Vitaminology & Trace Elements

Abayomi O. Akanji Professor of Clinical Pathology Faculty of Medicine Kuwait University

What are Trace Elements?
Trace elements are those elements that occur in human and animal tissues in mg/kg amounts or less. Essential when:
– deficient intake ►impairment of function – restoration with physiological amounts of only that element prevents/alleviates impairment.

Classification of Trace Elements
 Defined biochemical functions + signs of deficiency in humans
 Fe, Zn, Cu, Co, I, Mo, Se, fluoride

 Signs of deficiency; no clear biochemical functions
 chromium, boron

 Clear biochem function; no clear deficiency signs
 manganese

 No clear biochemical functions/ deficiency signs
 Ni, Si, Va, arsenic, Br, Pb, tin, Li

Trace Element Functions
 amplification- small amounts produce dramatic effects on the body e.g. Fe deficiency & anaemia  specificity- cannot be effectively replaced by chemically similar constituents  homeostasis- regulated mechanisms for absorption, storage and excretion - storage proteins such as ferritin & metallothioneins important in regulation of Fe, Zn, Cu  interactions- overabundance of one trace element can interfere with metabolic use of another e.g. large dietary Zn affect Cu absorption.

Assessment of trace element status
• clinical response to therapeutic supplementation
• measurement of metalloenzyme activities • tissue levels, but usually invasive to obtain – Hair & fingernails often used, but subject to environmental contamination, tap water, shampoo, soap – other body fluids : blood, RBC, urine, saliva, semen - but levels do not always effectively reflect tissue status • levels of binding proteins:
– caeruloplasmin for Cu – ferritin for Fe. *VERY IMPORTANT TRACE ELEMENTS STUDIED ELSEWHERE* IRON - haematology, anaemia; IODINE - thyroid hormones

Copper
- essential trace metal present in many intracellular enzymes

e.g. cytochrome oxidase, superoxide dismutase, tyrosinase, - present in plasma in association with the copper-binding protein, caeruloplasmin. Balance: (next slide) Laboratory Assessment: 1. serum copper : ~10-22 µmol/L, ~ 90% bound to caeruloplasmin 2. serum caeruloplasmin - normal adult levels 200-600 mg/L - an acute phase reactant. - levels useful in interpretation of serum copper levels. 3. urinary copper : ~ 0.1µmol/day

Copper balance

Cu deficiency: typically found in: - Premature babies : copper stores in liver laid in 3rd trimester - adults : malabsorption e.g. after intestinal surgery, prolonged parenteral nutrition Cu toxicity : usually iatrogenic ►renal tubular damage Inborn Errors of Cu Metabolism: Wilson’s disease (hepatolenticular degeneration): • results from copper deposition in liver, brain, kidney, and lens of eyes • defect in gene encoding for enzyme responsible for Cu excretion in bile and urinary reabsorption • high urinary and tissue Cu, low serum Cu & caeruloplasmin Menke’s Syndrome : rare and fatal • presents in children as growth failure, mental retardation, bone and vascular lesions, hair and skin changes. • X-linked genetic defect in copper transport and storage • ▼serum, liver, brain Cu, ▼caeruloplasmin & cytochrome oxidase activity

Biochemical Changes in Wilson’s disease

Zinc
 essential

trace metal present in up to 200 metalloproteins with a wide variety of functions
e.g. carbonic anhydrase, RNA/DNA polymerases, alcohol dehydrogenase, alkaline phosphatase, steroid hormone receptors

 present in all protein-rich foods in plasma, bound to
Albumin 90% α2-macroglobulin 10%

major role in protein synthesis, gene expression, stabilization of nucleic acids and subcellular organelles and wound healing.

