Lecture 32 - Nutritional Disorders

The Clinical Biochemistry of Nutritional Disorders Prof. Abayomi Akanji Clinical Chemistry Unit Department of Pathology Faculty of Medicine Kuwait University

Classification Overnutrition  classically common in developed countries where there is excessive caloric intake resulting in obesity  excess accumulation of body fat Undernutrition  classically seen in developing countries where there is inadequate caloric and protein intake  reduced body fat  also called protein-energy malnutrition  Occasionally seen in developed countries in certain diseases and circumstances.

Obesity • A state of excess adipose tissue mass • Generally equivalent to increased body weight, but not always so – – lean but very muscular individuals may be overweight without having increased adiposity.

• Body weights are distributed continuously in populations, so that a medically meaningful distinction between lean and obese is somewhat arbitrary.

 Obesity more effectively defined by assessing linkage to morbidity or mortality.

Definition of obesity • Obesity is excess body fat accumulation with multiple organ-specific pathological consequences • Obesity categorized by body mass index (BMI) - calculated as weight (kg)/height (m)2 • BMI > 30 = obesity; also reflected by increased waist circumference • Waist circumference = better assessor of metabolic risk than BMI because: – more directly proportional to total body fat and amount of metabolically active visceral fat

Classification of body fatness based on BMI according to WHO BMI

Classification

< 18.5 18.5-24.9 25-29.9 30-39.9 ≥ 40

Underweight Healthy Overweight Obese Morbidly obese

Obesity as a Global Problem  Very important public health problem worldwide.  Prevalence in adults:  15-30% in Europe and North America  40-50% in Kuwait and Arabian Gulf  Rapid increase in rates in childhood & adolescence Age of adolescence =10-19 yr - ~ 20% world population  Prevalence of Adolescent Obesity: – Europeans & North Americans: 16-27% – Gulf Arabs: Saudis 27%; Kuwaitis 28%.  About a quarter of all adolescents are obese with significant public health, medical and psychological implications

Prevalence of obesity worldwide. Adapted from Haslam D, James WP. Lancet 2005;366: 1197-209

Haslam, D. et al. BMJ 2006;333:640-642 Copyright ©2006 BMJ Publishing Group Ltd.

Clinical Definition of Obesity Classically 2 easily measurable or calculated indices • Body mass index (BMI): generalized obesity • waist/hip ratio (WHR): abdominal (visceral) obesity • Visceral obesity correlates well with metabolic syndrome and risks of CHD & type 2 diabetes Other indices: -- anthropometry (multiple skin-fold thickness; WC) – densitometry (underwater weighing) – Imaging : CT; MRI – Bioelectrical impedance. • In children: weight and/or BMI percentile for age and sex

Aetio-pathogenesis of Obesity  Causes of obesity remain elusive – likely heterogeneous  chronic excess of nutrient intake vs. level of energy expenditure  complex neuroendocrine/metabolic systems regulate energy intake, storage, and expenditure Role of Genes versus Environment –  Familial – Adoptees; identical twins  Environment: famine; wealth  Genes/environment interaction - specific diets; availability  Cultural factors — relate to availability and composition of the diet and to changes in the level of physical activity. Nutrition & Energy Expenditure • increased energy intake + decreased energy expenditure (or combination) • ? Role of leptin – an adipostat • What is the status of food intake in obesity? – Do the obese eat more than the lean? – generally true • What is the state of energy expenditure in obesity? – studies inconclusive

Leptin – a product of the ob gene – secreted by adipose cells – Acts primarily through the hypothalamus – its level of production provides an index of adipose energy stores – High levels decrease food intake and increase energy expenditure

•Mouse ob gene mutation: – ob/ob mice develop severe obesity, insulin resistance, and hyperphagia. – Another mouse mutant, db/db, which is resistant to leptin, has a mutation in the leptin receptor and develops a similar syndrome.

Humans:  The ob gene is present in humans and expressed in fat.  Several families with morbid, early-onset obesity caused by inactivating mutations in leptin/leptin receptor  Mutations/polymorphisms in the leptin/leptin receptor genes not important in common forms of obesity - most obese people have increased leptin levels but not mutations of either leptin/receptor ►? functional "leptin resistance."

