BIOCHEMISTRY AND HUMAN NUTRITION

Module 4. Human nutrition

Lesson 30
MILK INTOLERANCE AND HYPERSENSITIVITY

30.1 Introduction

Among those over the age of five, approximately 90-95% of black individuals and 20-25% of white individuals throughout the world will have partial or complete lactose intolerance."There is a great deal of confusion between milk allergy and lactose intolerance, both adverse reactions attributable to milk. Different mechanisms cause different adverse reactions. The resulting symptoms may be quite different from or confusingly similar to each other.

30.2 Milk Intolerance

• Food intolerance is an adverse reaction to food that does not involve an immune response. Several basic mechanisms produce clinical manifestations of food intolerance. For example, the failure to digest lactose due to a deficiency of lactase leads not only to inefficient utilization of dietary lactose but also to a disordered gastrointestinal physiology.
• Metabolic or biochemical abnormalities can alter the intermediary metabolism of a substance. Inborn errors such as phenylketonuria and galactosemia have this effect and are described as follows.

30.2.1 Lactose intolerance

• Among many human populations, adults are unable to metabolize the milk sugar lactose and experience gastrointestinal disturbances if they drink milk. Lactose intolerance, or hypolactasia, is caused by a deficiency of the enzyme lactase, which cleaves lactose into glucose and galactose. (Fig. 30.1)

Fig. 30.1 Hydrolysis of lactose

• Lactose cannot be completely digested and absorbed in the small intestine and passes into the large intestine, where bacteria convert it to toxic products that cause abdominal cramps and diarrhea.
• In lactase deficient, patients lactose gets accumulated which is a good energy source for microorganisms in the colon, and they ferment it to lactic acid and generate methane (CH₄) and hydrogen gas (H₂). The gas produced creates the uncomfortable feeling of gut distention and the annoying problem of flatulence.
• The lactic acid produced by the microorganisms is osmotically active and draws water into the intestine, as does any undigested lactose, resulting in diarrhea. If severe enough, the gas and diarrhea hinder the absorption of other nutrients such as fats and proteins.
• The problem is further complicated because undigested lactose and its metabolites increase the osmolarity of the intestinal contents, favoring the retention of water in the intestine.
• In most parts of the world where lactose intolerance is prevalent, milk is not used as a food by adults, although milk products predigested with lactase are commercially available in some countries.

30.2.2 Phenylketonuria (PKU)

• PKU is an autosomal recessive metabolic genetic disorder characterized by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). This enzyme is necessary to metabolize the amino acid phenylalanine ('Phe') to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine. If, however, the condition is left untreated, it can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. In the past, PKU was treated with a low-phenylalanine diet.
• All PKU patients must adhere to a special diet low in phenylalanine. This requires severely restricting or eliminating foods high in phenylalanine, such as meat, chicken, fish, eggs, nuts, cheese, legumes, cow milk and other dairy products.

30.2.3 Galactosemia

• It is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Galactosemia is not related to and should not be confused with lactose intolerance.
• Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation. Lactose in food (such as dairy products) is broken down by the enzyme lactase into glucose and galactose. In individuals with galactosemia, the enzymes needed for further metabolism of galactose are severely diminished or missing entirely, leading to toxic levels of galactose-1-phosphate in various tissues, as in the case of classic galactosemia, resulting in hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, brain damage, and ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.
• Galactose is converted into glucose by the action of three enzymes, known as the Leloir pathway. Accordingly, there are 3 known types of Galactosemia; type 1, 2 and 3

Type-I – deficiency of enzyme Glactose-1-phosphate uridlylyl transferase
Type II –defeciency of enzyme Glactokinase
Type III –defeciency of enzyme UDP galactose epimerase

30.3 Milk Hypersensitivity

• Allergy is a hypersentivity reaction and defined as any unusual or exaggerated response to a particular substance, called an allergen, in a person sensitive to that substance.
• Allergies are the result of the reactions of the body’s immunologic processes to “foreign” substances (chemical substances in such items as foods, drugs, insect venom) or to physical conditions. The reaction is caused by an allergen, either alone or coupled with a hapten, that stimulates the production of antibodies.
• Subsequent exposure to previously sensitized antibody-producing cells may precipitate an allergic reaction. The symptoms range from sneezing to vomiting, from headaches to hives, from edema to diarrhea, and many more, some minor and some quite serious.
• These effects are believed to be due to the release of histamine by an immunologic reaction.
• Many individuals are particularly sensitive to certain foods, just as others are to pollen or other particles in the air they breathe. Some foods are more likely to produce allergic reactions than others, but practically all foods can produce an allergic reaction in some people.
• Proteins are often considered the causative agents, and undoubtedly they are in most cases, but there are some assertions in the literature that fats and even carbohydrates can be responsible.
• Many different foods have been associated with allergies. They all contain proteins, one or more of which enter the body across the intestinal epithelium and elicit an immune response; however, any major alteration in the protein such as heat denaturation usually results in the loss of its allergenic properties. For example, raw or pasteurized milk may cause an allergic reaction, but if the same milk is boiled - a process which denatures the proteins – the sensitive individual may be able to consume it without an allergic reaction.
• The foods which cause allergic reactions most frequently are milk, eggs, wheat, corn, legumes, nuts, and seafood. Also some people are allergic to strawberries and other berries, citrus fruits, tomatoes, and chocolate. Foods which rarely cause allergic reactions include rice, lamb, gelatin, peaches, pears, carrots, lettuce, and apples.
• The best treatment after the offending food or foods is identified, is to plan an adequate diet that does not contain the allergen.

30.3.1 Milk proteins as allergens

• Hypersensitivity to milk proteins is one of the main food allergies and affects mostly but not exclusively infants, while it may also persist through adulthood and can be very severe.
• Different clinical symptoms of milk allergy have been established. The diagnosis of milk allergies differs widely due to the multiplicity and degrees of symptoms, and can be achieved by skin or blood tests.
• Cow milk contains more than 20 protein allergens that can cause allergic reactions.
• Casein fractions and β-lactoglobulins (β-lg) are the most common cow milk allergens. Human milk is free of β-lg, similar to camel milk . On the contrary, β-lg is a major whey protein in cow, buffalo, sheep, goat, mare and donkey milk.
• Caseins in milk of the different species differ in fraction number, amino acid composition, and their peptide mappings. β -Casein is the major fraction in goat casein, which is similar to human casein and different from cow casein .
• Different procedures can reduce the allergenicity of cow milk proteins by heat or enzymatic treatments to some degree .
• Genetic polymorphism of milk proteins play an important role in eliciting different degree of allergic reactions. Goat milk is less allergenic than cow milk because of the absence of α-S1 casein which is typical for goat breeds.

30.3.2 Immunological mechanisms in milk allergy

• IgE-Mediated CMA (Immediate Hypersensitivity)

These are commonly mediated by a specific class of antibodies, known as immunoglobins (IgE), which are normally generated as part of immune reactions to parasitic infections, but for reasons that are partly understood can also be generated in following exposure to environmental agents, such as pollen, dusts, and foods. (Fig. 30.2)

• Non-IgE-Mediated CMA (Delayed Hypersensitivity)

These non-IgE-mediated reactions tend to be delayed, with the onset of symptoms occurring from 1 hour to several days after ingestion of milk. Hence, they are often referred to as "delayed hypersensitivity". A number of mechanisms have been implicated, including type-1 T helper cell (Th1) mediated reactions, the formation of immune complexes leading to the activation of Complement, or T-cell/mast cell/neuron interactions inducing functional changes in smooth muscle action and intestinal motility.

Fig. 30.2 Ig-E Medicated milk allergy