Metabolic & Nutritional Diseases Flashcards
METABOLIC DISORDERS
Genetically Determined Errors of Metabolism
- These disorders are 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.
- Functional and/or morphologic changes may occur and in some instances (e.g.phenylketonuria, galactosemia) may be ameliorated by therapy.
- In many disorders, the carrier state can be identified to permit genetic counseling.
- By the testing of amniotic fluid before birth or appropriate screening at birth, metabolic disorders can be detected.
- Since these disorders rarely occur, the in utero testing can usually assure parents that their child will be normal.
- Many of these metabolic disorders are characterized by autosomal recessive transmission and, in many cases, the chromosome on which the defective gene is located 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.
- Indirect effects are also exerted on other metabolic pathways or functional elements.
Clinical Expression: The neurological complications present in many of these disorders range from specific focal abnormalities to mental retardation.
- The precise reason for the mental retardation is not clear.
- There is marked variation in the age of onset, rate of progression and organ and skeletal involvement among disorders and among variants of each disorder.
- This is due to factors such as the different isoenyzmes involved, solubility of accumulated products for excretion, and the specific biochemical reactions occurring in various organs.
- Phenylketonuria
- Galactosemia
- Lysosomal Storage Diseases
a. Tay-Sachs Disease (GM2 Gangliosidosis)
b. Niemann-Pick Disease, Types A and B
Phenylketonuria
PKU is a disorder of amino acid metabolism in which the enzyme responsible for the conversion of phenylalanine to tyrosine is deficient (affects about 1 in 12,000 live births).
- This results in increased blood levels of phenylalanine, which impairs normal brain development, and increased urinary excretion of phenylpyruvic acid.
- Morphologically within the brain there is hypomyelination, gliosis, and microcephaly.
- There is no lysosomal storage in neurons.
Clinical features include severe mental retardation, seizures and hyperactivity, as well as decreased pigmentation of the hair and skin (due to decreased melanin production from tyrosine).
Because these consequences can be avoided by restriction of phenylalanine in the diet and supplementation with tyrosine, nearly all newborns are screened (e.g. Guthrie test-serum analysis).
Many female PKU patients treated with diet early in life reach childbearing age and are clinically normal, but they may have markedly increased serum phenylalanine levels if no longer on a restricted diet.
- Children born to such women are profoundly mentally retarded and have multiple congenital anomalies (recall that phenylalanine is a teratogen!).
- Thus it is essential that maternal phenylalanine levels be lowered by dietary restriction prior to conception
Galactosemia
Galactosemia is a disorder of carbohydrate metabolism in which a deficiency of galactose-1-phosphate uridyl transferase leads to accumulation of galactose-1-phosphate and galactosuria and hypergalactosemia.
- Normally, lactase splits lactose, the major CHO of mammalian milk, into glucose and galactose in the intestinal microvilli.
- Galactose is then converted to glucose in several steps in which this enzyme takes part.
- Metabolites of galactose and other of its metabolites accumulate in many tissues including liver, spleen, kidney, cerebral cortex and the lens of the eye.
Clinical features include 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.
Lysosomal Storage Diseases
Lysosomes contain a variety of hydrolytic enzymes that are involved in the breakdown of complex substrates such as sphingolipids and mucopolysaccharides, into soluble end products.
- These large molecules may be derived from the turnover of intracellular organelles or may be acquired from outside by phagocytosis.
With a lack of a lysosomal enzyme, 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, fortunately they are rare.
- They can be classified on the basis of the underlying metabolic defect (e.g. primary lysosomal hydrolase defect; post-translational processing defect of lysosomal enzymes; transmembrane protein defects).
Clinical expression is variable when infants and children are affected, progressive mental and motor deterioration and death is the usual pattern.
There are many variants, some of which have a milder form with adult onset.
a. Tay-Sachs Disease (GM2 Gangliosidosis)
b. Niemann-Pick Disease, Types A and B
Tay-Sachs Disease (GM2 Gangliosidosis)
Characterized by accumulation of gangliosides within the brain as a result of the catabolic enzyme defect, in this case a deficiency in the α subunit of hexoaminidase A, necessary for the degradation of GM2.
