Ignoring our evolution: the ‘pandemic’ of over-nutrition and under-activity. Not simply a metabolic syndrome?

Authors


Evolution has meant that our prefrontal lobes are too small, our adrenal glands are too big, and our reproductive organs apparently designed by committee; a recipe which, alone or in combination, is very certain to lead to some unhappiness and disorder.

– Christopher Hitchens

The ‘metabolic syndrome’: past vs present

Perhaps the first recognition of a relationship between common metabolic and cardiovascular diseases dates back to 1923 [1]. From the early 1970s onwards, there has been widespread recognition of an association between: obesity (central/abdominal more than general [2, 3]); insulin resistance (impaired fasting glucose and impaired glucose tolerance escalating onto type-2 diabetes mellitus); dyslipidaemia (raised triglycerides, lowered high-density lipoprotein cholesterol, reduced low density lipoprotein particle diameter and increased post-prandial lipaemia); and hypertension. This association was given the status of a syndrome called, amongst many things, ‘the metabolic syndrome’, ‘the multiple metabolic syndrome’, ‘the insulin resistance syndrome’ and ‘syndrome X’. The purpose of diagnosing this syndrome in an individual was to raise awareness of the increased but potentially modifiable risks of cardiovascular disease. However, despite more than thirty years of enthusiasm for this clinical entity, the question has recently been asked by many, including one of the early promoters [4]: is it still a useful concept?

A great deal of time and energy has been expended on defining the diagnostic criteria of this syndrome [5, 6], but far too little on the value and consequences of making the diagnosis [4]. In addition, important associations are widely recognised but not included in any of the diagnostic criteria. They include [7]:

  • increased sympathetic nervous system activity;
  • increased renal sodium retention;
  • elevated plasma levels of plasminogen activator inhibitor-1 and fibrinogen;
  • hyperuricaemia and decreased renal uric acid clearance;
  • increased endothelial-monnuclear cell adhesion and elevated plasma concentration of cellular adhesion molecules;
  • elevated plasma concentration of asymmetric dimethylarginine [8] and a reduction in endothelial-dependent vasodilation.

Further complexity is exemplified by the apparently contradictory effects of a number of the principal mediators such as uric acid [9] and ghrelin [10]. Whilst debate over the definition and usefulness of the term ‘metabolic syndrome’ has occupied some, an increasing recognition of the worldwide ‘pandemic’ of over-nutrition and under-activity, which is the basis of the metabolic syndrome, has stimulated dramatic advances in our understanding of the consequential cellular and tissue pathophysiology.

The industrialisation of food production and distribution has led to excess calorie intake in the majority, though shamefully, under-nutrition and even starvation remain prevalent amongst the most vulnerable in all societies. At the same time, lifestyles have become more sedentary. Biological systems adapt through evolutionary processes to changing environmental conditions, favouring mutations that enhance reproduction. As a species, we evolved in conditions of relative caloric (and sodium) restriction and with the necessity of significant daily physical activity. As a consequence, we have extensive and effective responses to caloric restriction and high intensity, physical activity, but lack any adaptive physiological (negative feedback) or behavioural responses to the opposite set of conditions [11].

It appears that frequent and recurrent caloric excess results in a pro-inflammatory state [12], dyslipidaemia [13], and insulin [14] and leptin [15] resistance. At a cellular level, chronic excess energy supply damages mitochondrial dynamics, resulting in the accumulation of dysfunctional units and increases in reactive oxygen species generation [16]. At an organism level, these phenomena impair appetite control [17] such that we continue to seek food despite first, not needing it, and second, its harmful effects [11]. In addition, chronic caloric excess results in neuro-inflammation, which causes central dysregulation of metabolic homeostasis [18]. We are designed to store excess calories as adipose tissue and thus, with frequent and recurrent exposure, we become obese. Adipose tissue has emerged as the driver of the pro-inflammatory state and the multiple endocrinopathies [19, 20] that result in end-organ damage. Both what we eat (in particular, saturated fats, sucrose, fructose and high fructose corn syrup [21]) and our intestinal microbiome (reduced microbiological diversity, reduced levels of bacteroidetes and a high ratio of firmucutes to bacteroidetes [22]) appear to play a role, but frequent and recurrent calorie intake in excess of need seems to be the primary driver. In addition, there is some evidence that environmental pollution from industrial chemicals, especially agro-chemicals, may be a significant co-factor [23]. Furthermore, epigenetic factors, principally acquired during fetal development (and hence a reflection of maternal health), may both predispose individuals and potentially create inheritable traits in later generations [24, 25].

Excess sodium intake is commonly associated with over-nutrition. Together with increased renal sodium retention and induction of sympathetic over-activity [8], this results in a high co-prevalence of hypertension. The organ/tissue-specific sequelae of these pathophysiological processes are not limited to the cardiovascular system and are briefly detailed in Table 1.

