Food Intolerances
Biochemical and
Physiological Reactions
Characteristics of Food Intolerances
Non-immunologically-mediated reactions
 May be a result of:
 Enzyme deficiencies
 Malabsorption
 Many mechanisms imperfectly
understood

2
Characteristics of Food Intolerances

Dose-related:
 Individual limit of tolerance
 As quantity exceeds this, symptoms
increase in incidence and severity
3
Carbohydrate Intolerance





Patients complain of abdominal fullness, bloating,
and cramping within 5-30 minutes after ingesting
carbohydrate
Watery diarrhoea occurs from 5 minutes to 5
hours after ingestion
Occasionally vomiting
Excoriation of perianal skin and buttocks due to
acid (pH less than 6) stool in babies and children
Adults do not usually experience such a low stool
pH
4
Carbohydrate Intolerance:
Causes of Intestinal Symptoms

Non-hydrolysed carbohydrates (polysaccharides,
oligosaccharides and disaccharides) pass into the large
intestine causing:


Osmotic imbalance: induces a net fluid secretion into the
gut lumen resulting in loose stool
Increased bacterial fermentation resulting in production of:

Organic acids (acetic, lactic, butyric, propionic)


increase osmotic imbalance
Gases such as carbon dioxide and hydrogen

cause bloating and flatulence
5
Carbohydrate Intolerance:
Causes of Intestinal Symptoms



Increased bulk results in increased stool
volume
Increased fluid and acid environment stimulate
intestinal motility and accelerate intestinal
transit time.
Increased speed of intestinal transit results in:
loose stool since fluid is not absorbed from
food
 secondary malabsorption of fat

6
Disaccharidase Deficiency

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
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Carbohydrates are broken down by digestive enzymes
to oligosaccharides and finally disaccharides
Disaccharides are broken down by disaccharidases
produced by brush border cells in the small intestine
to monosaccharides
Monosaccharides are absorbed by active transport or
facilitated diffusion
Deficiency in disaccharidases results in
malabsorption of disaccharide which passes into large
bowel
Symptoms result from:


Changes in osmotic pressure
Fermentation by micro-organisms
7
Lactose Intolerance





Due to lactase deficiency
Lactase splits lactose into monosaccharides:
 Glucose
 Galactose
Monosaccharides absorbed by active transport
Undigested lactose moves into colon:
 Change in osmotic pressure
 Provides substrate for microbial fermentation
Results in
 Excess fluid
 Organic acids
 Gases including hydrogen
8
Types of Lactose Intolerance
Three types of lactose intolerance:
1. Congenital alactasia
 Present from birth
2. Idiopathic lactase deficiency
 Natural attrition after infancy
 Affects about 80% of the world’s adult population
3. Secondary lactase deficiency
 Results from damage to the lactase-producing
brush border cells, often as a result of intestinal
infection
 Usually temporary condition that resolves once the
infection of intestinal damage resolves
9
Tests for Lactose Intolerance
Tests require ingestion of lactose: usually 50 gm
lactose powder
 Hydrogen breath test: positive >20 ppm
 Blood glucose or galactose levels: increase indicates
negative test
 Reducing substance in stool: presence indicates
positive test (Fehlings solution changes colour from
blue to red)
 Fecal pH: low pH indicates lactose fermentation and
hence positive test
10
Management of Lactose
Intolerance

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Only the milk sugar, lactose, needs to be avoided
Milk proteins are tolerated
Lactose occurs in the whey (liquid) fraction of
milk
Milk products free from lactose and free from
whey are safe
These foods include:



Milk treated with lactase (Lactaid; Lacteeze)
Hard cheeses (whey is removed; casein remains and is
fermented to form cheese)
Many people tolerate yogurt, where lactose is broken
down by bacterial enzymes
11
Sucrase-Isomaltase Deficiency
Primary deficiency is rare: it is inherited as
an autosomal recessive gene
 Greenland and Canadian Inuit have an
unusual incidence of 10% of the population
 Appears when sucrose enters the child’s
diet, usually when fruit juice is introduced
 Severity of symptoms depends on the
quantity of sucrose in the diet
 Management: Avoidance of all sources of
sucrose