Storage of GM2 occurs within neurons, axon cylinders of nerves, and glial cells throughout the CNS.
- Affected cells appear swollen or ‘foamy’ with lipid vacuolation.
Tay-Sachs disease is most common among Ashkenazi Jews (the frequency of heterozygous carriers is estimated to be 1 in 30).
- Heterozygotes can be detected by estimating the level of hexosaminidase in the serum or by DNA analysis.
In the most common variant, infants appear normal at birth but motor weakness begins to develop at 3 to 6 months of age, followed by mental retardation, blindness, and severe neurologic dysfunction.
- Death occurs within 2 or 3 years
Niemann-Pick Disease, Types A and B
These disorders are characterized by a primary deficiency of acid sphingomyelinase and the accumulation of sphingomyelin.
In type A, the breakdown of sphingomyelin into ceramide and phosphorylcholine is impaired and excess sphingomyelin accumulates in phagocytic cells and neurons.
- The organs most severely affected are the spleen, liver, bone marrow, lymph nodes, and lungs.
- In addition, the CNS is involved and affected neurons are enlarged and vacuolated as a result of the storage of lipids.
- This variant manifests itself in infancy with massive visceromegaly and severe neurological deterioration.
- Death usually occurs within the first 3 years of life.
Patients with type B variants have organomegaly but no neurologic symptoms.
Estimation of sphingomyelinase activity in leukocytes or cultured fibroblast can be used for the diagnosis of suspected cases as well as carriers; antenatal diagnosis is possible by enzyme assays or DNA analysis.
Other examples of genetically based metabolic disorders
Autosomal dominant metabolic disorders:
- familial hypercholesterolemia
- mutations in the LDL receptor impair transport of LDL into cells - acute intermittent porphyria
- impaired heme synthesis and the accumulation of the intermediate porphyrin
- the low levels of the missing enzyme porphobilinogen deaminase (PGBD) (an enzyme in heme biosynthesis pathways) are generally not sufficient to cause symptoms; however, activating factors such as hormones, drugs, and dietary changes may trigger symptoms.
X-linked recessive metabolic disorders:
- diabetes insipidus
- Lesch Nyhan syndrome.
- the lack of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) causes a build-up of uric acid in all body fluids and leads to symptoms such as severe gout, poor muscle control, and moderate retardation, which appear in the first year of life.
- A striking feature of LNS is self-mutilating behaviours – characterized by lip and finger biting – that begins in the second year of life.
- Abnormally high uric acid levels can cause sodium urate crystals to form in the joints, kidneys, central nervous system, and other tissues of the body, leading to gout-like swelling in the joints and severe kidney problems.
- Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease.
- Because a lack of HPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.
Acquired Metabolic Disorders
Acquired metabolic disorders are 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 disulfide), or they may be secondary to derangements of renal or liver disease.
Acquired disorders 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.
Atherosclerosis
Diabetes Mellitus
Atherosclerosis
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:
- Hypertension
- Hyperlipidemia (hypercholesterolemia)
- Smoking
- 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.
Diabetes Mellitus
Diabetes mellitus is a complex metabolic derangement, characterized by either a relative or absolute lack of insulin resulting in hyperglycemia.
- Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or both.
Chronic hyperglycemia and the metabolic dysregulation of diabetes is associated with damage in many organ systems, particularly the kidney, eyes, nerves, and blood vessels.
The two most common forms of diabetes are referred to as Type 1 (insulin-dependent; juvenile-onset) and Type 2 diabetes (non-insulin dependent; maturity-onset diabetes).
Type 1 Diabetes
Characterized by 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, the 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.
Type 1 has a complex pattern of genetic association
- between 90% to 95% express HLA-DR3 or DR-4 (class II MHC alleles)
- An autoimmune pathogenesis is supported by the presence of an infiltrate of mononuclear cells in and around the islets of Langerhans.
Evidence now suggests that sensitized cytotoxic T lymphocytes damage the beta cells.
- There is also evidence that environmental factors may be involved - for instance a virus may be an initiating trigger.
