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Pathobiology: Nutritional Diseases (Kupsky) INTRODUCTION: General Considerations: Adequate diets should provide: o Energy (adequate carbs, fats and proteins) o Amino acids and fatty acids (essential and non-essential) o Vitamins and minerals Inadequate diets: o Primary malnutrition: deficiency of intake o Secondary malnutrition: deficiency due to inadequate absorption, impaired use or storage, excess loss or increased need Deficiencies: often occur in combination and in the setting of other diseases FAT SOLUBLE VITAMINS (A,D,E,K): Distinguish from Water Soluble: Normal body stores of fat soluble vitamins (usually in the liver) are generally higher Fat soluble vitamins require effective pancreatic and biliary function for dietary absorption Vitamin A (Carotene Family): Normal Functions: o Component of visual pigment (rhodopsin) o Maintenance of specialized epithelia (ie. mucus-secreting) Affects transcription of specific genes through interaction with DNA (RAR and RXR receptors) o Effects on metabolism (including fatty acids) o Resistance to infection and stimulation of the immune system Dietary Sources: o Animal-derived products (retinol and other forms from fish, eggs, liver, milk products) o Leafy green/yellow vegetables (carotenoids, beta-carotene) Storage: ~90% stored in Ito cells of the liver Deficiency States: o Possible Causes: General undernutrition Conditions causing fat malabsorption o Manifestations: Nyctalopia (Night Blindness): due to decreased rhodopsin in retinal rods and cones Squamous metaplasia of corneal epithelium and secretory glands: Eyes: o Xeropthalmia (dry eye) o Keratomalacia (corneal ulceration) Other areas: o Skin adnexal duct epithelium (follicular hyperkeratosis) o Upper airway o Urinary tract Susceptibility to infection: especially measles Predisposition to neoplasia (?): due to squamous metaplasia Vitamin D (Cholecalciferol Family): Normal Function: maintenance of serum Ca and P levels for adequate BONE MINERALIZATION o Active Form: facilitates Ca and PO4 absorption in the small intestine by activating synthesis of Ca++ binding proteins o Receptors for Vitamin D: located in man organs (bone, parathyroid, kidney, intestine, brain etc.) Sources and Metabolism: o Sources: Meat, dairy products, additives (fortified foods) UV conversion of 7-dehydrocholesterol in the skin to D3 o Metabolism: D2 (food) or D3 (skin) transported to the liver via D-binding protein transporter Undergoes 25-hydroxylation in the liver (using 25-hydroxylase enzyme) 25(OH)D Undergoes 1-hydroxylation in the kidney (using 1-hydroxylase enzyme) 1,25(OH)2D, which is the active form - Deficiency States: o Causes: Inadequate dietary intake with chronic underexposure to light Malabsorption due to biliary or intestinal diseases Chronic liver disease Chronic renal disease Induction of hepatic cytP450 enzymes (degrade steroids) Defective hydroxylase enzymes (vitamin D-dependent rickets) o Manifestations: result in failure of MINERALIZATION of osteoid Rickets (Children): failure to mineralize osteoid in a growing skeleton Bowing deformities of long bones and spine Overgrowth of cartilage at the epiphyseal plates in limbs and along the ribs Produce a number of deformities o “Rachitic rosary” of the rib cage o Craniotabes o Frontal bossing o Pigeon breast Osteolmalacia (Adults): inadequate mineralization of osteoid during bone remodeling Decreased bone density on radiographs Excess osteoid Minimal deformity, but susceptibility to microfracture Vitamin K (Menaquinone Family): Normal Function: co-factor for microsomal carboxylases o Important for clotting factors II, VII, IX and X (allows factors to interact with Ca++ and phospholipid surfaces to generate thrombin) Sources: leafy green vegetables and intestinal bacteria Metabolism: o Converts glutamyl residues into gamma-carboxyglutamates (provides Ca++ binding sites on molecules) o Generates an inactive vitamin K epoxide, which must be recycled back to active vitamin K by a hepatic reductase enzyme Warfarin: inhibits the recycling of vitamin K (inhibit hepatic