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 Underweight
18.5-24.9 Healthy
25-29.9 Overweight
30-39.9 Obese
≥ 40 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) Increased risk
• Diabetes (RR ~ 1-2)
• Hypertension • Cancer (many cancers
• Dyslipidaemia in men and women)
• Breathlessness • Impaired fertility/
• Sleep apnoea PCOS
• Gall bladder disease • Low back pain
• Increased risk during
Moderately increased risk (RR ~2-3) anaesthesia
• Coronary heart disease or heart failure
• Fetal defects arising
• Osteoarthritis (knees) from maternal obesity
• Hyperuricaemia and gout
• Pregnancy complications - pre-eclampsia
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 Lipids
• ▼ ~10 mmHg in syst & diast • ▼10% TC
BP in hypertensive patients • ▼15% LDL-C
• ▼30% TG
Diabetes • ▲ 8% HDL-C
• ▼50% in fasting glucose for
newly diagnosed patients
Mortality
• >20% ▼in all cause
At risk for diabetes e.g IGT mortality
• >30%▼in fasting/2hr insulin • >30%▼in deaths
• >30% ▲in insulin sensitivity related to diabetes
• 40-60% ▼in incidence of • >40% in deaths related
diabetes 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 Underweight
18.5-24.9 Healthy
25-29.9 Overweight
30-39.9 Obese
≥ 40 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 protein-
energy 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 edema edema

standard for age) present absent

60-80% kwashiorkor Under-nutrition

Marasmic
< 60% marasmus
kwashiorkor
A malnourished child - Marasmus
 Contrasting features of kwashiorkor and marasmus

Feature Kwashiorkor Marasmus

Definition protein▼ calories► Starvation, calories ▼
Clin features Children 6mo-3yr Infants < 1yr
Growth failure Growth failure

muscle wasting, fat tissue retained Muscle + fat wasting

Generalized edema Edema absent

Enlarged fatty liver No hepatomegaly

hypoalbuminaemia hypoalbuminaemia

anaemia anaemia

Hair dyspigmentation Emaciated look

Morphology 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.