12
Fructose Intolerance



Fructose intolerance is an inability to absorb free
fructose
Intestinal fructose absorption depends on a lowaffinity transporter molecule, GLUT2 that will carry
the monosaccharides glucose, fructose and galactose
across the small intestine epithelium.
This carrier mechanism is facilitated by glucose,
which permits lower concentrations of glucose to be
taken up by the cell by an active process
13
Fructose Intolerance



Glucose is preferentially absorbed
An excess of fructose will result in inefficient
absorption of the fructose
The unabsorbed fructose moves into the large bowel
where it causes:




An increase in osmotic pressure
Net influx or reduced outflow of water
Acts as a substrate for microbial fermentation with
production of gas (especially hydrogen) and organic acids
Resulting in loose stool or frank diarrhoea
14
Fructose Intolerance:
The Problem Foods

It is usually only necessary to avoid the foods
that contain considerably more fructose than
glucose These foods include:

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Apple
Pear
Cherry
Blackcurrant
Watermelon
Honey
High fructose corn syrup
Agave syrup
15
Pharmacologic Agents in Foods

Vasoactive amines:
 Histamine
 Tyramine
 Phenylethylamine
 Octopamine
 Serotonin

Methylxanthines
 Caffeine
 Theobromine
 Theophylline
16
Pharmacologic Agents in Foods

Pharmacologic properties may be expressed in
two ways:
 Chemical reacts directly with body tissue in
a dose-dependent fashion
 Chemical reacts with a mediator system that
acts on the body tissue
17
Histamine



Histamine-mediated reactions may be
clinically indistinguishable from food
allergy
Histamine sensitivity is becoming
recognized as a disease entity quite distinct
from allergy
“Idiopathic” urticaria and angioedema is an
example of histamine sensitivity
18
Symptoms of Histamine Excess

Vasodilatation

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Hypotension:

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Flushing
Reddening
Tachycardia (Increased heart rate)
Increased vascular permeability
 urticaria (hives)
 angioedema (swelling)
 rhinitis (stuffy nose)
 rhinorrhea (runny nose)
 otitis media (earache)
19
Symptoms of Histamine Excess
continued

Pruritus (itching)

Increase in gastric secretions


Heartburn
Reflux

Headache; usually not migraine

Symptoms of anxiety; panic attack
Rarely momentary loss of consciousness
Fatigue; listlessness
Confusion



20
Other Effects of Histamine Excess


Increase in incidence and severity of
anaphylactic reactions
Increase in incidence and severity of
eczema
21
Mechanism of Histamine Sensitivity

Excess histamine is controlled by two
enzyme systems:
Histamine N-methyltransferase (HMT)
 Diamine oxidase (DAO)



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Normally DAO rapidly degrades histamine
to its inactive metabolites (imidazole
compounds) which are excreted in urine
HMT prevents prolonged binding of
histamine to its receptors
Prevents histamine-induced symptoms
22
Mechanism of Histamine Sensitivity
Symptoms develop when:
 Excessive amounts of histamine exceed
the enzymes’ capacity to break it down
 There is a lowered enzyme capacity for
histamine breakdown
 Drugs inhibit enzyme action (e.g.
isoniazid)
23
Sites of Diamine Oxidase Production

DAO produced in various tissues, especially:

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Jejunum
Ileum
Kidney
Thymus
Placenta
Many women experience relief of symptoms
of allergy and histamine sensitivity during
pregnancy
24
Sources of Histamine in Foods

Histidine can be decarboxylated to histamine
by intestinal bacteria

May develop in fish that have been
improperly processed and refrigerated,
especially:


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Tuna
Mackerel
Bonito
Bluefish
Mahi mahi]
In shellfish, where intestine is not removed
25
Sources of Histamine in Foods