reductase) Deficiency States: o Deficiencies are Rare: Efficient recycling of vitamin K epoxide by hepatic reductase Synthesis of vitamin K by bowel flora is a continuous source o Causes: Neonates: no gut flora and poor placenta transport of vitamin K Hemorrhagic disease of the newborn Diffuse liver disease: Fat malabsorption (ie. obstructive jaundice) Loss of hepatic reductase Long-term antibiotic therapy: kill gut microbes Warfarin therapy: prevent recycling of vitamin K o Manifestations: Bleeding Diathesis: bleeding episodes are the only clinical manifestation Hematomas, hematuria, melena, echhymoses, gingival bleeding etc. Vitamin E (Tocopherol): Normal Function: antioxidant that inhibits the formation of oxygen radicals; also plays a role as a signaling molecule (may be more important than role as antioxidant) Sources: o Vegetable oils (wheat germ, sunflower) o Fatty fish, liver, fish liver oils o Eggs o Butter Structure and Metabolism: o Structure: phenol-like aromatic head attached to saturated hydrocarbon side chain Structure allows the molecule to sit in membrane lipid layers - Phenolic hydroxyl group readily oxidized (protects membrane lipids from oxidation by free radicals) o Metabolism: Vitamin E radical formed by oxidation by a free radical is recycled by reduction (system using vitamin C and glutathione) Deficiency States: o Deficiencies are Rare: due to efficient recycling o Causes: Severe fat malabsorption (biliary tract disease, cystic fibrosis) Premature infants susceptible (low levels of vitamin E at birth PLUS oxidative stresses such as oxygen therapy) o Manifestations: Spinocerebellar degeneration (degeneration of long peripheral and central axons; rare) Hemolytic anemia (especially in newborns) Increased susceptibility to ischemic heart disease WATER SOLUBLE VITAMINS (B1, OTHER B VITAMINS, C): General: Small, inorganic molecules that are require in small amounts for metabolism Usually cannot be synthesized in sufficient amounts (body stores are limited and can be easily depleted) Often involved in universal energy utilization pathways, and therefore, deficiency results in systemic syndromes Thiamine (B1): Normal Functions: involved in reactions where aldehyde groups are transferred o ATP synthesis (oxidative decarboxylation of alpha-ketoacids) o Pentosephosphate pathway (transketolase co-factor) o Maintenance of normal nerve membranes and conduction Sources: widely available in the diet, although scare in highly refined foods (ie. white flour, polished rice) o Low intracellular reserves (especially located in muscle, heart and brain) Deficiency States: o Primary Nutritional Deficiency: RARE, except in cases of profound food deprivation or a scanty diet consisting only on processed foods o Secondary Deficiency: due to chronic alcoholism (more common) Inadequate diet and increased utilization Genetically transmitted transketolase abnormality found in many alcoholics (autosomal recessive) Some foods may also interfere with B1 function (tea, coffee, raw shellfish) Clinical Syndromes: o Dry Beriberi: peripheral neuropathy (due to degeneration of myelin) with symmetric numbness (sensory), weakness (motor) and loss of reflexes; primarily in distal lower extremities o Wet Beriberi: CV syndrome of peripheral vasodilation and high-output mycocardial failure (due to energy depletion), leading to peripheral edema o Wernicke Korsakoff Syndrome: Wernicke’s Encephalopathy: acute syndrome Eye movement abnormalities (nystagmus, opthalmoplegia) Ataxia Dysarthria (speech muscles affected) Confusion/disorientation Korsakoff’s Psychosis: chronic syndrome Retrograde amnesia Inability to acquire new information (anterograde amnesia), which may lead to confabulation Riboflavin (B2)/Pyridoxine (B6)/ Niacin (B3): Normal Functions: important cofactors in numerous energy pathways and special synthetic pathways o Riboflavin (B2): critical component of FMN and FAD, important in oxidation-reduction reactions o Niacin (B3): component of NAD/NADP important for electron transport reactions o Pyridoxine (B6): cofactor for numerous biochemical reactions (transamination, decarboxylation) Required for production of melanin, porphyrin, serotonin and catecholamines - Sources: o Ribioflavin: meat, dairy, vegetables o Niacin: grains, legumes, seed oils, meat (small amount); can also be synthesized from tryptophan o Pyridoxin: found in virtually all foods (processing can destroy it) Deficiency States: o General (Group as a Whole): often show up in tissues with rapid cell turnover or active metabolism Epithelium: dermatitis, glossitis Bone marrow: anemia Neural tissues: neuropathy, dementia o Riboflavin Deficiency: Cause: in developing countries or in chronic alcoholics Manifestations: Cheilosis: cracks and fissures at the edge of the mouth (first and most characteristic sign) Glossitis: red-blue cyanotic color of the tongue Dermatitis: greasy, scaling skin on the face and genitalia o Niacin Deficiency: Cause: in developing countries or in chronic alcoholics Manifestations: Pellagra: 3 Ds o Dermatitis: bilateral symmetric rash on sun-exposed areas; red, thickened and scaling skin o Diarrhea: atrophy of columnar epithelium of the gut; interferes with water absorption o Dementia: degeneration of neurons in the brain and tracts in the spinal cord o Pyridoxine Deficiency: Manifestations: resemble niacin and/or riboflavin toxicity Dermatitis Cheilosis Glossitis Neuropathy (abnormally high levels of B6 can also cause this) Vitamin C (Ascorbic Acid): Normal Functions: o Anti-oxidant/free radical scavenger o Biosynthesis (NTs, carnitine, bile acids) o Immune function o Collagen cross-linking (lysine, proline hydroxylation) Sources: leafy green vegetables, tomatoes, citrus fruits Deficiency States: o Depletion of Body Stores: occurs in 30-40 days without dietary intake o Excess Intake: excreted in the urine o Causes: most common in the elderly, chronic alcoholics or in association with underlying disease Deficiency Syndromes: o Scurvy (Adults and Children): Bleeding tendency Impaired wound healing (weak granulation tissue) Dermatologic changes Gingival changes with periodontal infections o Moeller-Barlow Disease (Acute Infantile Scurvy): Results in impaired PRODUCTION of osteoid, leading to overgrowth of cartilage and bowing deformities Vitamin B12 and Folate: Normal Functions: both are coenzymes in DNA synthetic pathways o B12 (methylcobalamin): Required to covert homocysteine to methionine; occurs via donation of methyl group from N5-methyl tetrahydrofolate, which is converted to THF in the process Deficiency: creates deficiency of THF - - Prosthetic group on methylmalonyl CoA mutase enzyme (involved in lipid metabolism) Deficiency: interrupts lipid metabolism and causes an accumulation of methylmalonate and propionate, which can cause neuronal membrane damage o THF: required for synthesis of nucleotides (cofactor for thymidylate synthetase) Etiology of Deficiency of B12 and Folate: o Source of B12: humans completely dependent on dietary animal sources Body reserves last for years, therefore, deficiency is usually secondary o Causes of Secondary Deficiency of B12: Malabsorption syndromes of small intestine Ileal resection or ileal inflammatory diseases Competitive uptake by tapeworms or bacterial overgrowth Increased requirements (pregnancy, malignancy) Intrinsic factor deficiency (gastrectomy, pernicious anemia) Pernicious Anemia: production of autoAbs to IF or to the gastric parietal cells that synthesize and secrete it o AutoAb Targets: Prevent binding of IF and B12 Prevent binding of IF-B12 to ileal R o Other Issues: chronic inflammation and repair lead to gastric gland atrophy, achlorhydria, intestinal metaplasia, and B12 deficiency o Diagnosis: positive Schilling test (assesses failure to absorb oral cobalamin) Other inherited defects o Source of Folate: ample in most diets (green vegetables, some fruits, some animal proteins) Primary deficiency uncommon except in those with really deficient diets o Causes of Secondary/Relative Deficiency: Lack of vitamin B12 results in secondary folate deficiency* Pregnancy Infancy Hemolytic anemias Disseminated cancers Drugs that inhibit folate absorption (oral contraceptives, phenytoin) Anti-neoplastic