Metabolic and nutritional disorders

Question 1

What are the major nutrients required for proper development and growth?

Answer 1

• macronutrients (fat, carbohydrate and protein)
• micronutrients (vitamins and minerals; essential amino acids and fatty acids)
• water

Question 2

Describe genetically determined errors of metabolism

Answer 2

Metabolic disorder
- generally associated with specific enzyme deficiencies and result in blockage of amino acid, carbohydrate, or lipid metabolism, with reduction of some substances and accumulation of others.
- carrier state can be identified to permit genetic counselling in many disorders by testing of amniotic fluid before birth or appropriate screening at birth
- disorders seldom occur
- many are characterized by autosomal recessive transmission (often chromosome of defective gene has been determined)
- functional and pathological damage may be produced by: loss of end product of a reaction due to enzyme deficiency, accumulation of substances prior to the metabolic block or production of toxic metabolites.

Question 3

What is Phenylketonuria (PKU)?

Answer 3

• disorder of amino acid metabolism in which the enzyme responsible for the conversion of phenylalanine to tyrosine is deficient.
• results in increased blood levels of phenylalanine - impairs normal brain development - and increased urinary excretion of phenylpyruvic acid
• within the brain there is hypomyelination, gliosis and microcephaly. No lysosomal storage in neurons

Question 4

What are the clinical features of PKU

Answer 4

• severe mental retardation, seizures, and hyperactivity as well as decreased pigmentation of the hair and skin (due to decreased melanin production from tyrosine)
• women with PKU can be normal with treatment - it is imparative that treatment continue during pregnancy (prior to conception). If not children born are profoundly mentally retarded and have multiple congenital anomalies.

Question 5

What is the treatment of PKU?

Answer 5

Restriction of phenylalanine in diet and supplementation with tyrosine.
- newborns are screened (Guthrie- test-serum analysis)

Question 6

What is Galactosemia?

Answer 6

• disorder of carbohydrate metabolism. Deficiency of galactose-1-phospphate uridyl transferase leads to accumulation of galactose-1-phosphate and galactosuria and hypergalactosemia.
• normally this enzyme takes part in one of the steps in which galactose is converted to glucose

Question 7

What are the clinical features, and diagnosis of galactosemia?

Answer 7

• jaundice, liver damage (fatty change, widespread scarring, hepatomegaly), cataracts, neural damage (nerve cell loss, gliosis, edema).
• accumulation of galactose in the kidney impairs amino acid transport resulting in aminoaciduria.
• without appropriate dietary therapy (i.e. removal of galactose from the diet), long term complications such as cataracts, speech and neurological deficits and mental retardation occur in older children.
• diagnosis can be established by assay of transferase in white or red blood cells; antenatal diagnosis is possible by enzyme assays or DNA analysis.

Question 8

What is lysosomal storage disease?

Answer 8

• normally lysosomes contain hydrolytic enzymes that are involved in the breakdown of complex substrates
• a lack of lysosomal enzymes, means catabolism of the substrate remains incomplete leading to accumulation of partially degraded insoluble metabolites within the lysosomes.
• over 40 lysosomal storage diseases have been identified (but they are rare)
• can be classified based on the underlying metabolic defect: primary lysosomal hydrolase defect, post-translation processing defect of lysosomal enzymes, and transmembrane protein defects.
• clinical expression is variable when infants and children are affected, progressive mental and motor deteriorate and death is the usual pattern. Many variants tho which have milder forms with adult onset.

Question 9

What is Tay-Sachs disease (GM2 gangliosidosis)?

Answer 9

• accumulation of gangliosides within the brain as a result of the catabolic enzyme defect - deficiency in the a subunit of hexoaminidase A, necessary for the degradation of GM2.
• affected cells appear swollen or ‘foamy’ with lipid vacuolation
• most common among Ashkenazi Jews (heterozygous carriers = 1 in 30).
• in most common variant, infants appear normal at birth but motor weakness begins to develop at 3-6 months of age, followed by mental retardation, blindness and severe neurologic dysfunction. Death occurs within 2-3 years

