Lifestyle and Quality of Life

Michael Angastiniotis; Aurelio Maggio; John Porter

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Cappellini MD, Farmakis D, Porter J, et al., editors. 2021 Guidelines: For the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 4th edition. Nicosia (Cyprus): Thalassaemia International Federation; 2023.

2021 Guidelines: For the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 4th edition.

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CHAPTER 14Lifestyle and Quality of Life

Authors: Michael Angastiniotis, Aurelio Maggio, and John Porter.

Introduction

Patients with optimally treated thalassaemia can now enjoy a near-normal life and lifestyle, and experience full physical and emotional development from childhood to adulthood.

According to the WHO definition (set out in the constitution, WHO, 2021), health is a state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity. Healthcare professionals should, beyond following clinical protocols, have the clear aim of reducing as far as possible the degree to which the disease interferes with the patients’ personal and social lives. This is achieved by recognising the limitations that the disease imposes but also the effect that the treatment regimens have on the patients’ lifestyles, and the time that these treatments steal from normal living. Recognition of these challenges comes with knowledge of all aspects of the disease, with experience, by learning from patients, and through providing a holistic approach to patients. Beyond managing the physical condition, healthcare staff should be willing to listen to any queries that the patients may bring up and be able to advise on all lifestyle issues.

Leading a ’normal‘ life is an often-expressed priority for patients. This includes social integration (Politis et al., 1990), connecting and interacting with people and contributing to society, despite counter forces that the disease and its treatment bring, which can lead to isolation and, in some societies, stigmatisation. Marginalisation will lead to depression and possibly increase health risks. These issues, and the broader concept of quality of life, become more prominent as longer survival and minimisation of complications are achieved through modern treatment. The concepts of quality of life, social integration, living and experiencing life beyond health preservation, are interwoven. Psychosocial support as described in Chapter 15 is a necessary component of management, as is high quality and well organised holistic care. The healthcare team should have these concepts in mind and be able to guide patients on a variety of lifestyle matters. Below are some of the issues that patients may seek answers to. Although the thalassaemia healthcare team is responsible for providing the answers to such matters, all too often no answers or misleading answers are provided. This chapter aims to provide a foundation from which healthcare professionals can respond with confident and informed guidance to their patients.

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Activities – sports – how far can I go? Social life – dancing, smoking, and alcohol – what is allowed?

Exercise and Participation in Sports

A frequent enquiry from patients concerns their ability to work and participate in sports. In general, physical and recreational activities should be encouraged, as this is an important aspect of healthy and normal living, as well as a means towards social integration. Limitations in chronic disease must however be recognised. Physical capacity can be influenced primarily by the degree of anaemia, and cardio-circulatory and pulmonary function, which are important to the oxygenation of tissues. Additionally, in a chronic condition such as thalassaemia, other co-morbidities may be present, such as cardiac, liver and endocrine dysfunction. For the most part, clinical evaluation focuses on the contribution of respiratory and cardiovascular function to exercise tolerance. Ergometry is used in the majority of studies (mainly cycle ergometry or treadmill), with respiratory function tests to measure aerobic capacity (e.g. VO2max) and cardiovascular investigations using echocardiography and cardiac magnetic resonance to examine cardiac function through assessment of maximum heart rate responses, stroke volume reserve, and the effects of iron overload (Marinov et al., 2008; Nanas et al., 2009; Vasileiadis et al., 2009). Collectively, all existing studies have concluded that there is exercise limitation in transfusion-dependent thalassaemia patients. Factors contributing to this limitation include the degree of anaemia, iron overload affecting heart function – especially through vascular inflammation (Sohn et al., 2013) – and even restrictive lung dysfunction (Piatti et al., 2006).