Histamine is produced by microbial action in
manufacture of foods such as:

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Cheese
Fermented meats and sausages
Wine
Beers
Vinegar
Yeast extract
Sauerkraut
26
Sources of Histamine in Foods

Some foods contain high levels of histamine
naturally, especially:


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Spinach
Aubergine
Plant foods may produce histamine during the
ripening process, for example


Tomato
Cherries
27
Sources of Histamine in Foods

Some foods may release histamine by a
non-immunologically mediated mechanism
which is presently unknown. Such foods
include:

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Egg white
Strawberry
Alcohol (ethanol)
Citrus fruits
28
Other Sources of Histamine

Compounds that release histamine:
 Food


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additives, especially:
Benzoates
Tartrazine and other azo dyes
Sulphites
29
Other Extrinsic Sources of Histamine

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Microbial flora of the large bowel includes
species that synthesise histidine
decarboxylase
Microbial enzymes act on food residue
forming histamine
If diamine oxidase (DAO) in the gut is
deficient, histamine is absorbed into
circulation
When there is normal DAO activity only
1% of extrinsic histamine enters circulation
30
Tyramine sensitivity


Symptoms:
 Urticaria
 Migraine headaches
 Sharp rise in blood pressure
Due to:

Vasoconstriction induced by dietary tyramine
 Directly because of lack of tyramine breakdown in
the intestine, liver, or arterial walls
 Indirectly via secretion of epinephrine or
norepinephrine, which is normally kept at unreactive
levels by MAO-A
31
Tyramine Sensitivity:
Characteristics

Mechanism of action:
Low levels of monoamine oxidase
(MAO-A and MOA-B) enzymes


Causes of low MAOs:
Genetic predisposition
 Monoamine oxidase inhibiting drugs (e.g.
antidepressants such as Parnate; Nardil)

32
Tyramine in Foods

Formed by microbial action in food
preparation, especially:
 Cheese
 Wine
 Yeast
 Vinegar
33
Tyramine in Foods

Small amounts occur naturally in
some foods:
Chicken liver
 Avocado
 Banana
 Plum
 Tomato
 Aubergine

34
Sensitivity to Food Additives

Characteristics common to persons sensitive to
food additives:

History of asthma and rhinitis - sometimes with
urticaria and angioedema

Aspirin sensitive
35
Additives Most Frequently Causing
Intolerances

Tartrazine (and other artificial colors)

Sulphites

Preservatives:

Benzoates

Sorbates

Monosodium glutamate (MSG)

Nitrates and nitrites
36
Symptoms of Tartrazine Sensitivity

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Asthma
Urticaria
Angioedema
Nausea
Migraine headaches
Some evidence of neurological
and behavioural reactions
37
Postulated mechanisms to explain
Tartrazine Sensitivity

Inhibition of the cyclo-oxygenase
pathway of arachidonic acid
breakdown.

Histamine release from mast cells
38
Allergic Response:
Secondary Mediator Release
Arachidonic acid
Cyclo-oxygenase
PROSTAGLANDINS (PG2)
Lipoxygenase
LEUKOTRIENES
LTA4
PROSTACYCLIN (PGI2)
LTC4
LTD4
THROMBOXANE (TX)
LTB4
LTE4
39
Foods Frequently Containing Tartrazine
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Soft drinks
Liqueurs and cordials
Sweets and confectionery
Ready-to-eat cereals
Jams and jellies
Ice cream, sherbet, milk shakes
Commercial gravies and soup mixes
Flavor packets
Pickles, relish, salad dressings
Prepared baked goods
Smoked fish and fish products
40
Foods Frequently Containing
Tartrazine



Snack foods
Meal replacements
Any food containing “artificial color” may contain
tartrazine unless it is labeled “tartrazine free”
Non-food items:
 Medications (prescription and OTC)
 Vitamin and mineral supplements
 Toiletries and cosmetics
41
Sulphite Sensitivity