Question 10

What is Niemann-Pick disease? Types A and B

Answer 10

Characterized by a primary deficiency of acid sphingomyelinase and the accumulation of sphingomyelin.
1. Type A: breakdown of sphingomyelin into ceramide and phosphorylcholine is impaired and excess sphingomyelin accumulates in phagocytic cells and neurons. This variant manifests itself in infancy with massive visceromegaly and severe neurological deterioration. Death usually occurs within the first 3 years.
- organs most severely affected are the spleen, liver, bone marrow, lymph nodes, and lungs.
- CNS is involved and affected neurons are enlarged and vacuolated as a result of the storage of lipids.
2. Type B: have organomegaly but no neurologic symptoms.
- estimation of sphingomyelinase activity in leukocytes or cultured fibroblast can be used for diagnosis of suspected cases as well as carriers; antenatal diagnosis is possible by enzyme assays or DNA analysis.

Question 11

Describe acquired metabolic disorders

Answer 11

Largely due to lifestyle and unhealthy dietary habits (atherosclerosis, obesity and diabetes), exposure to environmental or industrial pollutants or toxins (e.g. carbon monoxide, cyanide, carbon disulphide), or they may be secondary to derangements of renal or liver diseases.
- those associated with hypoxia are the most common. in most cases the underlying cause of hypoxia and ischemia is related to the presence of atherosclerotic plaques in large and medium-sized arteries.

Question 12

What is Atherosclerosis?

Answer 12

Begins early in life but usually remains clinically silent until it has progressed to the point where it results in disease. The earliest pathological lesion, called a fatty streak, can be found in teenagers. Some of these slowly progress and develop into the mature atherosclerotic lesion, the fibro-fatty plaque which narrows the vessel lumen.
- major modifiable risks for atherosclerosis are:
1. hypertension
2. hyperlipidemia (hypercholesterolemia)
3. smoking
4. diabetes mellitus
Other risk factors include obesity, type A personality/ stress, elevated serum homocysteine levels, and inflammation marker - C-reactive protein. Non-modifiable risks include age, sex (male> female) and family history.

Question 13

What is diabetes mellitus?

Answer 13

A complex metabolic derangement characterized by either a relative or absolute lack of insulting resulting in hyperglycaemia. Results from defects in insulin secretion, insulin action or both.
- chronic hyperglycaemia and the metabolic dysregulation of diabetes is associated with damage in many organ systems, particularly the kidney, eyes, nerves and blood vessels.
There is type 1 and type 2 diabetes

Question 14

Describe type 1 diabetes

Answer 14

Insulin-dependent; juvenile-onset
- few if any functional beta cells in the pancreatic islets of Langerhans and substantially reduced or no insulin secretion (an absolute deficiency of insulin).
- usually develops during childhood, peak incidence at puberty
- body fat is metabolized as a source of energy and its oxidation produces ketone bodies that lead to metabolic acidosis.
- glucose is markedly increased in the blood and urine.
- prominent symptoms include increased urine output (polyuria), increased thirst (polydipsia) and weight loss.
- has complex pattern of genetic association; between 90-95% express HLA-DR3 or DR4 (class MHC II alleles).
- autoimmune pathogenesis is supported by the presence of an infiltrate of mononuclear cells in and around the islets of Langerhands. Evidence suggest that sensitized cytotoxic T lymphocytes damage the beta cells, and also evidence that environmental factors may be involved (e.g. viruses).

Question 15

Describe type 2 diabetes

Answer 15

Reflects a failure of the beta cells to meet an increased demand for insulin. Almost 10% of persons over 65 years are affected and 80% of persons with type 2 are overweight.
- Caused by a combination of peripheral resistance to insulin action and an inadequate response of insulin secretion by the pancreatic-B-cells i.e. a relative insulin deficiency.
- Approximately 80-90% of those with diabetes have type 2.
- Pathogenesis is still unknown, but both environmental and genetic factors play a role. Multifactorial inheritance is a key factor in the development of Type 2 (e.g. mutation in glucokinase gene found in one inherited form, but pure genetic forms are rare. 60% of patients have either a parent or a sibling with the disease; concordance rates in identical or fraternal twins are significantly higher than in the population at large.
- Sedentary lifestyle and poor dietary habits that lead to obesity increase the risk for developing diabetes (risk for type 2 increases as the body mass index increases).
- Insulin resistance, i.e. resistance to the effects of insulin on glucose uptake, metabolism or storage, is characteristic of diabetic individuals, especially those who are obese. Links between obesity and insulin resistance include excessive amounts of free fatty acids (FFAs) and a number of adipocyte-specific products (adipocytokines, e.g. leptin, adiponectin, and resistin)
- Unlike type 1, there is no consistent reduction in the number of beta cells in the pancreas and no morphological lesions. In states of insulin resistance, insulin secretion is initially higher for a given glucose level (a compensatory hyperglycemia). This can often maintain normal glucose for years (a pre-diabetic state). Eventually beta cell hyperplasia becomes inadequate and there is a decrease in beta cell mass and clinical progression.