The global thalassaemia population is not homogeneous, with thousands of patients surviving and functioning with low haemoglobin levels and poor adherence to chelation therapy. The prevalence of complications therefore varies, depending largely on the quality of treatment. A universal and all-encompassing guideline on how much exercise can be taken cannot therefore be formulated, and an individualised approach based on a comprehensive clinical assessment (which may include ergometry) is advisable. In general, pre-adolescent children are allowed to exercise without restrictions, if treated according to accepted standards. If maintained at low haemoglobin levels, careful cardiorespiratory assessment is necessary. From early adolescence, iron accumulation and tissue damage may be evident in the heart and endocrine glands if chelation has been sub-optimal. For this reason, even though routine daily activity is unrestricted, exercise tolerance should be assessed at regular intervals. We have seen from previous chapters that annual cardiological assessment is already recommended (see Chapter 7) for all thalassaemia patients from an early age since iron accumulation may occur early in their lives (Berdoukas et al., 2013). Careful evaluation is recommended if athletic activity is contemplated.

In addition to the above, consideration must be given to all co-morbidities, including bone disease, which is common at all ages in thalassaemia patients. In addition to pain, which may limit mobility, the propensity to fractures must also be considered whenever giving advice concerning exercise and sport. In a well-publicised case, a patient with thalassaemia major ran the London marathon on two occasions. This is an inspiration for all patients across the world, and proof that modern treatment can lead to a normal quality of life. However, in the spectrum of thalassaemia care that exists across the world, this example is sadly relevant to only a minority of optimally treated patients.

Education

In a recent survey involving thalassaemia and sickle cell patients from across Europe, 21% of patients over the age of 18 years had completed university education (Corrons et al., 2014). In a more recent review of 230 patients from Cyprus 53.5% had completed tertiary education (Sitarou unpublished data), which compares well with the general population of Cyprus in which 39.4% are university graduates. This should dispel any doubts concerning the ability of patients to achieve a full education, despite reports of a cognitive impairment in patients (Tartaglione et al., 2019). Factors associated with chronic illness, rather than the disease per se, could play a potential role in the development of cognitive dysfunction (Economou et al., 2006). In the USA, 82% percent of school age children were at expected grade level (Pakbaz et al., 2010). The main limiting factor expressed by patients is the need to interrupt educational sessions in order to meet clinic and transfusion appointments, which are in most clinical services, during daytime working hours. Adjusting day transfusion services to include evening and weekend sessions, to suit patients in full-time education or employment, will greatly assist their achievement of social integration and their contribution to society (see Chapter 17) and this should be a priority for health-care professionals and managers offering the service. In addition, medical teams should be ready to liaise with educational services and especially schoolteachers, to provide information and education concerning thalassaemia, and the ability of patients to perform in school, recognising that concerns and sometimes even prejudice from teachers may adversely affect student performance. Prejudice is also a feature in the playground, where bullying and negative behaviour can make the young thalassaemia patient feel different and isolated, which can have a lasting effect on their self-image. Feeling different can also have personal consequences in countries where thalassaemia is viewed as an ‘immigrant disease’, potentially leading to racial and ethnic issues (Dyson et al., 2010). These issues require educational intervention for and by teachers.

Employment

Many adult thalassaemia patients are employed without difficulty. However, problems do still exist due to several factors, which originate in part from patients but also from employers and the social environment more generally. Many patients who have not benefitted from adequate psychosocial support still have low self-esteem and feel that ‘poor health’ does not allow them to work. Even in Europe where overall services are regarded as achieving a high level, these problems remain prevalent. In the survey referred to above (Enerca 2014), of more than 300 patients over 20 years of age, half were fully employed, while 19% were working part time and 31% were unemployed. These figures far exceed national unemployment statistics, although it should be noted that 14% of those unemployed were so through their own choice. This indicates that a significant number of patients are having difficulties and need support from their healthcare team as well as social services. Prejudice from employers is however still an issue in many parts of the world (Wahab et al., 2011). The reasons given include repeated absences, again reinforcing the need for out-of-hours clinic and transfusion sessions, but also a fear that ‘something may happen’ as a result of the disease, and the belief that such an employee may not be able to do the job.

The United Nations Convention on the Rights of Persons with Disabilities (United Nations, 2006) clearly states in Article 27 that parties must recognise the right of persons with disabilities to work on an equal basis with others, prohibiting discrimination on the basis of disability, assuring equal remuneration for work of equal value as well as safe and healthy working conditions. In view of this, the thalassaemia care team have a duty for advocacy on behalf of their patients, educating the public in general but also individual potential employers. The team should also instil a positive attitude in their patients concerning their ability to work. For manual tasks it may be necessary to assess the individual’s ability according to the same protocol used in assessment for exercise and sports, exercising caution if heart disease or osteoporosis is present.