Zinc Balance

Laboratory Assessment of Zinc Metabolism
1. serum zinc: < 5.0 µmol/L = deficiency – Levels fall during an acute phase reaction to injury or infection 2. Other body tissues and fluids: - urine, saliva, semen, hair, RBC, WBC 3. best demonstration of marginal zinc deficiency - positive response to supplementation

Inborn Disorders of Zinc Metabolism
1. Acrodermatitis enteropathica : retarded growth, hypogonadism,

dermatological and ophthalmic lesions, GIT disturbances. - Low serum Zn + symptoms reversed by Zn supplementation 2. Sickle cell disease : ? reason

Skin lesions in zinc deficiency – acrodermatitis enteropathica

Acquired Disorders of Zinc Metabolism
Zinc deficiency • Associated with:
- pregnancy: from increased fetal demands - Nutritional: low zinc diet with high fibre content - chronic alcoholism: increased urinary zinc excretion - GIT disease; malabsorption; prolonged parenteral nutrition

• Features: growth retardation, testicular atrophy, oligospermia, hepatosplenomegaly, dermatitis, poor wound healing. • Reversed by Zn supplementation. Zinc toxicity : uncommon • usually iatrogenic from environmental exposure (zinc fumes). • Accidental ingestion : GIT symptoms.

Chromium
• essential trace metal, important in glucose and lipid metabolism • potentiates insulin action –
– deficiency ►insulin resistance

• present mainly in meats and whole-grain products • in plasma, bound to β-globulins, specifically transferrin Balance : • poorly absorbed in upper small intestine - only 0.3-2.0% of dietary intake. • Significant occupational exposure from steelmaking, electroplating leather tanning and photographic industries

Disorders of Chromium Metabolism
Laboratory Assessment : serum chromium: 0.12-2.10 µg/L urine chromium: 100 - 200 ng/day Others : hair 0.1-4.1 µg/g RBC 20-36 µg/L Chromium deficiency : Causes : - GIT disease and malabsorption - prolonged parenteral nutrition Features : insulin resistance; Reversed by Cr supplementation. Chromium toxicity : usually iatrogenic from occupational exposure ►allergy, conjunctivitis, dermatitis, GIT symptoms, hepatitis.

Selenium
• present in enzymes: glutathione peroxidase, thyroxine deiodinase • important as an anti-oxidant and in thyroid hormone metabolism • present mainly in meats, dairy, cereals and grains • in tissue, present as selenocysteine and selenomethionine Laboratory Assessment : • serum selenium: 46-143 µg/L; urine selenium: 7.0-160 µg/L • Others: hair 0.2-1.4 µg/g; RBC 75-240 µg/L • Assay of RBC glutathione peroxidase activity Selenium deficiency : Causes : - GIT cancer, pregnancy, protein-calorie malnutrition - prolonged parenteral nutrition Associated with : Keshan disease - an endemic cardiomyopathy in China Kashin-Beck disease : endemic osteoarthritis in China Selenium toxicity: • associated with loss of hair and nails, skin lesions, CNS abnormalities.

Fluoride
• unique action in preventing tooth decay • inorganic fluoride readily absorbed in small intestine and distributed almost entirely in bones and teeth. • tightly regulated by renal excretion • significant dietary contribution from drinking water • other sources: seafood, tea, cow milk, cereals • excessive intake : mottled teeth, skeletal changes, ligament calcification Laboratory Assessment : concentrations : serum: 10-200 µg/L; urine : 0.2-3.2 mg/L; RBC: 450 µg/L

•Manganese
– constituent of many metalloenzymes – • arginase, pyruvate carboxylase, superoxide dismutase – activator for enzymes: • hydrolases, kinases, decarboxylases – associated with formation of connective & bony tissue, reproduction & growth functions, CHO & lipid metabolism – widely distributed in tissues • highest concns in bone, liver, pancreas – poorly absorbed from small intestine – homeostasis maintained primarily through biliary excretion Significance
- proven role in manganese-dependent enzymes - No direct evidence of human manganese deficiency.