Question 16

What are the diabetic complications?

Answer 16

• The long term complications of diabetes in kidneys, eyes and nerves and blood vessels are the same in both type of diabetes and are the principal cause of morbidity and mortality in diabetes.
• Complications of diabetes relate to the severity of hyperglycemia and length of time of the disease. The effects on a number of organs are severe and incapacitating and include peripheral neuropathy, atherosclerosis or macrovascular disease, microvascular disease and diabetic retinopathy (a leading cause of blindess) and nephropathy (30-40% ultimately develop kidney failure).
• The hallmark of diabetic macrovascular disease is accelerated atherosclerosis affecting the aorta and large and medium-sized arteries. Myocardial infarction caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics. Gangrene of the lower extremities as a result of advanced vascular disease is about 100 times more common in diabetics than in the general population and is a common reason for lower limb amputation in diabetics. The renal artery is also a target for severe atherosclerosis, but the most damaging effects of diabetes are exerted at the level of the glomeruli and the microcirculation. The most important glomerular lesions are capillary basement membrane thickening, a diffuse mesangial cell proliferation and increase in mesangial matrix (diffuse mesangial sclerosis); and nodular glomerulosclerosis. Diabetic nephropathy is a leading cause of end-stage renal failure requiring dialysis or renal transplantation.
• Visual impairment including total blindness is a consequence of long-standing diabetes and may take the form of retinopathy, cataract formation or glaucoma. The lesion in the retina take two forms:
  1. Nonproliferative retinopathy - intraretinal or preretinal hemorrhages, retinal exudates, microaneurysms, venous dilations, edema and thickening of the retinal capillaries (microangiopathy)
  2. Proliferative retinopathy - neovascularization, fibrosis; vitreous hemorrhages can result from rupture of new vessels and subsequent retinal detachment as the hemorrhage organizes.

Question 17

Describe nutritional disorders

Answer 17

Nutritional disorders occur when nutrients are either deficient or ingested in excess.
- in North America, primary nutritional deficiencies are rare and are usually only seen as a secondary effect of disorders such as alcoholism, malabsorption syndromes, acute or chronic illness, overly restrictive dietary practices, or as a result of liver or kidney disease. Secondary nutritional deficiencies arise when there is an alteration in absorption and uptake, impaired metabolism, utilization or storage of nutrients, increased excretion or loss, or increased need of essential nutrients.
- At the opposite end of the energy spectrum, obesity due to excess caloric intake is becoming increasingly more common in North American adults and children.

Question 18

List some of the nutrional deficiencies

Answer 18

• protein-calorie malnutrition or protein energy malnutrition
• marasmus
• kwashiorkor
• anorexia nervosa and bulimia
• vitamin deficiencies

Question 19

Describe protein-calorie malnutrition or protein energy malnutrition

Answer 19

Is a direct result of inadequate dietary protein intake coupled with a deficient intake of the carbohydrates and fat necessary to provide an adequate energy source.
- Most common victims are children in the developing world, where malnutrition (reduction to less than 60-80% of normal weight) is a leading cause of death in children under the age of 5.
- Two forms of protein-calorie malnutrition are recognized - marasmus resulting from caloric deficiency of all nutrients, and kwashiorkor resulting from a deficiency in dietary protein alone.

Question 20

Describe Marasmus

Answer 20

• Common among children in the non-industrialized world when breast feeding is stopped and the environment in which the child and family is living does not provide adequate nutrients of any kind.
• Characteristically these children appear extremely emaciated (‘skin and bones’) with decreased body weight, diminished subcutaneous fat, muscle wasting (muscular protein is broken down as a potential source of energy), wrinkled face, depigmentation of the skin and hair (known as flag sign in the latter) and dermatoses are present.
• The pulse, blood pressure and body temperature are low. Diarrhea is common, due to atrophy of small intestine villi (which further impairs the ability to absorb nutrients). Immune responses are impaired and children suffer numerous infections (bacterial, viral or parasitic).