Marriage and Reproductive Life

Getting married and having a family is widely accepted as a key goal in one’s life, and thalassaemia patients have a good record in forming relationships. In an updated report from Cyprus, (2020 unpublished data) of 318 patients over the age of 18 years, only 35% had not married. In the same group of patients, 64% had children. These figures cannot be achieved where the majority of patients are children, and where stigmatisation limits patient opportunities to form stable relationships. Several studies have reported that as many as 51% to 80% of transfusion dependent thalassemia (TDT) patients may have pubertal failure, sexual dysfunction and/or infertility, due to hypogonadism (De Sanctis et al., 2018). From an early age, patients should be seen by an endocrinologist to avoid hypogonadism as detailed in Chapters 8 and 9. The thalassaemia team should also provide general support and encouragement to the patients and has a duty to coordinate the multidisciplinary team which oversees both the preconception optimisation of both men and women and cares for the woman through her pregnancy and delivery.

Nutrition

Questions relating to nutrition are often posed by patients and their parents, since daily needs may influence the patient’s health. Indeed, it has been suggested that the growth failure observed in children may be partially related to undernutrition (Skordis & Kyriakou, 2011). To test this hypothesis, the effect of a high calorie diet on partial or complete correction of impaired growth in thalassaemia major children who were unaffected by endocrinopathy or cardiomyopathy has been studied (Soliman et al., 2004). The results showed that increasing caloric intake significantly increased insulin growth factor 1 (IGF-1), skin fold thickness, mid-arm circumference and body mass index (BMI), thus at least partially improving growth. This observation is consistent with other studies (Fuchs et al., 1997). It therefore seems logical to recommend a high caloric intake during growth, especially as the difference between intake and expenditure is greater in young children (Fung et al., 2012). In addition, there are many reports of vitamin and micronutrient deficiencies in thalassaemia, which may also affect growth (Goldberg et al., 2018; Ozturk, Genc & Gumuslu, 2017). It is important therefore to look at some of the important vitamin and minerals in more detail.

Zinc

Zinc is an essential element which in thalassaemia can be reduced either because it is removed by iron chelating drugs (Erdoğan et al., 2013) or because of inadequate dietary intake, poor absorption (Fung et al., 2012) or increased urinary loss with prolonged use of thiazide diuretics that are sometimes used in patients with cardiac failure. Zinc deficiency has been demonstrated in thalassaemia and has been shown to affect growth, bone health, sexual maturation, and glucose homeostasis (Fung et al., 2015). Zinc deficiency may also cause hair loss, diarrhoea, skin disorders and loss of appetite. In addition, it is also essential for the immune system – particularly for lymphocyte function (Tienboon, 2003).

There have been few studies examining the effects of supplementation in thalassaemia major. Some show improvement in both bone health and linear growth in the short term and glucose homeostasis (Matter et al., 2020). However, the long-term safety and acceptability of continued supplementation need to be evaluated (Fung, 2016).

Monitoring zinc levels every 6 months, especially in patients on regular chelation is recommended and, if indicated, supplements should be prescribed (the normal range in blood is 70-120 μg/dl). However, plasma zinc is a sensitive measurement when there is a major deficiency but if the deficiency is moderate this may not be registered and a so a normal result does not exclude a deficiency. The levels in plasma may also be influenced by the level of plasma proteins, liver disease, infections, pregnancy and also the time of sampling in relation to meals (Sandström, 2001); above all the level will be influenced by the iron chelating agents which have been shown to increase excretion (Erdoğan et al., 2013) and by the taking zinc supplements. For these reasons interpretation of results should take these factors into consideration and supplements should be avoided 24 hours before the test; the same may be argued concerning the iron chelating agents even though there is no study to support this at present. Leukocyte zinc may be another approach to estimate deficiency but this has not been properly investigated in thalassaemia patients

Zinc supplements are available in various formulations, with different contents of elemental zinc. It is recommended that whichever formulation is chosen, 15 mg up to a maximum of 40 mg/day of elemental zinc is prescribed, according to individual patient’s needs. Caution is needed for high doses, as toxicity can occur – including gastrointestinal irritation – as well as interactions with other minerals and medication.

