MMD Lecture 13 Nutrition Fall 2023.pptx
Transcript
Malnutrition • Kwashiorkor is a type of malnutrition seen in developing countries and is caused by a deficiency of protein in a diet that is adequate in calories. • Kwashiorkor results in lack of cellular development due to the failure to synthesize normal amounts of proteins. • There is hypoalbumin...
Malnutrition • Kwashiorkor is a type of malnutrition seen in developing countries and is caused by a deficiency of protein in a diet that is adequate in calories. • Kwashiorkor results in lack of cellular development due to the failure to synthesize normal amounts of proteins. • There is hypoalbuminemia (reduced oncotic pressure) which leads to edema: there is also diarrhea, atrophy of the pancreas and intestinal mucosa. • Rarely observed in affluent countries 1 Malnutrition • Marasmus is caused by a sever deficiency of both protein and total calories: chronic PEM. Protein, energy and nutrient intake are all inadequate. • This is generalized starvation, with symptoms including muscle wasting (emaciation), weakness, and anemia. • Seen in children 6 to 18 months who are fed diluted or poorly mixed formulas • Anorexia nervosa 2 Vitamins • Vitamins are micronutrients that we must obtain in the diet in small amounts. They are essential for normal growth and development. • Vitamins are organic molecules that are either watersoluble or fat-soluble. • Water-soluble vitamins – B complex and C. • Fat-soluble vitamins – A, D, E, and K. 3 Water-Soluble Vitamins • Water-soluble vitamins and/or their derivatives function as coenzymes for enzymes involved in metabolic pathways. • Some fat-soluble vitamins function as hormones, some as anti-oxidants. 4 Thiamine (B1) • The coenzyme form is thiamine pyrophosphate (TPP), which is involved in reactions of energy production. • TPP is a coenzyme for pyruvate dehydrogenase (pyruvate acetyl CoA) and for a TCA cycle enzyme. 5 Thiamine Deficiency • Severe deficiency disease is beriberi: characterized by neurological disorders, paralysis, palpitations, cardiomyopathy, muscle atrophy and weakness, loss of weight. • Inhibition of glutamate production and Gamma-aminobutyric acid GABA due to inhibition of the TCA cycle • Severe thiamine deficiency is called Wernicke-Korsakoff syndrome, or Wernicke encephalopathy. • This is characterized by eye muscle weakness, poor muscular coordination (ataxia), loss of memory (amnesia). • Commonly observed in chronic alcholism • If not treated, it can lead to coma and death. 6 Riboflavin (B2) • Riboflavin is a constituent of the coenzymes FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). • These coenzymes function as electron carriers for oxidoreductases. • Deficiency thereof is not associated with a major human disease. 7 Niacin (Nicotinic Acid) (B3) • Niacin is a constituent of the coenzymes NAD+ (nicotinamide adenine dinucleotide) and NADP+ (nicotinamide adenine dinucleotide phosphate). • These coenzymes function as electron carriers for oxidoreductases. • Some niacin can be synthesized endogenously from tryptophan--an essential amino acid. 8 Niacin Deficiency • Niacin deficiency disease is pellagra, characterized by dermatitis, dementia, and diarrhea (the three Ds). • Niacin deficiency is also related to ingestion of an unbalanced amino acid mixture containing inadequate tryptophan. 9 Pyridoxine (Vitamin B6) • The coenzyme form is pyridoxal phosphate (PLP). • This coenzyme is required by enzymes involved in amino acid metabolism, such as transaminases. • In the 1960’s, when infants were fed a formula lacking this vitamin, they developed seizures and hyperirritability. • Why? Pyridoxal phosphate is a cofactor involved with the enzyme glutamic acid decarboxylase (GAD), which converts glutamic acid to GABA. • Isoniazid, used in the treatment of TB, can produce a B6 deficiency. • How? • Its metabolites directly attach to and inactivate pyridoxine species. • Second, it directly inhibits the enzyme pyridoxine phosphokinase: • This enzyme activates pyridoxine to pyridoxal 5' phosphate--the cofactor in many "pyridoxine-dependent" reactions. 10 Folic Acid (B9) • The coenzyme form is tetrahydrofolate (FH4) and derivatives. • FH4 functions as a carrier of 1-carbon groups for enzymes catalyzing 1-C transfer reactions. • Tetrahydrofolate derivatives are required for nucleotide synthesis and for the synthesis of methionine from homocysteine. 11 Folate Deficiency • A folate deficiency leads to decreased availability of nucleotides, which will lead to impaired DNA synthesis and cell division. • This impairment in hematopoietic cells accounts for the signs and symptoms of megaloblastic anemia. • During the first few weeks of fetal development will lead to neural tube defects (spina bifida). 12 Folate Deficiency • Megaloblastic anemia is a bone marrow disorder in which normal maturation of rbc’s is impaired, leading to low hemoglobin levels and a high number of megaloblastic cells in the bone marrow. • The red blood cells are macrocytic with fragile membranes. • A folate deficiency also causes homocysteinemia, because FH4 derivative is required to convert homocysteine to methionine. 13 Folate Analogs • Folate analogs, like methotrexate (amethopterin), are chemotherapeutic agents. • Folate analogs act as competitive inhibitors of dihydrofolate reductase (FH2 FH4). • This leads to an inhibition of nucleotide synthesis, with a consequent inhibition of DNA synthesis of rapid cell division. 14 Vitamin B12 (Cobalamin) • The coenzyme forms are methylcobalamin and deoxyadenosylcobalamin. • A reaction that requires B12 is the conversion of homocysteine to methionine. • Intestinal absorption of B12 requires a glycoprotein called intrinsic factor (IF), which is synthesized in the parietal cells of the stomach. • Large amounts of B12 are stored in the liver. 