Pulmonary involvement in Fabry disease has received less attention than the effects of the disease on the kidneys, nervous system or heart. However, data from FOS –the Fabry Outcome Survey – are now helping to elucidate the pulmonary manifestations of Fabry disease. Twenty-three patients out of a cohort of 67 analysed in FOS have been identified with airway obstruction, as defined by a ratio of forced expiratory volume in 1 second to forced vital capacity of less than 0.7. This prevalence is much greater than would be expected in the general population, with the main risk factors appearing to be increasing age and male gender. Spirometric analysis has revealed that the airway obstruction is clinically much more similar to chronic obstructive pulmonary disease than to asthma. Although little is known about the anatomical changes responsible for airway obstruction in patients with Fabry disease, airway wall hyperplasia and/or fibrosis are potential causes. Treatment of patients with moderate or severe airway obstruction should include inhaled bronchodilators, and individuals who smoke should be encouraged to stop. Further studies and future analyses of FOS data should determine whether enzyme replacement therapy is able to help or prevent the pulmonary manifestations of Fabry disease.

Historical background

Although the original patient described by Fabry in 1898 had 'asthma', frequent respiratory tract infections, and died of lung disease at the age 43 years [1], reports of pulmonary involvement in Fabry disease are uncommon.

In 1972, Bartimmo and colleagues performed pulmonary function studies and pulmonary scintiphotography in three brothers aged 31, 34 and 38 years. In the absence of clinical or laboratory evidence of diffuse pulmonary parenchymal or vascular disease or dysfunction in these patients, the investigators concluded that pulmonary involvement had little clinical or functional impact on patients with Fabry disease, and that pulmonary symptoms were mainly associated with other conditions (i.e. cigarette smoking or cardiac disease) [2].

Before the findings of Bartimmo et al. were published, however, some interesting pathological data on lung involvement in Fabry disease had been reported. In 1947, Pompen and co-workers found that the bronchial mucosal cells in an autopsy case were much 'taller' than normal and the cytoplasm was vacuolated and pale [3]. Moreover, the bronchial and pulmonary vessels showed thickened walls due to hypertrophy and vacuolization of the smooth muscle fibres of the media. Abnormalities of the pulmonary vasculature had also been reported by others [4–6]. For example, in 1968, a histological and electron microscopic study of lung tissue carried out by Bagdade et al. revealed that the lipid inclusions in the lung were similar to those present in other tissues [4].

Hence, in contrast to kidney and heart involvement, it remained unclear for some time whether significant clinical or physiological pulmonary dysfunction occurs as a consequence of sphingolipid deposits. More recently, this has been clarified by several studies.

In 1978, Kariman and colleagues reported the case of a 32-year-old hemizygous man complaining of morning cough and exertional dyspnoea as a result of climbing two flights of stairs [7]. The patient was an active smoker, with a creatinine clearance rate of 110 ml/minute and a serum α₁-antitrypsin level within the normal range. Pulmonary function tests revealed severe obstruction, hyper-inflation and a mild impairment of carbon monoxide diffusion, and the chest X-ray was compatible with severe bullous emphysema. The authors concluded that significant pulmonary involvement could occur even in the early stages of Fabry disease, before there was clinical evidence of multiple system involvement, and that cigarette smoking could be an aggravating factor.

In 1980, Rosenberg and colleagues carried out physiological studies and obtained ventilation and perfusion scans for seven patients with Fabry disease (6 males, 1 female) aged 29–64 years [8]. All were found to have significant airflow obstruction. Five of the patients were smokers, but the extent of obstruction in these individuals was disproportionate to that expected from cigarettes alone. In addition, cells obtained in the bronchoalveolar lavage fluid were found to have numerous sphingolipid deposits, suggesting that some of the functional abnormality might have resulted from intrinsic airway disease. Moreover, as the majority of these patients also had a reduced diffusion capacity for carbon monoxide, the authors postulated that there was destruction of lung parenchyma, as suggested by the observation of hyperinflation and bullae on chest X-rays in three of the patients. Emphysema is a well-known mechanism for loss of elastic recoil in the lung.

In 1991, Smith and colleagues reported autopsy findings for a 52-year-old male with Fabry disease who had chronic airway disease and in whom numerous electron-dense inclusions were observed within pulmonary arteries, arterioles, veins and alveolar walls on electron microscopy [9]. There were also numerous deposits in the smooth muscle cells of the media of muscular pulmonary arteries and veins, and in the endothelial cells of all vessels and capillaries, as well as in the alveolar interstitial cells. However, Smith et al. did not conclude that accumulation of sphingolipids in the lung could have affected the respiratory function of their patient.