Iron

In regularly transfused thalassaemia major patients the contribution of dietary intake of iron is not significant when compared with transfusional iron intake (see Chapter 3). However, intestinal absorption becomes more significant at low pre-transfusion levels. Globally, many transfusion-dependent patients do not receive blood transfusions before haemoglobin levels fall to 60 or 70 g/l, and iron absorption may rise up to 5 mg/day compared to 1-2 mg and so contribute to iron loading. In this group of patients on low blood transfusion in particular, dietary restriction of iron is important. Taking black tea with meals may reduce iron absorption, while foods rich in vitamin C will increase absorption. Needless to say that iron supplements have no place in the thalassaemia syndromes, TDT or NTDT; this includes pregnancy during which routine supplements are often given which include iron along with folic acid.

Calcium and Vitamin D

Calcium and vitamin D are the most commonly prescribed supplements for thalassaemia patients. Calcium homeostasis is intimately related to vitamin D, and deficiency of this vitamin in thalassaemia ranges in different reports from Thailand from 50.8% (Dejkhamron et al., 2018) to 90% (Nakavachara & Viprakasit, 2013). Vitamin D deficiency is defined as D25 <20 ng/ml (50 nmol/l) and insufficiency D25 = 20–30 ng/ml (50-75 nmol/l (WMA, Statement on Vitamin D Insufficiency, 2015; Wood et al., 2008). Vitamin D deficiency is also associated with poor bone mineralisation, contributing to thalassaemic bone disease and muscle weakness and, more importantly, can affect the heart muscle, causing left ventricular dysfunction associated with cardiac iron uptake (Wood et al., 2008). Low consumption of calcium • (Fung et al., 2012), and decreased intestinal calcium transport (Lertsuwan et al., 2018) found in thalassaemia patients, contribute to the disturbance in calcium homeostasis, particularly if hypoparathyroidism is present (see chapter 10).

Hypercaliuria has been demonstrated in thalassaemia related to renal tubular dysfunction (Quinn et al., 2011) and possibly to the use of deferasirox (Wong et al., 2016) with cases of nephrocalcinosis reported (see appendix 2 of chapter B2). Hypercalciuria with nephrocalcinosis was also previously described in deseferrioxamine treated patients, although a mechanistic link has not been established. Hypercaliuria does not seem to be related to dietary calcium intake (Quinn et al., 2011).

Vitamin D supplementation is recommended for all patients at a dose of at least 2000 iu/day (Fung et al., 2012). It is also recommended that vitamin levels are monitored every 6 months in thalassaemia patients (Nakavachara & Viprakasit, 2013). A diet high in calcium, including milk, cheese, and oily fish is also recommended. However, calcium at around 1 g /day is also recommended along with vitamin D in selected cases.

Folic acid

Folic acid is an essential element for the synthesis of nucleoproteins and since these are lost in the cell destruction of ineffective erythropoiesis, a deficiency of this vitamin is expected. Patients on high transfusion regimens, which suppress endogenous erythropoiesis in thalassaemia major, rarely develop folate deficiency, in contrast to those on low transfusion regimens. In view of the fact that many patients with thalassaemia major are transfused at low haemoglobin levels (and their folate status is unknown), as well as possible benefits from folic acid supplementation in reducing risks of thrombosis related to homocysteine levels and atherosclerosis (Baghersalimi et al., 2018; Qin et al., 2012), the possibility of providing folic acid supplements at 1-5 mg/day especially to patients on low transfusions, should be considered. This is especially so since we now have an ageing thalassaemia population more prone to thrombotic complications and atherosclerosis (Farmakis et al., 2020). The chances of toxic effects are low.

