LECTURE 25
MALNUTRITION and DISEASE
MAMMALIAN PATHOBIOLOGY
PATB 4130 / 5130
In affluent nations, we seldom stop to think about malnutrition as a significant cause of
morbidity and mortality or, if we stop to ponder even briefly, believe that this is mainly a problem
of impoverished or third world nations. There is a need to view malnutrition in a broader context.
The purpose of this lecture will be to acquaint you with some of these broad concepts and to cover
specific diseases, some prevalent as well as those that are uncommon, associated with malnutrition.
HOW DOES FAULTY NUTRITION DEVELOP? (slides 2-8)
Malnutrition can be either primary or secondary. Primary malnutrition is a situation in
which all or many key nutrients are lacking in the diet (this is basically starvation) or in which the
diet is deficient in specific nutrients. Secondary malnutrition, on the other hand, can be related to
a variety of underlying causes:
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Nutrients are present in adequate amounts and readily available but appetite is
suppressed. The failure to eat despite plenty of available food is termed inanition or
anorexia.
Nutrients are present in adequate amounts, readily available, and intake is adequate but
absorption and utilization are inadequate. There are a variety of these conditions and
some of these will be covered later in this lecture.
Nutrients are present in adequate amounts, readily available, intake is adequate, and the
body is able to absorb and utilize the food but there is increased demand for specific
nutrients to meet physiological needs. Again, there are a variety of these conditions
including prolonged extremes of cold weather, pregnancy, lactation, etc.
Protein-Calorie Undernutrition
(Protein-energy Malnutrition)
Primary protein-calorie undernutrition, simply put, is starvation in its truest sense.
Although the name would imply that this form of malnutrition is related to deficiency of protein and
carbohydrates in the diet, the deficiencies of available nutrients commonly include necessary
vitamins, minerals, and other food stuffs. Malnutrition is seldom simple. Additionally, concurrent
disease is common and definitely a complicating factor. This form of malnutrition occurs in animals
as well as humans. Obviously, primary protein-calorie undernutrition is a disease found mainly in
impoverished third world countries. It also occurs, however, in the very poor and elderly in
industrialized nations. It is estimated that 500 million suffer from mild to severe primary proteincalorie undernutrition worldwide. Estimates further suggest that 10 million individuals, mainly
children, die annually (slide 4). Kwashiokor and marasmus represent two extremes that are all too
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common in the news media. Kwashiorkor is due to a critical lack of protein in the diet despite
adequate caloric intake. This occurs when a newborn begins breastfeeding and an older child is
weaned and forced to subsist on a diet composed almost entirely of carbohydrates. Clinical signs
include apathy, subcutaneous edema, ascites, an enlarged fatty liver, hypoalbuminemia plus a host
of other abnormalities. What would be the possible pathogenesis of edema and ascites (lecture 11)
and the enlarged fatty liver (lecture 10) in these cases? In marasmus, there is a deficiency of both
protein and carbohydrates in the diet. There is no edema or enlarged liver as in the strict marasmus
syndrome. These children are bright and alert but with marked atrophy of skeletal muscle mass,
stunted growth, and other abnormalities. As mentioned, these are the two extremes; many cases
occur that overlap and the syndromes typically represent a continuum. In domestic animals, primary
protein-calorie undernutrition commonly occurs under conditions where the animals are totally
dependent on their owners to provide proper nutrition. Either from negligence, ignorance, and
misinformation or economic hardship, proper nutrition is not provided to these animals. In both
humans and animals, recovery is generally possible once proper nutrition is re-established except in
the most advanced cases.
Secondary protein-calorie undernutrition occurs despite availability of a proper diet (slide
5). As noted previously, this can occur from basically three main mechanisms. Examples of
decreased intake include poor dentition, dysphagia, and systemic diseases that lead to poor
appetite. Dysphagia means difficult swallowing. Impairment of cranial nerve functions that control
swallowing, space occupying masses and mechanical injuries are all disorders that can lead to
dysphagia. In horses, dysphagia and starvation are the cause of death in a disease known as
nigropallidalencephalomalacia. This disease is due to ingestion of plants (Russian knapweed and
yellow star thistle) that damage the brain. Cancer, as well as various cancer treatments, suppresses
appetite often leading to a catabolic (wasting) state or cachexia. The inability to absorb nutrients
(malabsorption) or faulty utilization of nutrients absorbed from the gut is another fairly common
cause of secondary protein-calorie undernutrition. A variety of underlying disease states can lead to
malabsorption or inadequate utilization of nutrients. Inflammatory diseases of the bowel,
hepatobiliary and pancreatic disease and intestinal parasitism are exemplary. Lastly are the factors
that increase requirements for nutrients. The requirements for growth in the young differ from
adult maintenance. Pregnancy and lactation increase the overall requirements for protein and
energy. In lecture 8, ruminant ketosis was mentioned. In high producing dairy cows, the demands of
lactation and late term pregnancy create a condition of negative energy balance. The affected cows
lose body weight accompanied by a drop in milk production. Eventually, the lower body weight and
decreased milk production re-establish a new equilibrium with available energy but by this time
there is a loss of production.