15 B12 Deficiency • The most common disease of B12 deficiency is the disease known pernicious anemia (chronic atrophic gastritis). • Pernicious anemia is caused by an autoimmune disease wherein there is autoimmune destruction of the parietal cells of the stomach. • Lack of IF(intrinsic factor) to B12 deficiency. 16 Pernicious Anemia • Symptoms include megaloblastic anemia and irreversible degeneration of the spinal cord. • Folate recycling is impaired. • Neurological manifestations include paresthesias, difficulty in balance, spastic gait, and dementia. 17 Vitamin C (Ascorbate) • Ascorbate is a coenzyme in the hydroxylation of proline and lysine residues in collagen, reactions that are required in the production of mature collagen. • Vitamin C is also an anti-oxidant (reducing agent). • Vitamin C deficiency causes scurvy, which is characterized by bleeding gums, loose teeth, fragile blood vessels, impaired wound healing. 18 Scurvy • Caused by a deficiency of dietary vitamin C associated with malnutrition • Ascorbic acid involved in a variety of biosynthetic pathways • Synthesis of collagen, ascorbic acid is a cofactor for 2 enzymes: prolyl hydroxylase and lysyl hydroxylase • Two enzymes involved in hydroxylation of the proline and lysine amino acids in collagen • Hydroxyproline and hydroxylysine are important for stabilizing collagen by cross-linking in collagen. Fat-Soluble Vitamins • These vitamins are associated with lipids of the diet. • Absorption of these vitamins requires the normal lipid absorption mechanisms, including emulsification by bile, normal mucosal cells, and transport in chylomicrons. 20 Fat-Soluble Vitamins • These vitamins are stored in the body in the liver and adipose tissue. • Some of these vitamins have hormone-like function, some have antioxidant function. 21 Vitamin A • Vitamin A has 3 active forms – retinol, retinal and retinoic acid. • Function: • Important in growth, reproduction, immunity and cell differentiation. • Help maintain healthy bones, skin and mucous membrane. • Visual cycle as a constituent of the visual pigment--rhodopsin. • -carotene from plants is provitamin A – it is converted in the GI tract to retinal. • -carotene functions as an antioxidant. • Animal sources provide vitamin A in the form of retinol and retinyl esters. 22 Vitamin A • They are absorbed and incorporated into chylomicrons. • Stored in the liver as retinyl esters to the tissue. • Delivered to tissue by retinol-binding protein (RBP). • Once delivered to the cell the cell will convert retinol to retinal or retinoic acid. 23 Vitamin A • In vision, retinol is carried to the retina and converted to retinal. It then combines with a protein opsin to form a pigment known as rhodopsin. It is an integral part of the visual cycle allowing us to see. • Retinoic acid affects gene expression. It acts like a steroid hormone, binding to retinoid nuclear receptors, and enhancing transcription of certain genes involved in differentiation of stem cell into various cell types. • Both retinol and retinal support sperm production and fertility. • All forms of Vitamin A are essential for proper bone growth. 24 Vitamin A Deficiency • Early symptom is night blindness. This is due to inefficient regeneration of rhodopsin. • Other symptoms include keratinization of epithelium and lack of mucus secretions; susceptibility to infections; drying and keratinization of the cornea (xerophthalmia) causing permanent blindness. • There are pharmacological uses for retinoic acids in the treatment of acne and psoriasis. • Accutane and Retin-A are forms of retinoic acid. 25 Vitamin D • Vitamin D3, cholecalciferol, is from animals (skin UV radiation). • Vitamin D2, ergocalciferol, is from yeast. • The active form of the vitamin is 1,25-dihydroxycholecalciferol, or calcitriol. • Function: • Calcitriol functions in calcium homeostasis primarily. • Also regulates cell differentiation and growth. • Calcitriol functions like a steroid hormone in intestinal mucosal cells, binding to a cytosolic receptor and inducing the synthesis of a calcium binding protein. 26 Vitamin D regulation of Blood Calcium Ultraviolet light causes a form of Cholesterol to be converted to an Inactive form of vitamin D cholecalciferol The liver then converts to 25-hydroxycholecalciferol (calcidiol) Through the action of PTH the Kidneys convert calcidiol to the active form of Vitamin D (calcitriol) Function of calcitriol: • Enhances the absorption of calcium and phosphoru from the small intestines • With PTH stimulates osteoclasts to break down bone and release calcium 28 Vitamin D Deficiency • Rickets, in children, entails improper mineralization of developing bone with resultant formation of weakened, soft pliable bones. Bowing of the legs. • Osteomalacia, in adults, entails demineralization of existing bone, which causes bone to become soft and susceptible to fractures in the hip, spine and other bones. • Osteoporosis, porous bones, is a condition of declining bone quality that impacts millions of Americans. It is progressive of both decline in bone density and strength. 29 Vitamin E • Also called -tocopherol. • Normally, free radicals are produced to remove unwanted molecules. • Functions as an antioxidant in the blood (LDLs) and in membranes. • It protects membrane phospholipids from attack by reactive oxygen species (ROS). 30 Vitamin K • Vitamin K is required for the post-translational modification of coagulation factors II (prothrombin), VII, IX, and X. • This reaction entails the conversion of glutamate residues on the proteins to -carboxyglutamate residues by carboxylation. • -carboxyglutamate residues of prothrombin are strong chelators of Ca++, a necessary function in the conversion of prothrombin to thrombin in the 31 Vitamin K • Vitamin K deficiency is associated with bleeding disorders. Vitamin K deficiency leads to hypoprothrombinemia. • Vitamin K deficiency is common in newborns, leading to hemorrhagic disease of the newborn. • Vitamin K antagonists are used therapeutically as anticoagulants to treat thromboembolytic disease. Examples are dicumarol and warfarin. 32