drugs that inhibit dihydrofolate reductase (methorexate, cyclophosphamide, 6-mercaptopurine) Deficiency States: o Deficiency impairs DNA synthesis: but RNA synthesis and protein production unaffected o Manifestations of Vitamin B12/Folate Deficiency: Megaloblastic anemia: large, ovoid (oddly shaped) RBCs Ineffective hematopoiesis: nuclear cytoplasmic dyssynchrony (nuclear maturation lags behind cytoplasmic maturation) Macrocytic anemia Hypersegmented PMNs NOTE: giving folate for treatment of vitamin B12 deficiency will improve anemia, but NOT neurological changes described below Diagnosis: Increased methylmalonic acid (B12 deficiency) Increased urinary formiminoglutamate (folate deficiency) o Manifestations of Vitamin B12 Deficiency: Subacute Combind Degeration: degeneration of myelin in the posterior and lateral tracts of the spinal cord Spastic paraparesis (paralysis of lower limbs) Sensory loss Painful paresthesias (burning, itching) TRACE METALS: Iron: Normal Function: essential in the function of Hb, myoglobin and other enzymes Metabolism: o Tightly regulated storage/availability: Potential cellular toxicity in high concentrations Sequestered from pathogenic organisms (also require iron) Limited ability to dispose of increased iron stores o Total Body Stores: higher in males than females 75%: Hb, myoglobin and enzymes 25%: hepatocytes and reticuloendothelial cells (storage form- ferritin) o Control of Iron Absorption: primary mechanism of regulation of total body iron stores; occurs at the level of the intestinal mucosa 10-15% of dietary iron is absorbed per day Hepcidin (secreted by the liver) inhibits the transfer of iron from mucosal cells to the plasma; therefore, iron remains in the intestinal cell bound to ferritin When iron is needed, ferritin-bound iron is liberated from these cells and transported in the blood via transferrin If it is not used, it is lost with the shed intestinal epithelium Causes of Iron Deficiency: o Dietary: especially meat restricted intake o Infants and Children: increased need, low iron content in milk o Chronic Blood Loss: menses, GI hemorrhage o Impaired Absorption: gastrectomy, chronic diarrhea Pathology of Iron Deficiency: o Microcytic Hypochromic Anemia: due to decreased heme synthesis o Decreased Iron-Containing Enzymes: Nail changes (spoon nails) Atrophic glossitis Esophageal webs o Plummer-Vinson Syndrome: atrophic glossitis + esophageal webs + microcytic hypochromic anemia o Lab Findings: Decreased serum ferritin Decreased bone marrow hemosiderin Increased total iron binding capacity (TIBC) due to increased transferrin Decreased transferrin saturation (generally 1/3 saturated) o Stages of Iron Depletion: Decreased ferritin and increased TIBC precede anemia Decreased Hb and hematocrit precede microcytic picture Deficiencies of Other Trace Metals: Cause: o Patients on total parenteral nutrition with inadequate supplementation o Interference with absorption caused by drug or other substance o Inborn errors of metabolism Syndromes: o Zinc: growth and wound healing o Copper: anemia and collagen defects o Iodine: goiter, hypothyroidism o Selenium: chronic pain, cardiac disease o Fluoride: susceptibility to tooth decay Iodine Deficiency: o Iodine deficiency inadequate thyroid hormone production stimulation of pituitary TSH secretion progressive enlargement of thyroid (GOITER) o Hypothyroidism may result from iodine deficiency; may also result from disturbances in Thyroid (primary) Pituitary (secondary Hypothalamus (tertiary) o Clinical Syndromes: Cretinism: impaired neurological development Myxedema: diffuse, systemic connective tissue edema with slowing of mental and physical functions VITAMIN TOXICITY: General: Overdose of water soluble vitamins may be harmless (if renal excretion normal) Fat soluble vitamins, iron and others may be toxic in large quantities Effective overdose may also result from inborn errors of metabolism Vitamin A: o Teratogenesis (13-cis retinoic acid) o Hepatic dysfunction (“polar bear liver” and fibrosis) o Increased intracranial fluid pressure (children; mimics brain