Yes, starvation or protein-calorie undernutrition does occur in animals (slide 6). In domestic
animals, the possible implications are allegations of animal neglect or animal cruelty. At the
diagnostic laboratory and certainly in clinical practice, disease diagnosticians and practicing
veterinarians are often called upon to determine whether or not starvation is primary or secondary;
usually a process of eliminating all possible secondary causes of malnutrition (slides 7 & 8).
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Malnutrition Involving Specific Nutrients (slides 9-33)
In this portion of the lecture, we will shift the focus from starvation to deficiencies of
specific nutrients. As with starvation, deficiencies of specific nutrients can be primary or secondary.
How would you develop an understanding of malnutrition involving specific nutrients as a causative
factor in disease? Can Koch’s postulates (lecture 3) be generally applied to nutritional disease? A
good starting point would be a basic understanding of the role specific nutrients such as vitamins
and minerals play in biochemical and metabolic pathways. What is their function and how do they
relate to other nutrients? This knowledge can suggest potential mechanisms in the pathogenesis of
disease related to specific nutritional deficiencies. Even with this knowledge of metabolic functions,
it can be difficult to correlate the possible mechanisms with specific lesions or disorders. In some
instances, specific nutritional deficiencies become more complex involving other nutrients,
intermediates in biochemical pathways, or other factors.
Take for example vitamin B12 (cyancobalamin) deficiency (slide 12). This vitamin is an
essential dietary nutrient in humans. Vitamin B12 in the diet comes almost exclusively from
microorganisms. Food from animal sources is seldom totally sterile. Plants/vegetables, on the other
hand, are not a good source of this vitamin. Sometimes a deficiency of vitamin B12 can be primary;
it is not present in sufficient quantities in the diet. More often, the deficiency is secondary;
malabsorption of vitamin B12 is a more likely cause. Intestinal parasitism and diverse diseases of the
lower small intestine can lead to malabsorption. Another cause of malabsorption relates to disease
of the stomach. Parietal epithelial cells of the gastric mucosa secrete hydrochloric acid as well as a
protein known as intrinsic factor. This protein binds vitamin B12 and the bound intrinsic factorvitamin complex is required for absorption from the intestine. Gastrectomy results in a deficiency of
intrinsic factor. Another disease, chronic atrophic gastritis, results in inflammatory (autoimmune)
destruction of parietal epithelial cells, a deficiency of intrinsic factor, and malabsorption of vitamin
B12 from the small intestine. Now, how do we link vitamin B12 deficiency with disease? There are
only two well recognized biochemical reactions that require vitamin B12. In short, one is a
methylation reaction involving vitamin B12 as the cofactor for a methytransferase required to
synthesize folic acid. Folic acid, the end product, is required for DNA synthesis. The second
biochemical reaction is conversion of methylmalomyl-CoA to succinyl-CoA. Disruption of this
reaction results in accumulation of methylmalonic acid and lack of succinyl-CoA; the end result is
believed to be defective formation of fatty acids and damage to neuronal membranes such as
myelin. Diseases associated with vitamin B12 deficiency are pernicious anemia and a neurological
disorder known as subacute combined degeneration of the spinal cord.
Examples of Disease Associated with Specific Nutritional Deficiencies (slides 13-33)
For this portion of the lecture, two specific deficiencies have been selected as examples and
both are associated with diseases in humans and animals; one a mineral (copper) and the other a
vitamin (B1, thiamine).
Copper deficiency. Copper has diverse functions and is involved as a co-factor for many critical
enzymatic reactions. Ceruloplasmin listed below deserves some additional clarification.
