Malnutrition

Topic 5

Module 5.1

Undernutrition – Simple and Stress Starvation

Lubos Sobotka
Peter Soeters
Remy Meier
Yitshal Berner

Learning Objectives

• To know how the body reacts to short-term and long-term starvation during non-stress
conditions;
• To understand the difference between simple and stress starvation;
• To know the consequences of stress on metabolic pathways related to starvation.

Contents

1. Definition and classification of malnutrition

2. Undernutrition
3. Aetiology of undernutrition
4. Adaptation to undernutrition – non stress starvation
5. Stress starvation
6. Summary

Key Messages

• Humans adapt well to short or a longer-term starvation, using their reserve stores of
carbohydrates, fat and protein;
• Reduction of energy expenditure and conservation of body protein are further reaction to
starvation. Energy stores are replenished during feeding period;
• Long-term partial or total cessation of energy intake leads to marasmic wasting;
• With the addition of the stress response, catabolism and wasting are accelerated and the
normal adaptive responses to simple starvation are overridden;
• Weight loss in either situation results in impaired mental and physical function, as well as
poorer clinical outcome.

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1. Definition and classification of malnutrition
Malnutrition can be defined as a state of nutrition in which a deficiency or excess (or imbalance) of
energy, protein and other nutrients causes measurable adverse effects on tissue/body form (body
shape, size, composition), body function and clinical outcome.
In broad term, malnutrition
includes not only protein-energy
malnutrition (both over- and under- Classification of energy and protein malnutrition
nutrition) but also malnutrition of
other nutrients, such as
micronutrients. Malnutrition
Malnutrition of micronutrients can
cause deficiency states or toxic
symptoms - these are discussed in
particular modules related to
Overnutrition Undernutrition
vitamins and trace elements.

Obesity Marasmus Kwashiorkor

or kwashiorkor-like
malnutrition
Fig. 1 Classification of
energy and protein
malnutrition

The most widely used classification of malnutrition is based on calculation of body mass index (BMI)
– see Table 1.

Table 1 Classification of malnutrition according to body mass index

(Body mass index (BMI) = weight (kg) / body height2 (m2))
Body mass index (kg/m2) Classification

Less than 18.5 Severely underweight

Less than 20 Underweight
20 to 25 Desirable or healthy range
Over 25 to 30 Overweight
Over 30 to 35 Obese (Class I)
Over 35 to 40 Obese (Class II)
Over 40 Morbidly or severely obese (Class III)

2. Undernutrition
Undernutrition can be defined as a state of nutrition deficiency, which is connected with adverse
consequences on physical functions or clinical outcome. Usually BMI < 20 kg/m2 identifies high
probability of undernutrition. However, individuals with BMI > 20 kg/m2 may be at risk of
undernutrition when losing unintentionally more than 10% weight loss over 3-6 months. In opposite
weight stable healthy individuals with a BMI < 20 kg/m2 can be without any functional changes
related to malnutrition.
Risk of undernutrition related clinical and functional problems can be predicted using nutrition
screening tool (see module 3.1).

3. Aetiology of undernutrition
Undernutrition results from an imbalance among nutrient intake and nutrient needs. The rapidity,
severity and clinical outcome of undernutrition are dependent on:
• difference between energy intake and energy expenditure;

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• nutritional status and energy reserves at the onset of the undernutrition - theoretical energy
reserves are shown in Table 2;
• extend of adaptive processes to the undernutrition;
• potential incidence of stress response (e.g. inflammation, bleeding, surgery) during a period of
undernutrition.

Table 2 The theoretical reserves of a 74 kg man although survival is unusual

when fat content is reduced below 3 kg and protein is depleted by more than
50% (Hill 1992)
Body substrate Substrate weight Energy content
( kg ) ( kcal )

Fat 15 141.000
Protein 12 48.000
Glycogen (muscle) 0.5 2000

Glycogen (liver) 0.2 800

Glucose (extracellular fluid) 0.02 80

Total 191.880

The main factors that lead to undernutrition are:

• disease;
• social and psychosocial factors.

Disease-related factors which lead to undernutrition

• insufficient food/nutrient intake (anorexia, taste disturbances, nausea, vomiting, treatment-
induced side effects, eating and swallowing difficulties);
• impaired nutrient digestion and absorption (especially in gastrointestinal diseases);
• increased requirements for nutrients (sepsis, trauma, endocrine disease);
• increased losses (e.g. from wounds, malabsorption and intestinal losses);
• catabolism.

