EFFECT OF HAEMOGLOBIN GENOTYPE ON EXERCISE TOLERANCE

EFFECT OF HAEMOGLOBIN GENOTYPE ON EXERCISE TOLERANCE.

 Chapter One

1.1            Introduction

1.2            Background of the Study

Anaemia, meaning “without blood” in ancient Greek is a common haematologic disorder affecting both developing and developed countries and is quantified by a deficiency in the iron containing oxygen (O2) carrier haemoglobin (Hb) stored within erythrocytes. The World Health Organisation (WHO) states that in the assessment of anaemia, “Hb concentration ([Hb] ) is the most reliable indicator of anaemia at the population level” Arnold H. R., Carrier E. B., Smith H. P., Whipple G. H. (1921). The WHO defines anaemia as an insufficient circulating [Hb] of <130 g^.l^-1 in men and <120 g^.l^-1 in women, with further adjustment made in pregnancy (<110 g^.l^-1) Banfi G., Lundby C., Robach P., Lippi G. (2011). Anaemia can occur at all stages of the human lifespan but is more commonly an affliction in older age. From a worldwide perspective, anaemia is a global burden to human health with an estimated quarter of the world’s population affected. Specifically, anaemia affects 1.62 billion people (95% CI: 1.50–1.74 billion), which corresponds to 24.8% of the global population (95% CI: 22.9–26.7%). A systematic analysis of global anaemia burden spanning 1990 to 2010 revealed that anaemia accounted for 68.4 million years of life lived with disability (YLD) in 2010, equating to 8.8% of global total disability from all conditions Bauer C. (1969). Updated figures from the Global Burden of Disease, Injuries and Risk Factors Study in 2013 showed that the total number of anaemia cases had increased to 1.93 billion, which corresponded to an increased age-standardised prevalence of 27%, although YLD (61.5 million YLDs) decreased compared to figures from 2010 Benesch R., Benesch R. E. (1967)

Iron deficiency is the single greatest underlying cause of anaemia (iron deficiency anaemia, IDA) at the global level in both sexes, accounting for 63% of the global total in 2013 [4] . IDA is also the leading cause of anaemia-attributable disability although the cause of anaemia does vary with geography, age and sex. Other leading causes of anaemia in both sexes are haemoglobinopathies (12% in females, 10% in males), gastrointestinal losses (5% in females and males), and malaria (5% in males) with gynecologic conditions (5%) unique to females and non-malarial infectious tropical diseases to males (4%) Bergfeld G. R., Forrester T. (1992) In addition, many chronic (and especially inflammatory) states also yield a ‘functional iron deficiency’ and blunted erythropoiesis, thereby resulting in ‘the anaemia of chronic inflammation’ (ACI) Berglund B., Hemmingson P. (1987)

Anaemia is thus a clinically important haematological condition encountered in various clinical settings and across many different disease states from the surgical patient, where it affects around one third of cases preoperatively Berlin G., Challoner K. E., Woodson R. D. (2002) to patients with inflammatory bowel disease (IBD) Bert P. (1882), liver disease (LD) Bodary P. F., Pate R. R., Wu Q. O. F., McMillan G. S. (1999) and chronic heart failure (CHF) Böning D., Maassen N., Pries A. (2011). Anaemia is associated with increased fatigue Böning D., Mrugalla M., Maassen N., Busse M., Wagner T. O. (1988), impaired functional capacity Böning D., Schweigart U., Tibes U., Hemmer B. (1975) and adverse surgical outcome Bouix D., Peyreigne C., Raynaud E., Monnier J. F., Micallef J. P., Brun J. F. (1998) as well as worsened prognosis in a variety of diseases from CHF Braumann K. M., Böning D., Trost F. (1982), cancer and chronic obstructive pulmonary disease (COPD) [16] . In the context of surgery, the reduced O2 carrying capacity of blood in anaemic individuals with resulting tissue malperfusion may be one mechanism increasing susceptibility to adverse postoperative outcomes Broun G. O. (1922).

For all these reasons, circulating haemoglobin concentrations are routinely measured in clinical practice. Once anaemia is identified, the cause of impaired haemoglobin synthesis or erythrocytosis, or of increased red cell destruction, is often sought and treatment (either of the underlying cause or through the administration of packed donor red cells) initiated. However, it is now becoming clear that this approach may be somewhat simplistic. [Hb] may be an imperfect index of the blood’s O2 carrying capacity, being reduced not only when the absolute mass of circulating haemoglobin (tHb-mass) falls, but also by an increase in the volume of plasma (PV) in which the red blood cells (RBCs) are suspended. But a low [Hb] might also be found when haemoglobin synthesis and erythrocytosis are normal, and when tHb-mass is normal (or even high), if PV is disproportionately expanded. Therefore, both tHb-mass and PV can affect [Hb] independently of one another. Despite this, neither factor is routinely considered or measured in clinical practice. However, such assessment may be important if the drivers of an altered [Hb] - and the appropriate therapeutic response- are to be truly understood.

Total haemoglobin mass, being independent of PV may represent a better guide of Hb content and systemic O2 carrying capacity given that each gram of Hb has the maximum capacity to bind 1.39 ml of O2 and a trivial amount of O2 is transported in plasma. Despite this, the relationship between tHb-mass and [Hb] has, however, been little studied in patient populations or across disease states and this is the first aim of my thesis to explore. Total haemoglobin mass can now be safely and reliably measured using the optimised carbon monoxide (CO) rebreathing (oCOR) method, refined by Schmidt and Prommer in 2005.

