Elastic tissue abnormalities in inherited haemolytic syndromes

Over the last years, the significant prolongation of survival of patients with β thalassaemia, as a result of the intensification of treatment, in combination with the closer and systematic follow-up of patients, has gradually broadened the clinical spectrum of the disease with previously unknown manifestations. In this context, a set of clinical and laboratory signs similar to those of inherited pseudoxanthoma elasticum (PXE) have been noticed [1]. PXE is a rare hereditary connective tissue disorder, characterized by generalized degeneration of the elastic fibres with cutaneous, ocular and vascular manifestations [2]. This abnormality may lead to several serious and life-threatening complications, such as blindness, premature coronary artery disease, and cerebral and gastrointestinal haemorrhage [2]. The occurrence of PXE findings in β thalassaemia patients has led, and continues to lead, an increasing number of investigators to study various aspects of the phenomenon and a growing body of evidence is being accumulated [1]. Accordingly, the potential risk of PXE-related complications prompted Cianciulli et al. to perform a long-term follow-up of thalassaemia cases, while other groups expanded the investigation to other inherited haemolytic syndromes and re-evaluated some similar findings observed previously in sickle cell disease (SCD) [3]. The first manifestations of a potential elastic tissue defect associated with haemoglobinopathies were angioid streaks, which represent breaks in the elastic fibres in the membrane of Bruch and are the typical ocular findings in inherited PXE. Angioid streaks have been described in SCD since the late 1950s [4]. Subsequent studies have reported a frequency of angioid streaks in SCD ranging from 1% to 22%, depending on the patients' age [5–7]. In β thalassaemia, an age-related occurrence of 20% was reported [1]. Angioid streaks have also been encountered in sickle thalassaemia with a frequency of 10%[8]. Sporadically, they have been seen in α thalassaemia (haemoglobin H disease) [9], haemoglobin AC disease (haemoglobin C trait carrier) [10] and β thalassaemia minor [11,12]. In a large series of angioid streaks, 50% of cases had PXE on diagnosis [13]. The possibility of a similar diffuse connective tissue disorder in SCD was raised by the report of the PXE syndrome in at least seven adult cases with SCD [14]. However, blind skin biopsies, performed in SCD patients with angioid streaks, failed to reveal any evidence of PXE [5,7]. In contrast, an autopsy series of unselected SCD patients revealed histopathological findings in the dermis and the arterial walls of multiple organs identical to those found in PXE [15]. A clearer relationship was introduced by Lippman et al. in 1985. Based on histopathology and biochemical analysis of skin biopsies, these investigators concluded that SCD appears to be associated with a wide spectrum of elastic tissue disorders resembling PXE, although less severe than PXE [16]. Subsequently, accumulated evidence from the literature has supported the concept of an underlying, generalized elastic tissue defect in the same haemoglobinopathies that were previously associated with angioid streaks. In β thalassaemia, the occurrence of PXE findings proved to be more profound and structurally identical to the inherited PXE [17]. In a 100-patient group with β thalassaemia, 16% of cases had PXE cutaneous lesions, 20% had angioid streaks and 26% had at least one of the two findings; however, none of the patients under the age of 19 years nor any of the 70 family members of cases with PXE findings showed any skin or ocular lesions [18]. The study by Cianciulli et al. confirms the high incidence of PXE-like skin, ocular and arterial manifestations in patients with β thalassaemia as well as their positive correlation with age [3]. In a previous study, the incidence of at least one of these findings reached the impressive percentage of 85% in older thalassaemic patients, aged over 30 years, with calcification of the posterior tibial artery found in 55%, angioid streaks in 52% and typical skin lesions in 20% of this patient group [19]. Besides SCD and β thalassaemia, the PXE syndrome has also been reported in sickle thalassaemia, in which typical cutaneous lesions were found in 5% and angioid streaks in 10%, all lesions being present after the age of 20 years [20]. PXE manifestations have also been found in a patient with β-δ thalassaemia [21]. Moreover, in the series presented by Cianciulli et al. four β thalassaemia patients were also heterozygous for an –α deletion [3]. It is interesting that subclinical disorders of the elastic tissue have been encountered, even in the first decade of life, in haemoglobinopathies as well as in hereditary spherocytosis. Surgical biopsies of spleen, liver and lymph nodes taken from patients with thalassaemia major, thalassaemia intermedia, sickle thalassaemia and hereditary spherocytosis have shown multiple defects of arterial and stromal elastic tissue, similar to PXE (characterized as 'elastorrhexis'), in the striking percentage of 90–96%[22,23]. It seems that the skin, ocular and vascular findings represent the evolving changes of an underlying elastic tissue disorder that starts early in life in these hereditary haemolytic disorders. A genetic link