 Median 744 (167–3233) 481  696 3456  1288 8728  929 82  1474

P ns ns 005 ns ns 2500 lg/l. Restrictive, restrictive pattern of lung disease.

Figure 3. Liver >2500 lg/l.








Discussion Pulmonary dysfunction has been neglected in TM patients and published data are often related to small paediatric populations. Therefore data are still contradictory and different pathogenetic mechanisms have been hypothesized to explain these lung alterations. The survival expectation of TM patients has been significantly extended to the fourth and fifth decades of life, which imply the possibility of developing of new complications not observed in past, including pulmonary disorders. The majority of authors usually report iron overload as the principal hypothetical responsible factor of pulmonary ª 2016 John Wiley & Sons Ltd British Journal of Haematology, 2017, 176, 309–314

Pulmonary Dysfunction in Thalassaemia Major Table V. Comparison between patients with reduced and normal DLCO.

Age (years) Hb (g/l) Serum ferritin (lg/l) LIC (mg Fe/g dry weight) Cardiac T2* MRI (ms)

Reduced DLCO (n = 25)

Normal DLCO (n = 38)


37  69 965  58 1210  999 Median 892 (267–4215) 673  955 3408  1410

37  74 981  85 1096  1068 Median 648 (167–4068) 396  368 3491  1249

ns ns ns ns ns

Values given as mean  standard deviation unless otherwise indicated. DLCO, carbon monoxide diffusion; LIC, liver iron concentration; MRI, magnetic resonance imaging.

abnormalities (Tai et al, 1996; Kanj et al, 2000), as it causes damage in the liver, heart and endocrine glands. In a similar way, iron accumulation in the lungs has been proposed as the cause of PFT abnormalities observed in TM patients. Through the production of free oxygen radicals, iron would cause a parenchymal fibrosis leading to a restrictive pattern and an impaired diffusion capacity (Mateos et al, 1998). However, only two reports have described this fibrosis through recognition of areas of air-trapping on imaging techniques (high-resolution computed tomography) and showed the presence of iron-laden macrophages in bronchoalveolar lavage suggestive of lymphocyte alveolitis and interstitial fibrosis (Filosa et al, 2000; Piatti et al, 2006). On the contrary, other studies did not find signs of this postulated fibrosis at autopsy(Cooper et al, 1980; Grisaru et al, 1990). Various studies have unsuccessfully searched for an association between pulmonary alterations and iron accumulation (estimated through serum ferritin levels or liver iron overload evaluated through T2* MRI): a relationship with serum ferritin levels has been described in a few cases (Kanj et al, 2000), but this association was not confirmed by other authors (Filosa et al, 2001; Abu-Ekteish et al, 2007; Bourli et al, 2012). The hypercoagulable status of TM patients, mainly splenectomized (Eldor & Rachmilewitz, 2002), and the subsequent microembolisms are other possible causes of lung function abnormalities (Sonakul & Fucharoen, 1992; Sumiyoshi et al, 1992); furthermore chronic hypoxia would lead to an aberrant alveolar growth, limiting the volume of air spaces (Cooper et al, 1980). Another hypothesis is represented by alterations of the ventilatory mechanics caused by the abnormal chest conformation deriving from growth retardation typical of TM or by hepatosplenomegaly. However this mechanism was not confirmed by the majority of studies of patients who had been splenectomized or not, where no differences in lung function were observed (Bourli et al, 2012). Furthermore, iron chelation therapy with desferrioxamine has previously been suggested as a cause of lung impairment (Freedman et al, 1990). In particular it would be linked to this chelators’ ability to mobilize free iron and favour the production of free radicals,which would amplify the oxidizing damage (Freedman et al, 1990). ª 2016 John Wiley & Sons Ltd British Journal of Haematology, 2017, 176, 309–314

Finally an association with a genetic structure has been described: most patients with a restrictive pattern had b°/b° genotype (Filosa et al, 2001). Our study confirmed, despite the limitation of being a retrospective analysis, the recent tendency to report a prevalence of restrictive pattern (35%) among lung dysfunction, together with a reduced diffusing capacity (34%). These alterations don’t always occur together in the same patients, although we did find that patients with a restrictive pattern have a significantly reduced DLCO. In the analysis, the group of patients with a restrictive pattern appeared to have higher levels of serum ferritin, supporting the role of iron overload in causing lung dysfunction. However, ferritin level is not always a good surrogate for organ iron overload, especially at low elevated values. In fact, similar to the literature (Dimopoulou et al, 1999; Dimitriadou et al, 2011), when considering all the patients, we could not find a relationship between restrictive pulmonary pattern and heart or liver iron overload. Although differences in iron kinetics and local acting factors could represent a possible explanation of this, the examination of a small subgroup of our patients produced interesting results. In fact, when considering only patients with very high serum ferritin levels (>2500 lg/l) we identified two distinctly different groups: in this setting, patients with restrictive pattern also had heart and liver iron overload. This could further suggest that severe iron overload is responsible for lung function alteration, in a similar way to that for liver and heart dysfunction. As it is reported in other studies (Piatti et al, 2006; AbuEkteish et al, 2007; Bourli et al, 2012), all the patients with lung dysfunction were asymptomatic. Data from our longitudinal study show that PFT abnormalities do not increase with time. It is important to note that the patients in our study were on a strict regular transfusion programme and received an optimal iron chelation therapy, so both of these approaches appear to be mandatory to prevent pulmonary dysfunction. It would therefore appear to be useful, especially considering the progressive aging of TM patients, to include PFTs in regular follow-up assessments, together with advising patients to avoid behaviours that could worsen pulmonary function, above all cigarette smoking. 313

F. Guidotti et al

Author contribution


FG, AM, EC, GP, MG and MDC designed and performed research, FG collected data, FG, AM, EC and GP analysed and interpreted data, DC performed statistical analysis, GP and VF performed PFTs, AR performed T2*MRI analysis, FG wrote the paper, FG, EC, GP and MDC contributed to the writing of this manuscript.

This work was supported by Progetto MIUR-PRIN2012: cod. 20128PNX83_002 and RC 2016 Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milano.

Conflict of interest The authors have no conflicts of interest to disclose.

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