Ceruloplasmin is the main copper-carrying protein in blood. Ceruloplasmin, sometimes referred to
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as ferroxidase, does have enzymatic properties and can catalyze the oxidation of Fe2+ to Fe3+
necessary for heme synthesis.
FUNCTION
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Energy production
Connective tissue integrity
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Heme synthesis
Neurotransmission
Myelin formation
Formation of melanin pigment
Antioxidants
ENZYME
Cytochrome C oxidase
Lysyl oxidase (collagen)
Ascorbate oxidase (bone)
Ceruloplasmin (ferroxidase)
Monoamine oxidase
Cytochrome C oxidase
Tyrosinase
Cu,Zn superoxide dismutase
From these different functions, it can be readily appreciated that copper is a key element in
the body and deficiency can be potentially associated with diverse clinical manifestations.
Deficiencies of copper can be either primary or secondary (slide 15).
In humans, copper deficiency is often secondary. One form of the deficiency is inherited as
an X-linked recessive trait and is known as Menkes Disease or Menkes kinky-hair syndrome first
characterized in 1962. Absorption by the intestinal epithelial cells seems adequate but transport of
copper to other tissues is deficient due to a defective copper-transporting ATPase. Clinical findings
reflect the diverse functions of copper in the body (slide 17) and begin early in life. Other
syndromes in humans associated with copper deficiency include a degenerative myelopathy similar
to the disease in sheep and goats to be described below (see slide 22). One form of the disease due
to degeneration of motor neurons in the spinal cord has a late onset and at least some cases have
been linked to overzealous supplementation with zinc.
In animals, copper deficiency is mainly a disease of ruminants and can be either primary or
secondary. Primary deficiency occurs in areas with copper deficient soils resulting in forage or grass
deficient in copper. Secondary deficiency is due to antagonism by other minerals in the diet
including molybdenum, zinc, and sulfates. Historically, copper deficiency has been associated with
several syndromes or abnormalities (slide 19).
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Falling disease of cattle is a syndrome of sudden death due to heart failure. Although
difficult to prove, the disorder has been associated with low copper. Hypothetically, the
cardiac failure has been attributed to lack of energy production due to reduced
cytochrome C oxidase activity.
Aneurysms are areas of weakness in the walls of arteries that result in saccular dilations
and the potential for rupture (slide 20). The weakness is attributed to reduced lysyl
oxidase activity necessary for cross-linking and stabilization of collagen and elastin. What
other disease has been mentioned in this class that is associated with aneurysms (see
Lecture 3, Marfan syndrome)?
Abnormal bone formation is attributable to ascorbate oxidase activity.
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Hair abnormalities include brittle, kinky, lightly pigmented hair (slide 21). What
enzymes would likely be involved in this effect?
Abnormal pigmentation in animals is typically most notable as a lighter pigmented hair
coat.
Enzootic ataxia / swayback is a disease of lambs and goat kids (slides 22, 23). The
disease can occur in a more severe congenital form with clinical signs at the time of birth
(swayback) or onset can be delayed until later in life up to six months of age (enzootic
ataxia). Analogies can be made between these CNS lesions (especially swayback) and
Menkes kinky hair disease in humans. Degeneration of motor neurons in the spinal cord
in lambs and kids has similarities with some forms of late onset copper deficiency in
humans as well as amyotrophic lateral sclerosis. Linkage to specific copper-associated
enzymes has not been done in animals. Possibilities include cytochrome C oxidase and
Cu,Zn-superoxide dismutase. Of interest, Cu,Zn-superoxide dismutase abnormalities have
been linked to some forms of amyotrophic lateral sclerosis.
Thiamine (vitamin B1) deficiency. Humans and carnivorous animals have an absolute dietary
requirement for thiamine. Very little thiamine is stored in the body. It is estimated that adult humans
require about 0.33 mg thiamine for each 1,000 kcal of energy consumed. Thiamine producing
bacteria in the rumen and gut of herbivores synthesize thiamine and there is no absolute or only a
minimal dietary requirement in these animals. The table below illustrates the thiamine content of
various foods.