Question 21

Describe Kwashiorkor

Answer 21

Results from a deficiency of a protein in a diet that is relatively high in carbohydrates. Most commonly seen in children who have been weaned, in this case to a starchy high carbohydrate diet. Many of the features of marasmus are also seen in this syndrome (growth failure and muscle wasting, flag sign, skin changes, atrophy of small intestine.
- Subcutaneous fat is normal, due to an adequate caloric intake. Also in contrast to marasmus, severe edema, hepatomegaly and fatty liver are present. Abdomen is characteristically distended due to ascites, hepatomegaly and flaccid abdominal muscles. Anemia, diarrhea and impaired immune function are present.
- Microscopically the liver shows extensive fatty change. The adequacy of CHO intake provides lipids to the liver, but the absence of protein leads to the inability to produce lipid transport protein with subsequent accumulation of fat within liver hepatocytes. This is a reversible change and the liver (as well as other changes) will revert to normal when adequate protein is provided.

Question 22

Describe anorexia nervosa and bulimia

Answer 22

Anorexia is a state of primary self-induced starvation resulting in severe weight loss. In bulimia the patient repeatedly binges on food and then induces vomiting.
- Both are most common in female teens and young adults in the developed world, secondary to obsession with attaining and maintaining thinness.
- Anorexia has a clinical picture similar to PEM, and there may be amenorrhea (absence of menstruation) and symptoms related to reduced thyroid hormones.
- Bulimia usually has less extreme weight loss, and major complications are related to frequent and/or forceful vomiting, such as electrolyte imbalances and esophageal tears (called Mallory-Weiss tears) with bleeding.

Question 23

Describe vitamin deficiencies

Answer 23

Vitamins are not synthesized in the body and must be obtained through dietary sources. Most vitamins act as cofactors or catalysts in metabolic reactions and are essential for growth, development and maintenance of optimum function. The 13 essential vitamins are divided into two classes - those that are fat soluble and can therefore be stored in tissue (A, D, E, and K) and the remainder that are water soluble and must be constantly ingested (multiple B vitamins, vitamin C).

Question 24

Describe vitamin A deficiencies

Answer 24

A leading cause of blindness world-wide. In the eye, vitamin A serves two purposes; one is in the maintenance of the specialized epithelial lining cells of the eye, and secondly, as a component of the visual pigment rhodopsin.
- With a decrease in vitamin A stores, squamous metaplasia of epithelial cells are replaced with keratinizing epithelial cells, which leads to a dryness of the cornea and conjunctiva (xerophthalmia).
- Keratin debris can build up in the eye and be seen as small opaque plages or Bitot spots. The cornea eventually becomes softened (keratomalacia) and extremely vulnerable to ulceration and/or bacterial infection that may lead to blindness.
- Vitamin A’s role in the rhodopsin pigment of the retinal rods (the components of the retina that discriminate light and dark) may result in an early indication of vitamin A deficiency, in the form of night blindness.
- Vitamin A may be ingested in the form of retinol (the primary form), retinal, retinoic acids or carotenoids (e.g. B-carotene) which are converted into retinol (vit A) in the body and found in yellow and leafy green vegetables (carrots, squash, spinach).

Question 25

Describe the deficiency of the water-soluble vitamin C (ascorbic acid)

Answer 25

Leads to the development of scurvy, characterized by bleeding tendency, hemorrhages and poor wound healing in adults and children, and bone defects in growing children (due to impaired osteoid formation).
- Ascorbic acid participates in a variety of biosynthetic pathways, and its role in activation of proline and lysine hydroxylases provides for hydroxylation and cross-linking of proline and lysine residues in collagen. Collagen which normally has very high concentration of hydroxyproline is most affected. For instance, poor collagen formation in blood vessels accounts for the predisposition to hemorrhages. Deficiency of vitamin C also leads to the suppression of collagen peptide synthesis, further leading to lack of tensile strength and vulnerability to enzymatic degradation in connective tissues.
- Vitamin C can also act as an antioxidant, directly by scavenging cellular free radicals and indirectly by regenerating the antioxidant form of vitamin E.
- Ascorbic acid is abundant in a number of fruits and vegetables, in milk and in some animal products (e.g. liver, fish). The majority of cases of scurvy in north america occur secondarily, in the elderly or in chronic alcoholics (who may ingest inadequate amounts of the vitamin).