Social and psychological factors which lead to undernutrition

• problems with shopping or preparing meals;
• anxiety;
• depression;
• poverty;
• lack of suitable or enjoyable food;
• environmental factors (nursing homes etc.);
• inadequate catering practices;
• anorexia nervosa;
• hunger strikers.

Metabolic consequences of undernutrition are dependent on clinical conditions (adaptive changes of

presence of stress, sepsis or critical illness).

4. Adaptation to undernutrition – non-stress starvation

Development of adaptive mechanisms to food shortage was necessary for survival of famine periods.
These adaptive changes allow to healthy subjects of normal initial body composition to survive more
than two months of total starvation.

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Short starvation (< 72 hours)
Short period of starvation is connected with:
• diminished insulin and increased glucagon and catecholamine secretions;
• increased glycogenolysis and lipolysis;
• hydrolysis of triglycerides in adipose tissue releases fatty acids (FFAs) and glycerol into the
circulation;
• increased gluconeogenesis from amino acids after depletion of glycogen stores.

Uncomplicated fasting (12-24 hours)

periphery

glucose glucose
140 g 100-
100-200 g
FA +
glycerol
gluconeo- glycogen
AA 75 g genesis

liver
fat
FA 40 g +
glycerol Fig. 2 Metabolic fluxes during
short term simple starvation
(non stress conditions).

Prolonged starvation (> 72 hours)

Beyond 72 hours starvation is connected with:
• further decrease in insulin level;
• glycogen stores depletion;
• reduction of energy expenditure related to physical activity;
• decline in resting metabolic rate by 10-15%;
• increased β-oxidation of fatty acids;
• increased production of ketone bodies in the liver;
• adaptation of the brain to using ketones as energy fuel;
• reduction in net tissue protein catabolism.

During simple starvation albumin concentration is unchanged, although plasma proteins with a
shorter half-life may be decreased.

Uncomplicated fasting (7 days)

periphery

ketone ketone
glucose bodies +
bodies
60 g glucose
66 g
FA +
glycerol
AA 20 g ketogenesis
gluconeo-
genesis
liver 100 g FA + fat Fig. 3 Metabolic fluxes during
glycerol
long term simple starvation (non
stress conditions).

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The modifications in metabolic processes during short and long term starvation are described in the
figure below.

Short term starvation (< 72 hours) Prolonged starvation (> 72 hours)

↑↑ Glycogenolysis Depleted glycogen stores

Glucose oxidation ↓ ↓ Glucose oxidation

↑ Lipolysis ↑↑↑ Lipolysis

↓ ↓

Ketogenesis ↑↑↑ Ketogenesis in liver

↑↑↑ Net protein catabolism ↑ Net protein catabolism

Energy expenditure
↓ Energy expenditure
transiently elevated

Fig. 4 The difference between metabolic reactions of short-term and long-term starvation.

5. Stress starvation
The reaction to starvation is altered during stress conditions like:
• burns;
• necrosis (acute pancreatitis, ischemic necrosis);
• severe infection and sepsis;
• penetrating and blunt injury;
• the presence of tumour cells;
• radiation;
• exposure to allergens;
• the presence of chronic inflammatory diseases;
• environmental pollutants.

In these situations, the normal adaptive responses of simple starvation, which conserve body
protein, are over-ridden by the cytokine and neuroendocrine effects of injury (Fig. 5, Fig. 6).

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 Raised blood lipids Fever Glucose synthesis

Effects of
cytokines TNF, Plasma copper
Production of
IL1 and IL6,
oxidant molecules Plasma Zn
during injury
and infection Plasma iron

Acute phase
proteins Appetite loss Loss of lean
and lethargy tissue and fat

Fig. 5 Effects of pro-inflammatory cytokines in infection, injury and inflammatory disease TNF-
Tumour necrosis factor, IL1- interleukin 1, IL6 – interleukin 6.

Proteolysis in peripheral
Gluconeogenesis tissues
Negative nitrogen balance
Neuroendocrine
stress response
Increased REE

Mobilisation of substrates
glucose/glutamine/fatty acids
Fluid retention
Insulin and GH
resistance

Fig. 6 Effects of the neuroendocrine stress response.