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Most common in asthmatics
Steroid-dependent asthmatics are most at risk
Adverse reactions to sulphites is estimated to be as high as
1% of the U.S. population
Sulphite sensitivity in non-asthmatics is considered to be
quite rare
Symptoms occur in most organ systems:
 Lungs
 Gastrointestinal tract
 Skin and mucous membranes
 Life-threatening anaphylactic reactions in asthmatics
have been recorded, but occur very rarely.
42
Symptoms Reported in Sulphite Sensitivity

Severe respiratory reactions: bronchospasm;
wheezing; “chest tightness”

Asthma in asthmatics

Flushing; “change in body temperature”

Hypotension (drop in blood pressure)

Gastrointestinal symptoms (abdominal pain,
diarrhea, nausea, vomiting)

Swallowing difficulty

Dizziness; loss of consciousness
43
Symptoms Reported in Sulphite Sensitivity

Urticaria (hives)

Angioedema (swelling, especially of the
mouth and face)

Contact dermatitis

Anaphylaxis (in asthmatics)

Anaphylactoid reaction (non-asthmatics)
44
Postulated Mechanisms to Explain Sulphite
Sensitivity
1. Sulphur dioxide is formed from sulphuric acid when
the sulphite dissolves

Acts as a direct irritant on hypersensitive airways
2. Sulphite acts as a hapten, combines with a body protein
to form a neoantigen that elicits antigen-specific IgE

Results in Type I hypersensitivity reaction
3. Enzyme deficiency:

Deficiency of sulphite oxidase system which
converts sulphite to the inert sulfate
45
Forms of Sulphites Permitted in Foods in
the UK

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E220 Sulphur dioxide
E221 Sodium sulphite
E222 Sodium hydrogen sulphite
E223 Sodium metabisulphite
E224 Potassium metabisulphite
E226 Calcium sulphite
E227 Calcium hydrogen sulphite
E228 Potassium hydrogen sulphite
E150b Caustic sulphite caramel
E150d Sulphite ammonia caramel
46
Sulphites Permitted in Foods


EU food labelling rules require pre-packed
food sold in the UK to show clearly on the
label if it contains sulphur dioxide or
sulphites at levels above 10mg per kg or
10mg per litre (or if one of its ingredients
contains it)
Non-pre-packaged foods (e.g. 'loose' foods
or foods prepared on the premises,
including take-aways and restaurant food)
are not covered by this labelling
requirement
47
Sulphite Sensitivity

Exposure to sulphiting agents poses very
little risk for individuals who are not
sensitive to sulphites

There is no evidence that avoiding all
sources of dietary sulphites improves
asthma

Sulphates do not cause the same adverse
reactions as sulphites. They are inert in the
body and need not be avoided by people
who are sensitive to sulphites
48
Sulphite Sensitivity

Sulphites in foods are not denatured by
cooking

Sulphites avidly bind to several
substances in foods, such as protein,
starch, and sugars.

Sulphites cannot be removed by washing
49
Benzoate Intolerance
Symptoms

Reported to induce:
 Urticaria
 Angioedema
 Asthma
 Rhinitis
 Purpura (allergic vasculitis)
50
Benzoates and Parabens:
Use in Foods

One of the most commonly used food additives
worldwide

Benzoic acid and sodium benzoate (benzoates) are
used as antibacterial and antimycotic agents in
foods and beverages

Benzoates are most effective as preserving agents
at an acidic pH

Benzoyl peroxide is used as a bleaching agent,
especially in white flour, white bread, and some
white Italian cheeses
51
Benzoates
Naturally occurring

Benzoates occur widely in nature as simple salts
(sodium, potassium), esters, and amides

Natural benzoates are present at the highest levels
in:

Cinnamon, Clove, Thyme, Nutmeg

Prunes

Black Tea

Berries

Especially Raspberry and Cranberry
52
Benzoates:
Mechanism of Intolerance

Mechanism of intolerance is unknown

Has been suggested to involve inhibition of the
cyclo-oxygenase pathway since a significant
number of benzoate sensitive people are also
sensitive to aspirin