Food
Serving
Thiamin (mg)
Lentils (cooked)
1/2 cup
0.17
Peas (cooked)
1/2 cup
0.21
Long grain brown rice (cooked)
1 cup
0.19
Long grain white rice, enriched (cooked)
1 cup
0.26
Long grain white rice, unenriched (cooked)
1 cup
0.04
Whole wheat bread
1 slice
0.10
White bread, enriched
1 slice
0.11
Fortified breakfast cereal
1 cup
0.5-2.0
Wheat germ breakfast cereal
1 cup
4.47
Pork, lean (cooked)
3 ounces*
0.72
Brazil nuts
1 ounce
0.18
Pecans
1 ounce
0.19
Spinach (cooked)
1/2 cup
0.09
Orange
1 fruit
0.10
Cantaloupe
1/2 fruit
0.11
Milk
1 cup
0.10
Egg (cooked)
1 large
0.03
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Thiamine is a coenzyme in three metabolic pathways (see slide 26):
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Transketolase – pentose phosphate pathway
Pyruvate dehydrogenase – glycolytic pathway
α-ketoglutarate dehydrogenase – citric acid cycle
Deficiency of thiamine can deprive the body of high energy phosphates, important intermediates for
other metabolic needs, certain neurotransmitters, and other compounds.
Thiamine deficiency in humans can be either primary or secondary. Inadequate intake is the main
cause in third world countries and low-income households where diets are high in carbohydrates
and low in thiamine such as milled or polished rice. Inadequate intake is also seen in about 80% of
chronic alcoholics and alcoholism is the major cause in developed countries. Only a relatively small
percentage of chronic alcoholics will develop clinical disease related to thiamine deficiency,
however, suggesting other factors may be involved. Although not universally accepted, some
studies have indicated that the transketolase enzyme in the clinically affected alcoholics binds
thiamine with less avidity than in other individuals. There are diverse causes of secondary thiamine
deficiency. An increased requirement is associated with pregnancy, lactation, hyperthyroidism,
increased physical activity and others. Malabsorption occurs in chronic intestinal disease and in
alcoholics (in addition to poor intake). Anti-thiamine factors in the diet include consumption of
large amounts of tea and coffee and foods with thiaminase enzymes such as raw shellfish,
freshwater fish, and some ferns.
All cells in the body typically have a requirement for thiamine but clinical disease in humans
associated with deficiency typically affects the heart (wet beriberi), peripheral nerves (dry beriberi),
and brain (Wernicke’s encephalopathy – Korsakoff psychosis; Wernicke-Korsakoff syndrome).
Overlap between these syndromes can occur.
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Wet beriberi is characteristically a syndrome of congestive heart failure. Clinical signs are
tachycardia, cardiomegaly, edema (giving this form of beriberi the name “wet”), and
dyspnea. What would be the mechanisms of edema?
Dry beriberi is a disease of the peripheral nerves. Here, sensory (“burning feet syndrome”)
and motor (muscle weakness) nerves as well as reflexes (often exaggerated) are affected.
Initially there is loss of myelin sheaths (demyelination) progressing to axonal degeneration.
Wernicke’s encephalopathy is a fairly acute syndrome involving degeneration in multiple
discrete areas of the brain (slides 28 and 29). In these brain areas, there are hemorrhage,
edema, vascular congestion and prominence, and preservation of neurons at least during
the early stages. Korsakoff psychosis accompanies most cases of Wernicke’s
encephalopathy. In this neuropsychiatric disorder memory deficits, involving recent
memory most severely, are characteristic.
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Thiamine deficiency in carnivores. Deficiency in carnivores (also called Chastek’s paralysis) is
typically due to feeding raw fish containing thiaminase enzymes or to destruction of thiamine in
feedstuffs by heating to over 100 degrees F. Thiamine is also destroyed by treating meat with sulfur
dioxide to preserve freshness. Cases have been reported in dogs, cats, mink, and foxes. The lesions
of the disease are very similar to Wernicke’s encephalopathy (slide 30).
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Thiamine deficiency in herbivores (ruminants). Thiamine deficiency in ruminants is enigmatic. As
mentioned previously, ruminants have no absolute dietary requirement and the lesions we regard as
related in some way to thiamine preferentially involve the cerebral cortex of the brain
(polioencephalomalacia) (slides 31, 33) rather than the brain stem as in Wernicke’s
encephalopathy and Chastek’s paralysis. In some scenarios, thiamine deficiency can be predicted
(slide 32). One is the ingestion of thiaminase-containing plants such as brackenfern. Probably one
of the more common causes is acidosis due to overconsumption of grain-based concentrated
rations. In this case, the drop in rumen pH results in the loss of thiamine-producing bacteria and an
overgrowth of bacteria producing thiaminase. Still another is the use of the coccidiostat
amprolium, Amprolium is a structural analog of thiamine. Other causes are somewhat more
difficult to reconcile with an absolute thiamine deficiency. These include deficiencies of cobalt,
diets high in sulfur, molasses-urea based rations, and consumption of plants such as Kochia
scoparia. The latter two may contain high sulfur. It is known that certain sulfur compounds can
destroy thiamine but the pathogenesis of the lesions in these cases as they relate to overt deficiency
is still debated. Clearly, the lesions are different from those seen in Wernicke’s encephalopathy and
Chastek’s paralysis. No matter the cause, in early cases there may be a good treatment response to
the administration of thiamine.