The most interesting and largest study on pulmonary involvement in Fabry disease was published recently by Brown et al. [10]. This study involved 25 affected men aged 16–54 years. Pulmonary complaints were common in these patients and included cough, wheeze or dyspnoea, but no haemoptysis. There were two cases of spontaneous pneumothorax, an incidence much greater than would be expected in the general population [11]. Nine patients (36%) had a reduced FEV₁:FVC ratio (ratio of forced expiratory volume in 1 second to forced vital capacity), consistent with airway obstruction, and six also had air trapping; four of the nine were non-smokers. The presence of obstructive impairment was strongly age dependent, as for heart and kidney involvement, with no patient younger than 26 years having a reduced FEV₁:FVC ratio. Interestingly, pulmonary symptoms were not associated with either cigarette smoking or cardiac disease, as previously suggested by Bartimmo et al. [2], and smokers with obstruction were not younger than non-smokers.

Eight of the nine patients underwent spirometry after receiving bronchodilator aerosol, and five (63%) of them exhibited a significant increase in FEV₁ [12]. There was no radiographic evidence of bullous emphysema, and single-breath diffusion capacity for carbon monoxide, which correlates with morphological emphysema, was normal in all patients [13]. A total of ten patients underwent methacholine challenge testing, and none of them exhibited a decline in FEV₁ of 20% or greater. This argues against airway inflammation, as disorders associated with extensive inflammatory changes (e.g. asthma, cystic fibrosis or chronic bronchitis) are frequently associated with positive challenge testing [14, 15]. The authors concluded that airway obstruction commonly occurs in patients with Fabry disease regardless of smoking history, and that it is strongly correlated with age, and most likely results from fixed narrowing of the airways by accumulated sphingolipids in bronchial epithelial and/or smooth muscle cells.

Recently, the Swiss Fabry group assessed pulmonary function in 44 patients with Fabry disease (27 men, 17 women). Twelve patients (9 men, 3 women) had an FEV₁:FVC ratio below 0.7, which is the cut-off point for defining chronic obstructive pulmonary disease (COPD); only one was an active smoker and one a previous smoker. FEV₁:FVC, expressed as a percentage of the predicted value, correlated with age (p = 0.005). The increase in FEV₁ after taking a β₂-agonist never exceeded 8% of the predicted value. These results confirm that there is a high prevalence of airway obstruction in Fabry disease, particularly in patients in the advanced stages of the disease [16].

Data from FOS

To date, spirometric data have been reported for 68 patients in FOS – the Fabry Outcome Survey. The data comprise FEV₁, FVC and the ratio of these two variables (available for 67 patients; Table 1), and are expressed as absolute values in litres or as a percentage of the predicted value according to the sex, age and height of each individual. This latter formulation is especially useful when comparing data from a cohort with heterogeneous anthropomorphic parameters.

Table 1

Summary of respiratory data from FOS – the Fabry Outcome Survey.

There is no single worldwide accepted definition of airway obstruction. The simplest and most commonly used criterion has been established by the Global Initiative on Obstructive Lung Disorders (GOLD) [www.goldcopd.com]. The cut-off FEV₁:FVC ratio is 0.7; if the ratio is below this value, patients are considered to have airway obstruction. Although straightforward, this definition may overestimate airway obstruction in older patients, as the FEV₁:FVC ratio declines with age. The definition put forward by the European Respiratory Society in 1995 takes this ageing effect into account, defining airway obstruction by an FEV₁:FVC ratio below 89% and 88% of the predicted value for females and males, respectively [17]. A consensus between the European Respiratory Society and GOLD criteria is expected in the near future.

The FEV₁:FVC ratios for patients in the FOS database are shown in Figure 1. Using the GOLD cut-off, 23 of 67 patients (34%; 9 females, 14 males) have airway obstruction (Figure 1a); according to the European Respiratory Society cut-off, 20 patients are considered to have airway obstruction (Figure 1b). Although these figures far exceed the prevalence of airway obstruction in the general adult population [18, 19], such cohorts are potentially biased by the two most frequent airway obstructive disorders, asthma and COPD, which occur in about 7% and 5%, respectively, of the general adult population.

Figure 1

Distribution of (a) the FEV1:FVC ratio (ratio of forced expiratory volume in 1 second to forced vital capacity) according to age, and of (b) the FEV1:FVC ratio expressed as a percentage of the predicted value for sex, age and height in patients with Fabry (more...)

Unfortunately, although the FOS database has information on 13 patients who are active or past smokers, and on 17 who have never smoked, the smoking status of 37 individuals is unknown. It is interesting to note that only two of the nine active smokers have significant obstruction based on the FEV₁:FVC ratio, suggesting that factors other than cigarette smoking are involved in this condition.

It is even more difficult to diagnose asthma in this population. In clinical practice, asthma is usually diagnosed when there is a compatible history of acute exacerbations with wheezing, cough and chest tightness, an atopic milieu (although this is not mandatory), and a significant response to bronchodilators on spirometry. As the precise mechanism of airway narrowing in Fabry disease is unknown, we cannot distinguish asthma from Fabry disease on the basis of spirometric reversibility. A thorough medical history must be obtained in order to identify with some confidence patients with Fabry disease who have clear bronchial asthma; this type of information is not available for the FOS cohort.