Specific syndromes associated with obesity GENETIC Gene encoding proopiomelanocortin (POMC); mutation ► severe obesity from failure to synthesize -MSH, a hypothalamic neuropeptide that inhibits appetite Genetic obesity syndromes in rodents: tub gene (hypothalamic peptide ? function); mutation► late-onset obesity. fat gene (carboxypeptidase E); mutation ► obesity Complex human syndromes with defined inheritance assoc with obesity: Prader-Willi syndrome: obesity, short stature, mental retardation, hypogonadotropic hypogonadism, hyperphagia ► chromosome 15 deletion Laurence-Moon-Biedl syndrome: obesity, mental retardation, retinitis pigmentosa, polydactyly, hypogonadotropic hypogonadism ENDOCRINE • Cushing's Syndrome - central obesity, hypertension, and glucose intolerance • Hypothyroidism - weight gain due to myxedema • Insulinoma - gain weight from overeating to avoid hypoglycemia • Craniopharyngioma/Hypothalamic Disorders: tumor, trauma, inflammation ► dysfunction of systems controlling satiety, hunger, energy expenditure ► varying degrees of obesity

Index of generalized obesity • most widely used method = body mass index (BMI) weight/height2 (kg/m2) • Mean BMI range for both men and women = 19 - 26 kg/m2 (in most populations); • at similar BMI, women have more body fat than men. • BMI of 30 is threshold for obesity in both men and women. • All-cause, metabolic, cancer, and cardiovascular morbidity begin to rise with BMI ≥ 25, ► cut-off for obesity should be lowered. • Overweight: BMI 25-30 - medically significant and worthy of therapeutic intervention, especially in the presence of risk factors such as hypertension and glucose intolerance.

Obese patients are at ▲ CVD risk: risk factors must be treated early and optimally. Effective treatment to prevent underlying cause (body fat accumulation) would make better clinical & economic sense and is now accepted as a reasonable target for drug development

Indices of abdominal obesity • Distribution of adipose tissue in different anatomic depots is important • Intraabdominal and abdominal s.c. fat more significant than s.c. fat in buttocks & lower extremities.

• Determined by waist-to-hip ratio (WHR) = waist/hip circumference • WHR >0.9 in women and >1.0 in men = Abnormal •

The major complications of obesity, including: – insulin resistance & diabetes – Hypertension & Hyperlipidaemia – hyperandrogenism in women are linked very strongly to intra-abdominal and/or upper body fat

• Mechanism - unknown but possibly related to: – Intraabdominal adipocytes very lipolytically active – NEFAs release into portal circulation has adverse metabolic actions, especially on the liver.

Stereotypical apple (metabolically harmful, more common in men) and pear (metabolically protective and more common in women) shapes. Obesity can contribute to musculoskeletal and psychological problems and have profound effects on quality of life

Waist-hip ratio and body fat distribution

High

Low

The correlation of visceral fat with waist circumference is strong. (Han TS et al. Int J Obes Relat Metab Disord 1997;21: 587-93)

Han, T. S et al. BMJ 2006;333:695-698 Copyright ©2006 BMJ Publishing Group Ltd.

Abdominal adiposity reflects intra-abdominal adipose tissue

From Ashwell M et al. 1985 Br Med J 290:1692-4

Health consequences of obesity Greatly increased risk (RR >3) •

• • • • •

Diabetes Hypertension Dyslipidaemia Breathlessness Sleep apnoea Gall bladder disease

Moderately increased risk (RR ~2-3) • • • •

Coronary heart disease or heart failure Osteoarthritis (knees) Hyperuricaemia and gout Pregnancy complications - pre-eclampsia

Increased risk (RR ~ 1-2) • Cancer (many cancers in men and women) • Impaired fertility/ PCOS • Low back pain • Increased risk during anaesthesia • Fetal defects arising from maternal obesity

Complications of Obesity

Body mass index at follow-up and relative risk for type 2 diabetes in participants in nurses' health study.