Vitamin E

Vitamin E, also known as α-tocopherol, is a fat-soluble vitamin, which is often depleted in thalassaemia patients. The main reason is that iron load in the liver, and associated liver damage, results in a reduction of serum lipids (Livrea et al., 1996), although reduced dietary intake has also been demonstrated (Fung et al., 2012). Supplements of vitamin E have been shown to reduce oxidative stress in thalassaemia (Pfeifer et al., 2008) and to reduce lipid peroxidation of red cell membranes (Sutipornpalangkul et al., 2012). However, these trials, using 400 iu/day, were for relatively short durations of treatment and with small patient numbers. Prolonged use, especially at high doses, requires more extensive trials in thalassaemia. However, a diet rich in foods that contain vitamin E can be recommended, with intake of foods including eggs, vegetable oils (e.g. olive oil, corn oil, safflower and sunflower oil), nuts and cereals.

Vitamin C

Vitamin C has antioxidant properties and can also be depleted in conditions in which there are increased free iron radicals causing oxidative damage. However, caution in recommending supplementation has been expressed because:

Vitamin C is known to promote the absorption of dietary iron, and even regularly transfused patients should control their intake of iron.
Vitamin C increases labile iron and therefore contributes to iron toxicity. However, the increased availability of chelatable iron allows deferoxamine (desferrioxamine) to excrete more iron. In order to avoid toxicity, the vitamin is given at the time of deferoxamine infusion at a dose not exceeding 2-3 mg/kg. This benefit is not seen with the other oral chelating agents and so its use with these agents is not recommended.

Anti-oxidant therapy

Iron overload and especially non-transferrin bound iron results in the production of a variety of reactive oxygen species (ROS), which lead to cell and tissue damage. Levels of antioxidant compounds such as vitamin A, carotenoids and vitamin E are decreased in β thalassemia major patients. In view of the antioxidant properties of vitamins and other mostly plant-derived substances, there have been several investigations of the possible benefits and especially of the effects on free iron and liver function (Elalfy et al., 2013; Livrea et al., 1996). Most studies, using combinations of substances, are on small numbers of patients and short duration of treatment, with one exception where the duration was 1 year. In transfusion-dependent patients, some benefit is demonstrated but there is also possible long-term toxicity, especially where vitamin C is concerned. For this reason there is no agreed guideline on their use in the everyday life of patients. However, encouraging the use of natural antioxidants such as curcuminoids, quercetin and green tea may be of some help, even though larger and longer duration studies are required to assess benefits and long term effects.

Supportive Treatments

Various substances, often derived from herbal sources, have been proposed to enhance treatment in thalassaemia. These often attract the attention of patients, and professionals should therefore be able to respond to any questions and be aware of the potential benefits, limitations or even dangers of these substances. Some of these are supported by clinical trials and should be considered in more detail.

L-Carnitine

Carnitine is a butyrate derivative – beta-hydroxy-gamma-trimethylaminobutyric acid – with potential benefits in thalassaemia, since it is believed to have anti-oxidant and cardioprotective properties. It is known to be essential for the metabolism of long-chain fatty acids and it is present in high energy demanding tissues such as skeletal muscle, cardiac muscle and the liver. In clinical trials, L-carnitine at a dose of 50 mg/kg/day given to small groups of patients for 3-6 months, the following benefits have been reported:

Improved heart function and improvements in exercise performance.
Significant improvement in pulmonary artery systolic pressure in patients with pulmonary hypertension (El-Beshlawy et al., 2008)
An increase in transfusion intervals (El-Beshlawy et al., 2007)
Reduced bone pain and muscle weakness (Tabei et al., 2013)

However, caution is needed in patients with seizures and those with hypothyroidism, since L-carnitine inhibits triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei (Benvenga et al., 2004).

Wheat grass

This is a popular health food prepared as a juice from the leaf buds of the wheat grass plant. It contains chlorophyll, vitamins, minerals and several enzymes. Wheat grass is believed to increase the production of red cells and increase the interval between transfusions, which has been demonstrated in a small number of patients and confirmed more recently (Singh et al., 2010). There do not appear to be side effects, but long-term benefit is uncertain.