The oCOR method has been widely used in sports medicine to measure tHb-mass and blood volume derivatives in elite athletes Calbet J. A., Lundby C., Koskolou M., Boushel R. (2006), following exposure to hypoxia (altitude training) Calbet J. A., Robach P., Lundby C., Boushel R. (2008) and in the context of blood doping Carroll S. B. (2007), but has rarely been applied in the clinical setting Chasis J. A., Mohandas N. (2008). If [Hb] is an imperfect index of tHb-mass and thus O2 carrying capacity, then this raises important questions about the way in which we measure and quantify Hb and define anaemia in patients. For example, should tHb-mass be measured as an adjunct to or used instead of [Hb] as a means of assessing Hb in patients? Furthermore, do we need to readdress ‘anaemia’ as a concept and should we be defining volume excess and tHb-mass deficit separately instead? Surgery, like exercise, places significant systemic hormonal and metabolic stress on the body. Whilst subject to some debate, O2 supply at a rate inadequate to prevent skeletal muscle anaerobiosis may underpin the occurrence of the anaerobic threshold (AT) during exercise, although other mechanisms may include the recruitment of muscle fibres with differing metabolic features Chasis J. A., Mohandas N. (2008). Regardless, the AT is an important submaximal marker of cardiorespiratory fitness [52] in health and disease. The maximal rate at which O2 can be transported from the environment to the mitochondria and utilised to support oxidative phosphorylation is termed the maximal or peak  ̇ oxygen uptake (VO2max, VO2 peak). The classical view is that VO2max is constrained by the limits of the cardiovascular system Cerretelli P., DiPrampero P. E. (1985), although this is not without controversy Chien S., Usami S., Dellenback R. J., Gregersen M. I., Nanninga L. B., Guest M. M. (1967). Nonetheless, it is widely considered that O2 delivery, and not O2 extraction at the muscle which predominates in limiting VO2max in exercising humans Chien S., Usami S., Taylor H. M., Lundberg J. L., Gregersen M. I. (1966), with cardiac output (Q) and the O2-carrying globular protein molecule Hb pivotal in this process Christ E. R., Cummings M. H., Westwood N. B., Sawyer B. M., Pearson T. C., Sonksen P. H., et al. (1997). Preoperative cardiopulmonary exercise testing (CPET) is considered the gold standard assessment of exercise capacity before surgery and is used to determine exertional O2 consumption (VO2) at AT and VO2 peak, as measures of ability to meet increasing O2 demands. The degree of surgical insult and the ability to meet the resulting additional postoperative O2 demand appear to be fundamental determinants of surgical outcome: individuals in whom such ability is impaired, and thus with reduced VO2 peak and AT, are at greater risk of adverse surgical outcome Connes P., Bouix D., Py G., Prefaut C., Mercier J., Brun J. F., et al. (2004). The cause of uncoupling of O2 supply and demand is multifactorial but likely an interaction between a patient’s existing comorbidities (e.g. cardiac disease or respiratory disease), and other conditions that impact O2 delivery &/or Q^̇. While Q^̇is well recognised as a key variable limiting exertional VO2 Connes P., Caillaud C., Py G., Mercier J., Hue O., Brun J. F. (2007), the impact of anaemia and reduced concentration of oxygen-carrying Hb is less recognised, although others have shown associations between [Hb] and cardiorespiratory fitness Convertino V. A. (1987) and enhanced exercise performance following acute changes in [Hb] Convertino V. A. (1991).

1.2     Statement of the problem

1.3     Research Objectives

1. To determine the degree to which total haemoglobin mass is correlated with haemoglobin concentration in different patient populations and disease states, and
2. To assess the feasibility of using the optimised carbon monoxide rebreathing method in sport activities.
3. To explore the relationship between both haemoglobin concentration and total haemoglobin mass and measures of alethes physical fitness, as determined by cardiopulmonary exercise testing.

1.4     Research Questions

What is the degree to which total haemoglobin mass is correlated with haemoglobin concentration in different alethes populations and disease states?

What is the feasibility of using the optimised carbon monoxide rebreathing method in sport activities?

What is the relationship between both haemoglobin concentration and total haemoglobin mass and measures of alethes physical fitness, as determined by cardiopulmonary exercise testing?

1.5     Hypotheses

There is no significant effect to which total haemoglobin mass is correlated with haemoglobin concentration in different patient populations and disease states.

There is no significant effect of the feasibility of using the optimised carbon monoxide rebreathing method in sport activities.

There is no significant effect of the relationship between both haemoglobin concentration and total haemoglobin mass and measures of alethes physical fitness, as determined by cardiopulmonary exercise testing.

1.6     Significance of the study

The findings of this study would be of benefits to physical and health education, coaches, educational administrators, government health policy makers, counselors and researchers.

This study would also be significant in the sense that its finding would serve as reference materials for future researchers to carry out further studies in the field of knowledge under study

The Ministry of health would benefit from the findings of this study in view of the revealed indices or how efficacious how hemoglobin affects their body function during exercises which will form the basis of their seminar/workshop on alethes training and retraining.

1.7     Scope of the study

EFFECT OF HAEMOGLOBIN GENOTYPE ON EXERCISE TOLERANCE.

1.7     Limitation of the study

It is inevitable that a survey research of this nature must have some constraints which impact on this study. The materials for a proper and effective research work constituted a major limitation and even the decision to use questionnaire in data collection constituted some limitation of the study, that is, how to get the true and required information from the workers.

Finally, there was an anticipation of the problem of convincing the respondents on the filling of the questionnaires and to give the true and required information. But for the quick intervention the class representatives the departments took time to clear the air and convince their course mates, helped me to accomplish my assignment.

EFFECT OF HAEMOGLOBIN GENOTYPE ON EXERCISE TOLERANCE.