tumor) o Non-toxic yellow skin discoloration from large doses of vegetable derived beta-carotene Vitamin B6 (Pyridoxine): o Peripheral neuropathy Iron: o Cause: diet, increased RBC turnoer, genetic disease Hemosiderosis (iron overload due to accumulation of hemosiderin; localized or systemic) Hemochromatosis (acquired or inherited defects) Vitamin D: o Hypercalciuria nephrolithiasis and metastatic calcifications PROTEIN ENERGY MALNUTRITION: Definition: clinical syndromes due to inadequate dietary intake of protein and calories to meet body needs Often seen in children in areas of famine BMI <16 Often coexists with presence of infections, toxic exposures and selective vitamin/mineral deficiencies (can modify what is seen clinically) Body Protein: Somatic Compartment: skeletal muscle Visceral Compartment: protein stores in organs (liver and blood) Pathogenesis: Marasmus: o Cause: severe deficiency of protein AND calories o Result: leads to depletion of the SOMATIC compartment o Compensation for Reduced Calories: Gradual metabolism of body fat and muscle mass Lessening of energy utilization (cellular ion pumps) o Manifestations: Gradual atrophy of muscle mass and loss of fat stores Edema is minimal or absent Low overall rate of metabolic activity (unless there is a concurrent illness or infection that increases it) Mental and emotional impairment Relatively well compensated for if onset of caloric restriction is gradual Kwashiorkor: o Cause: diet that is sufficient in calories but deficient in protein o Result: leads to depletion of the VISCERAL compartment o Manifestations: selective protein-intake deficiency leads to decreased protein synthesis Edema (decreased plasma oncotic pressure) Hepatomegaly (fatty change due to inability to synthesize lipid carriers) Hypermetabolic state (pathologic response to starvation, leading to increased cellular catabolism and worsening already low fuel stores) Mental changes (peevishness, mental apathy) Anemia (nutrient and vitamin deficiency) Vitamin A deficiency blindness (abnormal blood lipid transport) Depigmentation of hair and skin (scaly texture, brittle hair) Oxidative cell injury (imbalance in free radical production and disposal) o Caused/exacerbated by: Concurrent infection Small bowel bacterial overgrowth Selective deficiency of antioxidant nutrients (zinc, vitamin E) o Common Associated Diseases: Infections (parasitic and bacterial) Small intestine bacterial overgrowth Summary: Feature Kwashiorkor Marasmus Edema + Mental Changes + Hepatomegaly + (fatty change) Hair/Skin Changes + Anemia + +/Loss of Appetite + Muscle/SubQ Fat Spared Wasted Immune Status Impaired Impaired PEM-Like Syndromes in Clinical Medicine: Marasmus-Like States: cachexia; can develop in a variety of conditions o Severe heart failure o AIDS o Disseminated malignancy (nutritional and effects of cytokines) Kwashiorkor-Like States: nutritionally compromised patients o Sustained only on IV glucose in the hospital who become acutely ill (infection or other cause) EATING DISORDERS: Obesity: Definition: excess accumulation of fat representing an imbalance between energy intake and energy expenditure o BMI Classification: Stage I obesity >30 Stage II obesity >35 Stage III obesity >40 o Distribution: Central (Android) Obesity: accumulation chiefly around the trunk and viscera Peripheral (Gynoid) Obesity: accumulation in subcutaneous tissues o Related to: Increased size of adipocytes (hypertrophic obesity) Increased number of adipocytes (hyperplastic obesity) Body Weight: o Result of complex interaction between: Adipocytes Encodrine organs (pituitary, thyroid, adrenal) CNS (hypothalamus) o Regulation system designed to maintain energy balance: Afferent System: From fat cells (leptin, adiponectin) From GI organs (insulin, ghrelin, peptide YY) Central processing unit in hypothalamus (neuropeptide Y, pro-opiomelanocortin, AgRP, MSH) Efferent System: Regulating feeding behavior and energy expenditure Etiology of Obesity: complex and includes genetic, physiologic, psychologic and sociologic factors Energy Expenditure: o Basal metabolic rate (70%; determined