Silymarin

A derivative of milk thistle (Silybum marianum), silymarin, is a flavonolignan complex which has antioxidant properties and has been investigated extensively as a hepatoprotective agent. In recent publications, this role of silymarin has been confirmed and it has additionally been found to inhibit hepatitis C virus entry into hepatocytes (Blaising et al., 2013; Polyak, Ferenci & Pawlotsky, 2013). These benefits may be of use in thalassaemia patients who have liver damage from iron overload, and/or hepatitis B (HBV) or C (HCV) infection. There are also reports that it can potentiate the effect of iron chelating agents (Darvishi-Khezri et al., 2018). It is available in capsular form and usually dosed at 140 mg three times a day (420 mg) with no recorded side effects.

Alcohol

Patients with thalassaemia should be discouraged from consuming alcohol. Alcohol can potentiate the oxidative damage of iron and aggravates the effect of the hepatitis viruses on liver tissue. If the liver is iron loaded and/or infected by HCV or HBV, alcohol consumption may further promote progression to cirrhosis and hepatocellular carcinoma. Excessive alcohol consumption may also affect bone formation and is a risk factor for osteoporosis. In addition, alcohol may have unexpected interactions with medications.

Smoking

Tobacco must also be avoided since it may directly affect bone remodelling, which is associated with osteoporosis. In view also of the doubts concerning cardiorespiratory fitness for exercise (see the discussion above), it can be assumed that smoking will make matters worse and, of course, it carries all the adverse effects described in the general population.

Drug abuse

Substance abuse is common in most societies and a special danger among adolescents and young people. Thalassaemia patients attempting to ’fit in‘ and be accepted into peer groups are potentially vulnerable to experimentation with these drugs. There are no published studies on the prevalence of drug abuse in this cohort, but many clinicians have encountered isolated cases. Treating staff should be able to recognise patients who have a problem and be ready for transparent and frank discussions around these issues. Substance abuse can have serious consequences in thalassaemia patients with tissue damage affecting many vital organs.

Quality of Life

All the issues discussed in this chapter are addressed by a service which offers patient-centred and holistic care, alongside accepted clinical standards of care. The aim is to achieve autonomy in life, and to allow patients to satisfy their personal ambitions. In considering whether a healthcare team has been successful in its efforts, quality of life should be a major outcome measure. In an editorial, the Communication Committee of the European Hematology Association notes: “Quality of Life will, very soon, become completely integrated into patient care….In times when some haematological diseases are turning from acute, life threatening diseases into lifelong chronic conditions, assessing and maintaining Quality of Life becomes even more important for patients” (Chomienne et al., 2013).

How then is quality of life assessed? The concept of quality of life involves each patient’s perception of his or her own life and wellbeing, and since wellbeing includes psychological and social functions, which in turn are influenced by the physical state of health, any assessment must include all these dimensions. Several measures have been developed to evaluate quality of life, which explore domains such as physical state, emotional state and social circumstances. These domains are incorporated in questionnaires – of which several have been tested, validated and used in thalassaemia. The following are examples of the main instruments used:

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The WHOQoL questionnaire (Telfer et al., 2005). The PedsQoL Generic Core Scales (Clarke et al., 2010).

It is not the aim of this chapter to recommend any one instrument in particular, but to strongly urge thalassaemia clinics to adopt and use an instrument of their choice and apply it over time to their patients. Clinics should follow changes in their patients’ own evaluations and views, as each patient’s situation in each domain changes with alterations in treatment, or the appearance of complications (Gollo et al., 2013). These instruments can be used to monitor and evaluate individuals, as well as groups of patients, thus allowing them to evaluate service quality and clinic performance, and identify any weaknesses that need to be addressed.

Health related quality of life as estimated by these various tools cannot be used to make comparisons between care in different geographical regions. Variables include the disease severity of patient groups, past management of patients, the onset of complications, whether on oral versus parenteral chelation, the age of patients, and whether parents or children are responding (Gollo et al., 2013). Monitoring patient groups over time using the same instrument in the same clinical setting can, however, provide invaluable information on how patients are faring with the care they are receiving.

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Summary and Recommendations.

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