Type 2 Diabetes
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 diabetes are overweight
caused by a combination of peripheral resistance to insulin action and an inadequate response of insulin secretion by the pancreatic β-cells, i.e. a relative insulin deficiency
Approximately 80 to 90% of those with diabetes have type 2 diabetes
The pathogenesis of type 2 diabetes is still unknown, but both environmental and genetic factors play a role.
- Multifactorial inheritance is a key factor in the development (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
Sedentary lifestyle and poor dietary habits that lead to obesity increase the risk for developing diabetes
- the risk for type 2 diabetes 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 diabetics, 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 to overt diabetes.
Type 1 versus Type 2 Diabetes Mellitus
- Clinical
Type 1:
- Onset < 20 yrs
- Normal weight
- Decreased blood insulin
- Antibodies to islet cells
- Ketoacidosis common
Type 2:
- Onset > 30 yrs
- Obesity
- Increased blood insulin (early); normal to moderate decreased insulin (late)
- No antibodies to islet cells
- Ketoacidosis rare: nonketotic hyperosmolar coma
- Genetics
Type 1:
- 30 – 70% concordance in twins
- Linkage to MHC class II HLA genes
Type 2:
- 50-90% concordance in twins
- Pathogenesis
Type 1:
- Autoimmune destruction of β-cells mediated by T cells/humoral mediators
- Absolute insulin deficiency
Type 2:
- Insulin resistance in skeletal muscle, adipose tissue, and liver
- Beta cell dysfunction and relative insulin deficiency
- Islet cells
Type 1:
- Insulitis early
- Marked atrophy and fibrosis
- Beta cell depletion
Type 2:
- No insulitis
- Focal atrophy and amyloid deposition
- Mild β-cell depletion
Diabetic Complications
The long term complications of diabetes in kidneys, eyes, nerves and blood vessels are the same in both types of diabetes and are the principal cause of morbidity and mortality in diabetes
Glucose binds to a wide variety of proteins and over time form stable advanced glycosylation end (AGE) products through non-enzymatic glycosylation that can inactivate the function of the protein or cause cross-links to other proteins.
Intracellular hyperglycemia can stimulate the production of second messenger signaling molecules and hence cause activation of protein kinase C (PKC) which can have numerous downstream effects and result in the activation of pro-angiogenic molecules.
The increased flux of glucose into cells can also lead to its metabolism by the polyol pathway (via aldose reductase) and the formation of sorbitol within tissues. Sorbitol may be directly toxic or, in tissues such as the lens, cause an osmotic gradient that leads to swelling.
In experimental animals, aldose reductase inhibitors prevent the development of cataracts, retinal damage and early changes in the kidney, but in clinical trials have failed to significantly lessen the development of diabetic retinopathy
The 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 blindness) and nephropathy (30 to 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 takes two forms:
- Nonproliferative retinopathy - intraretinal or preretinal hemorrhages, retinal exudates, microaneurysms, venous dilations, edema, and thickening of the retinal capillaries (microangiopathy)
- Proliferative retinopathy – neovascularization, fibrosis; vitreous hemorrhages can result from rupture of new vessels and subsequent retinal detachment as the hemorrhage organizes.
Tight control of blood glucose with endogenously administered insulin remains the major means by which these complications can be minimized.
NUTRITIONAL DISORDERS
The major nutrients required for proper development and growth include both macronutrients (fat, carbohydrate and protein) and micronutrients (vitamins & minerals; essential amino acids and fatty acids) and water. Nutritional disorders occur when nutrients are either deficient or ingested in excess.
In developing countries the major nutritional disorders are due to the absence or deficiency of essential nutrients in the diet, while in North America, primary nutritional deficiencies such as this 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.
- NUTRITIONAL DEFICIENCIES
- Protein-Calorie Malnutrition or Protein-Energy Malnutrition
– Marasmus
– Kwashiorkor
- Anorexia Nervosa and Bulimia - Vitamin Deficiencies
- Vitamin A deficiency
- Deficiency of the water-soluble vitamin C - NUTRITIONAL EXCESS
- Obesity
- Vitamin Toxicities