by lean body mass- genetic, sex and age differences) o Thermic effect of food (15%) o Demands of physical activity (15%) Diseases and Conditions Linked to Obesity: o HTN o Hypercholesterolemia o Insulin resistance (T2DM) o CV disease/atherosclerosis o Some cancers (colon, breast, uterus, prostate) o Gallstones and pancreatitis o Orthopedic problems (osteoarthritis, gout, back pain) o Surgical morbidity and mortality Disorders of Aberrant Eating: Definitions: o Anorexia Nervosa: self-induced semistarvation o Bulemia: binge eating followed by purging o Female Athlete Triad: disordered eating, amenorrhea, loss of bone density o Binge-Eating Disorder: compulsive overeating without purging o Baryophobia: underfeeding of children to prevent later obesity Anorexia Nervosa: o Population: usually females (second decade) o Clinical Features: Rigid dieting/weight loss False body perception Fear of weight gain Preoccupation with food Ritualistic behavior involving food and exercise Binging/purging o Complications: Protein-energy malnutrition Hypoalbuminemia Endocrine dysfunction Amenorrhea Hypothyroidism Anemia Depression Bulimia: o Population: young adults; more often females than males; predisposed to be overweight o Clinical Features: Near normal weight Binge/purge cycles Impulsive behavior Various psychologic disorders Excessive exercise o Complications: Demineralization of teeth Electrolyte imbalance Damage to esophagus/stomach Aspiration pneumonitis Organ toxicity of emetics/laxatives DRUG-INDUCED NUTRIENT DEPLETION/ANTAGONIST: Drugs may produce nutrient depletion or antagonize normal nutrient metabolism Drug Nutrient Cholestyramine Vitamins A,D,E,K (fat soluble) Isoniazid Folate Pyridoxine B6 Pentamidine Folate Trimethoprim Folate Phenobarbitol Vitamin D Coumarin Vitamin K Alcohol Riboflavin, Thiamine, Folate Nitrous Oxide B12 nutrient deficiencies: Mechanism Bile acid sequestration Decreased absorption Schiff-base conversion Impaired utilization Impaired utilization Increased metabolism Impaired metabolism Tissue injury Excess degradation NUTRITIONAL CONSIDERATIONS IN MEDICAL PRACTICE AND HOSPITALIZED PATIENTS: Medical disease with therapeutically or etiologically relevant nutritional aspects: Diabetes mellitus (glucose intolerance) Atherosclerotic CV disease (abnormal lipid metabolism) Chronic renal disease (protein, hormone and drug metabolism) Chronic liver disease (protein, lipid metabolism, hormone and drug metabolism) Malignancies (cachekxia) Diseases associated with substantial excretory losses of nutrients: Protein losing enteropathy (fecal loss of protein) Nephrotic syndrome (urinary loss of protein) Exfoliative dermatitis (cutaneous loss of potein) Nutritional requires increase in medical and surgical patients: due to increase metabolic demands of illness, inflammation and repair Knowledge of nutritional requirements important to avoid iatrogenic malnutrition SIGNS OF MALNUTRITION ON PHYSICAL EXAM: Physical Finding GENERAL APPEARANCE Edema Cachexia and muscle atrophy CUTANEOUS Dermatitis Hyperkeratosis Koilonychia (Spoon Nails) Easily pluckable hair Alopecia (loss of hair) Ecchymoses, petechiae Decubitis ulcers MUCOUS MEMBRANES Bleeding gums Atrophic lingual papillae Glossitis Cheilosis Bitot’s spots Corneal clouding ABDOMINAL AND OTHER ORGANS Goiter Congestive Heart Failure Hepatomegaly Ascites or bowel distention MUSCULOSKELETAL Growth retardation Epiphyseal swelling Bone tenderness Muscle weakness NEUROLOGICAL Opthalmoplegia, nystagmus Dementia Peripheral neuropathy Associated Deficiency (or Excess*) Protein, refeeding syndrome* Protein, energy, selenium Niacin, riboflavin, essential fatty acids, zinc, vitamin B6, vitamin A Vitamins A and C Iron Protein-energy Protein-energy, Zinc Vitamins C, K Proteins, vitamin C, Zinc Vitamin C Niacin, folate, riboflavin, iron, protein, B12 Niacin, folate, riboflavin, B6, B12 Riboflavin, B6, niacin Vitamin A Vitamin A Iodine Thiamine, selenium Protein, vitamin A* Protein Protein-energy Vitamin C (kids), Vitamin D Vitamins C, D, A* Protein, vitamin D Thiamine Vitamin B12, niacin, copper* B6, thiamine