Overnutrition – Obesity (slides 34 – 39)
If a little is good, more is better, CORRECT? No, not when it comes to nutrition. In past
lectures, at least two diseases have been mentioned that are due to faulty nutrition but this time, the
diseases are due to ‘too much’ in the diet. Can you name these? How about too much phosphorus or
1,25-dihydroxycholecalciferol (see lecture 11). To wrap up this lecture, the form of malnutrition
rampant in the United States and some other industrialized nations will be briefly covered –
OBESITY.
Obviously, despite the importance, it will not be possible to cover this subject in depth. The
body mass index, a general measure of obesity, is the subjects weight divided by the square of the
height.
BMI = weight (kg or lbs) / height (m2 or in2)
A body mass index of 18.5 to 24.9 is considered normal. A BMI of > 40 is considered severely
obese.
The significance of obesity lies largely as a risk factor for the development of some serious
diseases. Virtually every organ system might be affected in some way or another by obesity.
Although there is still debate, diseases that may or are likely related to obesity include:
Ischemic heart disease (heart attack)
Hypertension
Renal disease
Diabetes mellitus
Stroke
Certain forms of cancer
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Although the adverse health effects of obesity are accepted and supported by medical
science, somewhat surprisingly, some overweight individuals seem to fair better than lean people
experiencing certain medical conditions. This contradiction was first described in 1999 in patients
undergoing hemodialysis and is called the obesity survival paradox. Since, the paradox has been
described in patients with other diseases.
The proposed causes and risk factors for obesity are varied and in at least some cases,
obesity is multifactorial. Diet, physical activity, genetics, underlying disease, environment and
others likely contribute.
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Kcal intake in the diet > Kcal burned is the #1 cause of obesity. Availability of
foodstuffs, diet, and more sedentary lifestyles are the main culprit. Too much food, too
little physical activity.
Genetics and neurobiological mechanisms. Studies of twins separated at birth provide
pretty good evidence that there is a genetic component. The children of overweight parents
tend to become obese even if adopted into a family with normal body weight or BMI.
There are a few rare hereditary syndromes associated with obesity including Prader-Willi
syndrome in humans and leptin receptor mutations in a mouse model of diabetes. A
variety of hormones or hormone-like substances have been discovered in recent years that
act on neurons in the hypothalamus that control appetite and metabolism and that have a
variety of other functions. Leptin, produced mainly by adipose tissue suppresses appetite
and probably is the most important long term regulator of the body’s fat stores.
Paradoxically, obese individuals typically have high circulating leptin levels. These
individuals may have developed a resistance to leptin and/or neural control mechanisms
regulating satiety may be flawed. Ghrelin is produced by cells in the stomach and
pancreas and stimulates appetite. Levels in blood are high prior to meals and drop after
food intake. Orexins (also called hypocretins) are produced by neurons in the
hypothalamus. Orexins stimulate food intake and orexin-producing neurons are inhibited
by leptin. Adiponectin is produced by adipose tissue and its actions are complementary to
leptin. Adiponectin activity may, however, be more importantly related to insulin and
glucose and fatty acid metabolism.
Medical and psychiatric illnesses. Some diseases such as hypothyroidism and psychiatric
disorders may increase the risk of obesity but obesity is not invariably a consequence.
Obesity is not regarded as a psychiatric disorder. Additionally, certain drugs used to treat
medical psychiatric illnesses may be associated with weight gain.
Socioeconomic status. Some studies have suggested that there is a correlation between
socioeconomic status and obesity but there is great diversity throughout the world.
Wealthy individuals can typically afford a balanced, more nutritious diet and may be more
cognizant of social pressures to be lean and fit. In contrast, individuals in higher social
classes in the developing world have higher rates of obesity.
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