There may be a similarity in sensitivity to:

Tartrazine and other azo dyes

Sorbates

Salicylates
53
Monosodium Glutamate (MSG)

Flavouring common in Chinese cooking and
increasingly used to flavour Western foods

Sensitive individuals report a variety of
symptoms that are usually classified as
“Chinese Restaurant Syndrome” (also
known as Kwok’s syndrome)
54
Most Frequently Reported Symptoms of
Sensitivity to Monosodium Glutamate

Headache, back of head and neck

Numbness of face

Tingling/burning of face and chest

Tightness in chest

Rapid heartbeat

Nausea, diarrhea, stomach ache

Weakness, balance problems

Confusion

Blurred vision

Chills, shakes, perspiration

Difficulty breathing

Asthma in asthmatics
55
MSG Sensitivity

Experts are widely divided on the subject of
MSG sensitivity

One review “led to the conclusion that
‘Chinese Restaurant Syndrome’ is an
anecdote applied to a variety of postprandial
illnesses”

Some clinicians have estimated that the
prevalence of “Chinese Restaurant
Syndrome” may be as high 1.8% of the
adult population
56
Proposed Mechanism of Action of
MSG

MSG is the sodium salt of glutamic acid

Glutamic ions are the active ingredients in MSG

Human plasma glutamate levels after a dose of
MSG (0.1 g/kg body weight) can increase to levels
greater than 15 times the basal concentration rate
in one hour

Glutamate acts as a precursor for the
neurotransmitter acetylcholine (as well as a
number of other physiological chemicals in the
body)
57
Proposed Mechanism of Action of MSG:
Acetylcholine toxicity

Acetylcholine reaches toxic levels in a very short
period of time

Acts on the brain and central nervous system

Symptoms ascribed to MSG sensitivity may be
caused by excessive levels of neurotransmitters
such as acetylcholine

However, correlation between plasma levels and
symptoms has not been shown
58
Characteristics of MSG Sensitivity

Vitamin B6 (pyridoxine) deficiency may occur in
some MSG sensitive people

Alcohol may increase the rate of absorption of
MSG and increase the severity and rate of onset of
symptoms

Symptoms usually occur about 30 minutes after
eating a meal high in MSG

Asthma occurs 1 to 2 hours after MSG ingestion,
and even as long as 12 hours later
59
Sources of MSG

Present in many flavouring mixtures:
Accent
Zest
Gourmet powder
Glutavene
Glutacyl
Chinese seasoning
Subu
Vetsin
Ajinomoto
Kombu extract
Mei-jing
Wei-jing
RL-50
Hydrolysed vegetable protein (HVP)
Hydrolysed plant protein (HPP)
“Natural flavour” (may be HVP)
60
Sources of MSG

Used as a flavouring in foods, especially in
Chinese cooking, in canned foods (e.g. soups), and
restaurant meals

Some sensitive individuals will also react to
monopotassium glutamate

Several foods, such as tomato, mushrooms, and
cheese contain natural glutamates
61
Nitrate and Nitrite Sensitivity

Nitrates and nitrites are used in foods as
preservatives

Particularly protective against Clostridium
botulinum

Impart flavour and color to manufactured foods,
especially meat
Symptoms

Reports of headache in sensitive individuals
62
Nitrates and Nitrites in Foods

Labels list sodium nitrate, potassium nitrate,
sodium nitrite, and potassium nitrite in
manufactured foods

Present at high levels in processed meats:
• Pepperoni
• Frankfurters
• Hot Dog Wieners
• Salami
• Bologna
• Other Luncheon Meats
• Bacon
• Ham
• Smoked Fish
• Some Imported Cheeses
63
Nitrates in Plant Foods

Nitrates occur naturally in plants: the major source
is nitrate-containing fertilizers

Some species of plants tend to accumulate nitrates
more than others:
• Spinach
• Celery
• Beets
• Lettuce
• Radishes
• Collards
• Turnip Greens
• Aubergine
64