Despite these limitations, it is obvious that there are more patients with airway obstruction than expected within this cohort, especially in the male population aged 20–50 years. Moreover, five patients (1 female, 4 males), all aged 40–60 years, have severe obstruction according to the GOLD criterion (i.e. they have an FEV₁ < 50% of the predicted value; Figure 2). There is a significant correlation between FEV₁, expressed as a percentage of the predicted value, and age in the male population, even though the former parameter is already adjusted for age (r = −0.64, p = 0.001). This indicates that male patients with Fabry disease have an accelerated decline in FEV₁ of about 40 ml/year, compared with 25–30 ml in the general population [20]. There was no statistically significant correlation between age and FEV₁ expressed as a percentage of the predicted value, among female patients (r = −0.24).

Figure 2

Distribution of FEV₁ (forced expiratory volume in 1 second), expressed as a percentage of the predicted value for sex, age and height, in patients with Fabry disease. The percentage of predicted FEV₁ correlated significantly with age in men, but not in (more...)

Potential mechanisms of airflow limitation in Fabry disease

Several structural abnormalities of both the airways and the lung parenchyma can lead to airway obstruction. Although still the subject of some debate and active research, the structure–function relationship for both asthma and COPD have been well established [18, 21]. By contrast, almost nothing is known about the anatomical alterations that are responsible for airflow obstruction in patients with Fabry disease (Table 2). Some mechanisms appear unlikely. Inflammatory cells have not been found in excess in the lungs of patients with Fabry disease. Acute and reversible bronchospasm, which is a classic feature of asthma, is not encountered in most patients. Moreover, acute reversibility testing with short-acting bronchodilators usually does not lead to an improvement in FEV₁ of the same magnitude as that seen in asthmatic patients [16]. Finally, airway hyper-responsiveness after a methacholine challenge test or administration of another agonist has not been reported in patients with Fabry disease.

Table 2

Potential mechanisms of airflow obstruction.

Based on clinical characteristics and pulmonary function tests, airflow obstruction in Fabry disease is similar to the fixed obstruction that characterizes COPD. Nevertheless, it is likely that the structure of airways and lung parenchyma in Fabry disease differs significantly from that in COPD. For example, recent published data show no evidence of emphysema in patients with Fabry disease [10]. Airway wall thickening through hyper-plasia and/or fibrosis is, among others, a potential alteration that could be responsible for airflow obstruction [19]. More studies on structure–function relationships are required to explain the pathophysiology of these clinical observations.

Treatment

There are no evidence-based recommendations for therapy in patients with Fabry disease who also have airflow obstruction; advice is therefore limited to the category of 'expert opinion'. All would agree that smokers with Fabry disease should be encouraged to stop smoking. It is likely that both active and passive smoking dramatically increase the risk of obstruction in these patients. Treatment of patients with moderate or severe obstruction, together with those who are symptomatic, should include the prescription of inhaled bronchodilators, such as long-acting β₂-agonists and atropine derivatives. There is no evidence, however, that steroids, either inhaled or systemic, are of any benefit in patients with Fabry disease, unless they have clinically apparent asthma. As with other chronic respiratory diseases, general measures, such as immunization against influenza and pneumococcal infection, are recommended.

The impact of enzyme replacement therapy on respiratory involvement in Fabry disease has not, to the best of our knowledge, been described. Long-term pulmonary function testing of patients receiving replacement therapy will be of utmost importance both for patients and for our understanding of the mechanisms involved.

Future areas of research

As respiratory involvement in Fabry disease has received little attention compared with other organ involvement, it will be important to gather more clinical data to characterize this manifestation of the disease. In particular, more extensive pulmonary function testing, including plethysmography, assessment of carbon monoxide transfer factor, acute reversibility testing or bronchial hyper-responsiveness challenge, will provide a more complete picture of the respiratory disorder. Imaging, particularly with high-resolution computed tomography, is now powerful enough to analyse the structure of small airways in asthma, COPD and cystic fibrosis [22]. When lung tissue is available from patients with Fabry disease, either as surgical specimens or from post-mortem studies, thorough morphometric studies with adequate stereological tools would be extremely useful in correlating the airway remodelling at the microscopic level to functional alterations [23]. Biological in-vitro studies comparing airway smooth muscle cells and lung fibroblasts harvested from patients with Fabry disease with those from controls might enable alterations in the growth properties of these cells or abnormal resistance to apoptotic stimuli to be identified. The presence of circulating growth factors, which are abnormally expressed in Fabry disease, should also be sought in vitro using live target cells or tissue.

Conclusions

Much remains to be clarified regarding our understanding of pulmonary involvement in Fabry disease. An essential and yet unfulfilled objective remains the reliable and systematic description of affected individuals in a robust clinical database. It is hoped that the FOS database will soon be able to provide the necessary information to fulfil this objective.

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