between PXE and these conditions, despite their clinical, structural and cytochemical resemblance to the inherited PXE, seems unlikely, as also stated by Cianciulli et al. [3]. For this reason, the term 'PXE-like lesions' was introduced to describe such findings [18,19,22]. The potential acquired form of the syndrome renders it one of the primary complications of these haemoglobinopathies and it may introduce an important novel aspect in the pathogenesis of PXE. Interestingly, data indicating the existence of an acquired form of PXE are not clear in the literature [1]. Concerning the pathogenesis, taking into consideration the high occurrence of PXE manifestations in haemoglobinopathies, a rational approach would consider some of the common characteristics of these haemolytic conditions, despite the lack of correlation between the elastic tissue defects and the patients' haematological parameters, also reported by Cianciulli et al. [1,3]. This concept is strengthened by the report of angioid streaks and elastic tissue disorders in other haemolytic states, including inherited spherocytosis and congenital dyserythropoietic anaemia type III [23–25]. It has been suggested that the elastic tissue injury in these patients may be the result of an oxidative process, induced by the combined and interactive effect of different factors [19]. Plasma membrane microparticles, derived from the oxidative damage of red cell membranes by the effect of denaturated haemoglobin products and free iron, are considered to elicit inflammatory and oxidative reactions [26]. Moreover, the unbound fractions of haemoglobin and haem, which exceed the binding capacity of haptoglobin and haemopexin in the context of chronic haemolysis, also have powerful oxidative properties [27]. Particularly in sickling syndromes, an excessive productionof free radicals follows the postocclusive tissue reperfusion [28]. Moreover, iron overload has a central role in multiple organ injury in these haemoglobinopathies. Unbound iron catalyses the formation of the most toxic hydroxyl radical through the Fenton and Haber–Weiss reactions, causing, in turn, peroxidation of membrane lipids and proteins [29]. The accumulated and prolonged effect of the above mechanisms may result in disturbance of the elastin metabolism and structural deterioration of elastic fibres [30]. Accordingly, oxidative stress constitutes a potential acquired mechanism affecting the same trans-membrane proteins, which are implicated in the pathogenesis of hereditary PXE. Elastic tissue abnormalities can be present even in the absence of tissue iron overload [23]. However, in β thalassaemia, which is characterized by iron excess, a finding of PXE seems to be more frequent and profound compared to the other hereditary haemolytic syndromes. This may imply that the greater iron load and its toxicity is an additional pathogenetic factor that enhancing the effect of the haemolytic process. The recognition of PXE manifestations and their complications in patients with β thalassaemia and the sickling syndromes may not be easy. Both PXE and the haemoglobinopathies have a broad clinical spectrum with multiple-organ involvement. As a result, PXE-related signs could be overlooked, obscured, or confused with the rest of the clinical manifestations of the primary disease. PXE-related complications may be misinterpreted or recognized only when they become quite severe. Hitherto, such complications have only sporadically been reported in haemoglobinopathies and this makes the contribution of Cianciulli's group a significant one [3]. It seems that thalassaemic cases with skin lesions probably bear a more severe impairment of elastic tissue that is expressed as profound vascular complications, as shown by the 12-year follow-up in this study. However, the vascular and ocular involvement exists even in cases without skin lesions [19,22,23,31]. Intracranial haemorrhages have been reported in thalassaemic patients who had only ocular signs of PXE (angioid streaks), while impaired visual acuity caused by subretinal neovascularization and haemorrhage has also been described in such cases [31–33]. Concurrently, in SCD the reported cerebrovascular manifestations include not only vaso-occlusive events but also haemorrhages; subarachnoid haemorrhages caused by ruptured intracranial aneurysms are a well-recognized cause of morbidity and mortality in adults with SCD [34,35]. Although investigators did not correlate these events to a generalized elastic tissue defect, pathology showed fragmentation of the internal elastic lamina of the arterial wall of the aneurysms while aneurysms were multiple and characterized by atypical localization [34,35]. In hereditary haemolytic syndromes, although the PXE-like finding appears to have a variable severity and frequency, with a generally milder and later onset compared to inherited PXE, it may lead to some severe complications. The current therapy for haemoglobinopathies has significantly improved patients' survival, especially in β thalassaemia, but it does not seem to have an equally beneficial effect on elastic tissue disorders. Therefore, a greater frequency of PXE-like manifestations is likely to be seen in the near future. The knowledge of this phenomenon can result in the early recognition of such complications and probably their effective therapeutic management.