Increase in mean systolic blood pressure in overweight and obese men and women compared with normal weight individuals. Data from Health Survey for England, 2003 (www.dh.gov.uk)

Prevalence ratios for hypertension by sex, age, and BMI category. Data derived from cross sectional data from the NHANES III study )

Odds ratios for hypertriglyceridaemia (triglycerides >1.7 mmol/l) by sex and BMI category. Data derived from cross sectional study of 6318 Taiwanese (3540 men, 2778 women) attending health screening centres in southern Taiwan in 2002-3 (Tsai et al. Am J Epidemiol 2004;160:557-65)

Prevalence ratios for hypercholesterolaemia by sex, age, and BMI category. Data derived from cross sectional data from the NHANES III study

Estimated metabolic and vascular benefits of 10% weight loss Blood pressure • ▼ ~10 mmHg in syst & diast BP in hypertensive patients Diabetes • ▼50% in fasting glucose for newly diagnosed patients At risk for diabetes e.g IGT • >30%▼in fasting/2hr insulin • >30% ▲in insulin sensitivity • 40-60% ▼in incidence of diabetes

Lipids • ▼10% TC • ▼15% LDL-C • ▼30% TG • ▲ 8% HDL-C Mortality • >20% ▼in all cause mortality • >30%▼in deaths related to diabetes • >40% in deaths related to obesity

Undernutrition/Malnutrition Patients lose weight when: • Intake/GIT assimilation of dietary calories < normal energy expendit • expenditure of body energy stores > energy assimilated by the body • metabolism of energy significantly impaired by disease process. The etiologies of malnutrition can be categorized according to: • decreased intake or assimilation of diet • increased loss of nutrients from the body • mixed mechanisms that reflect abnormal nutrient metabolism  Energy balance and body weight are sustained in health by the consumption of dietary energy (calories) in an amount = daily expenditure of energy. • Under-nutrition: intake/absorption of fewer calories than energy spent • Over-nutrition: less expenditure of energy than calories consumed.

Classification of body fatness based on body mass index according to World Health Organization

BMI

Classification

< 18.5 18.5-24.9 25-29.9 30-39.9 ≥ 40

Underweight Healthy Overweight Obese Morbidly obese

The development of malnutrition

Malnutrition • frequent component of acute and chronic illness • found in 50% of all hospitalized adults. • contributes to ▲in-hospital morbidity & mortality in both medical and surgical patients • Leads to frequent hospital admissions among the elderly • results from combination of starvation, abnormal assimilation of the diet, the stress response of illness, and abnormal nutrient metabolism

Protein energy malnutrition (PEM)  Definition: Inadequate consumption of protein and energy as a result of primary dietary deficiency or conditional deficiency causing loss of body mass and adipose tissue  Primary deficiency more frequent from socio-economic and geopolitical factors limiting quantity and quality of dietary intake - parts of Asia, Latin America and Africa  Spectrum includes:  Kwashiorkor: protein deficiency with sufficient calorie intake  Marasmus: starvation due to overall lack of calories  In developed societies like Kuwait: – not commonly seen – features of combined protein-calorie malnutrition (PCM) are seen in acute and chronic illnesses.

Common conditions associated with proteinenergy malnutrition in developed countries • Starvation unusual in developed countries – malnutrition due mainly to wrong food choices or food fads • Common non-nutritional causes of malnutrition are: – – – – – – – –

Sepsis Trauma Surgery – esp GIT with complications GI disease – esp involving small bowel Psychological – anorexia nervosa Malignancy Metabolic disease Severe chronic illness

Wellcome classification of protein-energy malnutrition

Weight (% of standard for age)

edema present

edema absent

60-80%

kwashiorkor

Under-nutrition

< 60%

Marasmic kwashiorkor

marasmus

A malnourished child - Marasmus

Contrasting features of kwashiorkor and marasmus Feature

Kwashiorkor

Marasmus

Definition

protein▼ calories►

Starvation, calories ▼

Clin features Children 6mo-3yr Growth failure

Infants < 1yr Growth failure

muscle wasting, fat tissue retained Muscle + fat wasting

Morphology

Generalized edema

Edema absent

Enlarged fatty liver

No hepatomegaly

hypoalbuminaemia

hypoalbuminaemia

anaemia

anaemia

Hair dyspigmentation

Emaciated look

Tissue atrophy except subcut fat

Generalised tissue atrophy

Complications of Kwashiorkor

Laboratory investigation of PEM • Anthropometry: triceps skinfold and midarm circumference • Calculation of under-nutrition based on body height and weight (% ideal body wt or pre-illness wt) • Biochemical tests to reflect: • Visceral (non-muscle) protein status: serum albumin, transferrin, retinol binding protein, prealbumin • Metabolic indices: creatinine-height index (somatic protein or muscle mass) and urinary nitrogen excretion (protein catabolism) • Immune status function: PEM results in depressed immune response (especially cell mediated) – assess with skin tests to various antigens, total lymphocyte count.