Cobalt: only known function: integral component of vit B12 Molybdenum: in metallo-enzymes: xanthine oxidase, aldehyde oxidase - no well-defined cases of dietary human deficiency

Vitamins
• Definition:
– unrelated organic catalysts that are not endogenously synthesized but necessary in trace amounts for normal metabolism

• Classification:
– Water soluble:
• B-Complex: B1 (thiamine), niacin, folate, riboflavin (B2), pyridoxine (B6), cyanocobalamin (B12), • Others: ascorbate (C)

– Fat-soluble:
• A (retinol), D (cholecalciferol), K (phytomenadione), E (tocopherol)

Vitamin deficiency
Causes: – Inadequate intake with normal requirements – Impaired absorption – Impaired metabolism (e.g. vitamin D) – Increased requirements e.g. pregnancy – Increased losses • • • Deficiencies typically multiple Vitamin deficiency ► mobilization of body stores ► tissue depletion ► biochemical impairment (sub-clinical deficiency ► frank deficiency Functions typically intracellular • Plasma concns do not reflect intracellular levels or function – unreliable • Tissue concns most reliable but not always easily available

Water-soluble Vitamins– folate & B12 not considered here Vitamin sources
B1 thiamine
B2 riboflavin B6 pyridoxine niacin Cascorbate Whole grain cereals, organ meats, flours, nuts, green vegs Milk, organ meats, eggs, green vegs Meat, poultry, fish, potatoes, vegetables

function
Cofactor in metabolism of pyruvate and 2-oxoglutarate and in pentose phosphate shunt (transketolase) Oxidation-reduction enzymatic actions Enzyme systems –amino acid transaminases, phosphorylases, decarboxylases

Whole grain, meat, fish, Coenzymes – NAD, NADP – in legumes, nuts, cereals, glycolysis and oxid phosphorylation Citrus fruits, tomatoes, Antioxidant, formation of connective melons, cabbage, straw tissue & catecholamines; cholesterol berries, green vegs metabolism

Fat-soluble Vitamins
Vitamin sources
A - retinol Animal – fish liver oils,
butter, milk, liver, eggs Plants – green/yellow vegs, margarine, fruits

function
Vision, growth of epithelia, immune responses, reproduction, anticancer agent; constituent of retinal pigment rhodopsin Antioxidant – membrane stability, cardiovascular disease prevention, RBC function; fertility

E–

Vegetable oils, wheat tocopherols germ, rice germ, nuts, legumes, green vegs K-

Green vegetables, Coagulation factors – prothrombin, spinach, cabbage, liver, VII, IX, X; osteocalcins – binding of synthesis in intestine calcium to proteins Fish liver oils, fortified Calcification of bone and teeth (will milk, sun exposure, be considered in greater detail later) small amounts in butter, eggs, liver, salmon

D– calciferol

VITAMIN DEFICIENCIES

Complications of Vitamin A deficiency

LESIONS RESULTING FROM VITAMIN A DEFICIENCY

LESIONS IN RICKETS

Complications of Thiamine (vitamin B1) Deficiency (Beri-beri)

Complications of Niacin Deficiency (Pellagra)

Complications of Riboflavin (vitamin B2) Deficiency

Complications of Ascorbate (Vitamin C) Deficiency

LESIONS IN SCURVY

Classification of Vitamins

Hypervitaminosis
Classically seen with fat-soluble vitamins: A, D Seen with excessive vitamin nutritional supplements • Hypervitaminosis A
– Acute toxicity: neurologic symptoms: headache, vomiting, stupor, papilloedema – Chronic toxicity: neurologic, skeletal (loss of cortical bone), cutaneous (fissuring, ulcers), hepatomegaly with parenchymal damage. – Symptoms subside with discontinuation of excess vit A intake

• Hypervitaminosis D: ▲intestinal absorption of Ca, PO4
► hypercalcaemia, hyperphosphataemia, bone resorption ►renal calculi, osteoporosis, metastatic calcification

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