Question 26

List some nutritional excesses

Answer 26

• obesity
• vitamin toxicities

Question 27

Describe obesity

Answer 27

An increase in adipose tissue beyond the normal requirements of the body. It is commonly assessed by measurement of the body mass index; BMI= kg/m^2 which expresses weight in relation to height.
- Normal BMI is in the range of 20-25, overweight is defined as BMI > 25 kg/m^2, and obesity as BMI > 30 kg/m^2.
- Other measures may include measures of skin-fold thickness (i.e. measure of the subcutaneous fat in the upper arm) or various body circumferences, e.g. ratio of waist-to-hip or simple waist circumference (obesity defined as > 40 inches in men, > 35 inches in women).
- The number of overweight and obese canadians has been steadily increasing over the past decades, with recent prevalence estimates of 57% overweight and 14% obese men and 35% overweight and 12% obese women.
- Hazards of obesity include an increased incidence of type 2 diabetes. 80% of type 2 diabetes occurs in obese persons. Type 2 diabetes is also known as ‘maturity-onset’ diabetes since it has been associated generally with obesity in adults.
- Most recent nutritional survey figures indicate increased incidence of obesity in children aged 7-13 years old (10% of boys and 9% of girls) and type 2 diabetes is now seen in much younger individuals. An estimated 16% (1999-2002) of children and adolescents aged 6-19 years are overweight - represents a 45% increase from the overweight estimates of 11% obtained from 1988-94.
- Obesity is linked to atherosclerosis and subsequent myocardial infarction (MI). also linked to other major risk factors for MI i.e. hypercholesterolemia, low levels of high density lipoproteins, hypertension and diabetes. Both childhood cholesterol level and an increased BMI predict increased carotid inter-media thickness (an indication of the presence of atherosclerotic narrowing) in adulthood. Risk factors in childhood and adolescence matter - the age range at which fatty streaks begin to be converted to more complicated, raised atherosclerotic plaques. Modification of risk factors in adults has been the target of preventive health programs, but increasingly it looks as if these risk factors, especially diet and cholesterol levels, avoidance of cigarette smoking and maintenance of a healthy body weight, need to be targeted in children and adolescence.
- Obesity and hypercholesterolemia are also associated with an increased incidence of gallstones, particularly in women. Increased weight will also contribute to the incidence of osteoarthritis in weight-bearing joints (e.g. hip, knee, spine), hypoventilation or “Pickwickian” syndrome, and the occurrence of varicose veins and hence deep venous thrombosis. Obesity has also been linked to an increased risk of some cancers (e.g. breast, prostate cancer, endometrial, colon, kidney, and esophageal cancer.

Question 28

Describe vitamin toxicities

Answer 28

Since water soluble vitamins are rapidly and easily excreted, consequences of excess vitamin intake are primarily associated with the fat soluble vitamins (A D, E and K).
- Vitamin A in excess is a teratogen and care must be taken in pregnant women not to exceed the daily recommended intake (5,000 IU0. consequences of excess vitamin A intake, due to its effects on cell differentiation and division, include bone abnormalities and fractures, hemorrhages, skin rashes and hair loss, liver failure and even death.
- Evidence suggests that vitamin E, a potent antioxidant, may lower the risk for various diseases, including heart disease, some types of cancer, cataracts, age-related macular degeneration, Parkinson’s disease, and Alzheimer’s disease. Earlier prospective studies found reduced rates of cardiovascular disease and death in those with the highest intakes of vitamin E in diet and supplements but recent data suggests that vitamin E provides no overall benefit for major cardiovascular-related events or cancer, nor does it affect total mortality or decrease cardiovascular-related deaths in healthy women.
- There are little to no conclusive research showing vitamin E is beneficial. Vitamin E or any food component by itself, cannot match the most effective ways to reduce disease risk - not smoking, getting regular exercise, maintaining a healthy weight, and eating an overall healthy diet.