As a result of cytokine and neuroendocrine reaction to stress the metabolic rate raises rather than
falls, ketosis is minimal, protein catabolism accelerates to meet the demands for tissue repair and
of gluconeogenesis and there is hyperglycaemia and glucose intolerance. Salt and water retention is
exacerbated and this may result in a kwashiorkor-like state with oedema and hypoalbuminaemia
(Table 3). The latter may also be exacerbated by protein deficiency.

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Table 3 Simple versus stress starvation
Simple starvation (> 72 h) Stress starvation

Metabolic rate ↓ ↑

Protein catabolism (relatively) ↓ ↑

Protein synthesis (relatively) ↓ ↑

Protein turnover ↓ ↑

Nitrogen balance ↓ ↓↓

Gluconeogenesis ↓ ↑

Ketosis ↑↑ -

Glucose turnover ↓ ↑

Blood glucose ↓ ↑

Salt and water retention ↑ ↑↑↑

Plasma albumin - ↓↓

Carbohydrate metabolism
Stress initiates a strong increase in endogenous glucose production and turnover. Glucose is an
indispensable substrate in this respect because part of the glucose breakdown (glycolysis) does not
require oxygen, while still furnishing energy. Lactate as result of anaerobic glucose metabolism is
important precursor of gluconeogenesis in liver (Cori cycle). Glucose metabolism during prolonged
starvation and stress reaction is shown in Table 4.

Table 4 Glucose metabolism during starvation and critical illness

Postprandial state Prolonged starvation Stress reaction

Gluconeogenesis Ð Ï ÏÏÏ

Glycolysis Ï Ð ÏÏÏ

Glucose oxidation ÏÏÏ Ð Ð

Glucose cycling Ï Ð ÏÏÏ

Protein and amino acid metabolism

Amino acids are, together with glycerol, the main substrates for „de novo” glucose production in
the liver. Moreover, particular amino acids, such as glutamine and branched-chain amino acids
(BCAA), are the only substrates that can be utilized in some peripheral or wounded tissues as a
source of energy and nitrogen. Muscle amino acids are also used for the synthesis of acute phase
proteins, albumin, fibrinogen etc. The degree of protein catabolism in sepsis is large which can
reach a daily loss of more than 1 kg of muscle tissue (Table 5).

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Table 5 Protein metabolism during starvation and critical illness
Postprandial state Prolonged starvation Stress reaction

Proteolysis Ð Ð ÏÏÏ

Proteosynthesis Ï Ð ÏÏ

Amino acid oxidation Ï Ð ÏÏÏ

Lipid metabolism
Accelerated rate of lipolysis is part of the metabolic response to severe illness, the resulting fatty
acid release can exceed energy requirements. Part of these fatty acids is oxidized and the
remainder is re-esterified to triglycerides. Ketogenesis is suppressed during critical illness combined
with starvation (Table 6).

Table 6 Lipid metabolism during starvation and a critical illness

Postprandial state Prolonged starvation Stress reaction

Lipolysis in fat tissue ÐÐ ÏÏÏ ÏÏ

Lipid oxidation Ð ÏÏÏ Ï

Ketogenesis ÐÐ ÏÏÏ Ï

Fatty acids –
− Ð ÏÏ
triglyceride cycling

Quantitative aspects of metabolic fluxes during stress starvation are shown in Fig. 7.

Stress fasting

periphery

glucose
glucose ischemic
200 g
140 g
tissue
glyco-
keto- gen lactate
AA 250 g gluconeo- genesis
genesis
liver
FA 20 g + fat
glycerol
Fig. 7 Metabolic fluxes during
stress starvation

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6. Summary
Humans adapt well to short or a longer-term starvation, using their reserve stores of carbohydrates,
fat and protein. Reduction of energy expenditure and conservation of body protein are further
reaction to starvation. Energy stores are replenished during feeding period. Long-term partial or
total cessation of energy intake leads to marasmic wasting.
With the addition of the stress response, catabolism and wasting are accelerated and the normal
adaptive responses to simple starvation are overridden. Weight loss in either situation results in
impaired mental and physical function, as well as poorer clinical outcome.
Previously malnourished subjects have fewer reserves with which to face an acute illness. They are
unable to release sufficient amounts of endogenous nitrogen in response to trauma and infection
with subsequent higher mortality, more complications and prolonged recovery. If surgery is planned
in these patients nutritional support improves physiological functions and lessens surgical risk.

References

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