Table 1. End-organ/tissue sequelae of over-nutrition, under-activity and consequent obesity.
Organ/tissueSequelae
MyocardiumObesity related cardiomyopathy leading to heart failure and atrial fibrillation [26, 27]
Vasculature (macro and micro)Atherosclerosis and maladaptation to ischaemia [28, 29]
Respiratory systemSleep disordered breathing, impaired ventilatory mechanics and obesity related asthma [30-32]
RenalChronic impairment (multifactorial: diabetes mellitus, hypertension, hyperuricaemia etc) with gradual functional loss [33]
LiverNon-alcoholic fatty liver disease progressing to hepatitis and cirrhosis [34]
BrainCerebrovascular disease and dementia (both Alzheimer's and vascular) [35]
Peripheral nervous Neuropathy [35]
Musculoskeletal

Quantitative and qualitative loss of skeletal muscle (‘sarcopenic obesity’) [36]. Osteoarthritis

(lumbar spine, hips, knees [37]) and gout [38]

Immune Impaired innate and adaptive responses [39]
Coagulation Hypercoaguable state and venous thromboembolism [40]
CancersIn particular of oesophagus, stomach, pancreas, gallbladder, liver, colon, breast endometrium and kidney (renal cell) [41]

What impact does this have on the practice of anaesthesia and critical care?

We are already seeing an increase in bariatric/metabolic surgery. Data from patients who have undergone various types of bariatric surgery and increasing knowledge of the relative importance of caloric intake and the ‘enteroendocrine’ system challenge the simplistic definitions of metabolic syndrome. The relationship between obesity and type-2 diabetes is becoming clearer. Obese patients undergoing profound caloric restriction [42] and bariatric surgery [43] rapidly normalise plasma glucose concentrations, and in both groups this is sustained, effectively reversing type-2 diabetes. Whilst surgical treatment offers the best chance of sustained weight loss, it is not clear how much contribution to improved glycaemic control is made by alterations in foregut endocrine modulation brought about by specific surgical procedures (Roux-en-Y gastric bypass and biliopancreatic diversion, as opposed to gastric banding). The distribution of fat (in particular, ectopic fat in the liver and pancreas) appears to be an important determinant of insulin resistance and the reduction of this ectopic fat deposition may be the best predictor of remission of type-2 diabetes with weight loss [44].

Pre-operative assessment of obese patients requires a thorough review of all of the possible related conditions to enable a considered decision about potentially modifiable risk factors and the timing of surgery. Perhaps, in addition to routine screening, the following should be considered: quality of blood pressure control (24-hour record); sympathetic overactivity/reduced heart rate variability (24-hour ECG); sleep disordered breathing (Epworth score); and functional respiratory system reserve (sitting and lying spirometry with pulse oximetry). Decisions should be individualised and take into account the urgency of the surgery, the willingness of the patient to adhere to lifestyle and medical interventions and the estimated risks and benefits of a proceed vs postpone strategy.

Peri-operative considerations depend on the usual variables of procedure, patient and anaesthetic preferences. Detailed planning should include the management of: chronic medications; limited cardiorespiratory reserve; glycaemic control; high thromboembolic risk; acute (often on chronic) pain; and vascular access. Intra-operative ventilation with positive end-expiratory pressure optimisation and recruitment manoeuvres are generally recommended. The role of pre-emptive, rescue and actively up-titrated, chronic non-invasive ventilation in the postoperative period has a growing evidence base [45]. There is an argument for creating specialist ‘pre-habilitation’ and enhanced recovery pathways for obese patients. Studies of this population repeatedly find increased peri-operative rates of all morbidities and, for certain procedures, also an increased mortality [46-50].

In the critical care setting, obese patients have a significantly higher incidence of all acute organ dysfunctions and although there are conflicting data regarding mortality risk [51, 52], length of stay and nosocomial complication rates are significantly higher. The most obvious consequence of these data is an additional pressure to increase critical care bed capacity. An appreciation of the chronic disease burden and lack of physiological reserve that may be associated with such patients is important. In the very obese, physiological measurements, fluid therapy, pharmacokinetics/pharmacodynamics and optimising drug therapies present considerable challenges.

Conclusions

The problem with ‘metabolic syndrome’ is that it both over-specifies and over-simplifies the complex effects of over-nutrition and under-activity, which result in chronic injury to all organs (not merely the cardiovascular system), impaired quality of life, premature death and a massive burden on healthcare and society as a whole. Although insulin resistance is important, the recognition of multiple adipose tissue endocrinopathies and the chronic pro-inflammatory state are of at least equal significance. Radical policy change and innovation, at both political and public health levels, are essential to develop and implement further effective primary and secondary prevention strategies for this ‘pandemic’. Meanwhile, the anaesthetist and intensive care specialist must find optimal strategies and resources to manage the planned and emergency healthcare needs of these complex and increasingly prevalent patients.

Competing interests

No external funding and no competing interests declared.

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