Monday, December 31, 2018

Vitamin deficiencies:


(1) vitamin C (ascorbic acid) :

·         Another name for vit. C is anti-scorbutic factor.
·         Functions: (a) hydroxylation of collagen i.e., lysine and proline. This step is crucial to enable each fibril to form a uniform and flexible connective tissues. Some tissues like skin, gum, bones and mucous membrane contain greater conc. of collagen and thus more susceptible to deficiencies.
·         (b) in the synthesis of adrenal steroid like dopamine, epinephrine, norepinephrine and carnitine (transfer fatty acid from the cell cytosol to mitochondria for energy production).
·         (c) good reducing agent and antioxidant.
·         (d) enhance iron absorption from intestinal tract by converting ferric to ferrous ions.
·         (e) folate metabolism.
·         (f) hydroxylation of tryptophan.
·         (g) bile acid synthesis.
·         Sources of vit. C: (humans cannot synthesize it due to absence of gulonolactone oxidase.)
·         Citrus fruits (orange, lemon, grapefruits), vegetables (spinach, sprouts, broccoli, tomato)
·         Ascorbic acid can be easily destroyed by heat. Biologically half-life is about 30 min.
·         There is no storage site for it.
·         Deficiencies: (1) Scurvy: clinical manifestation can be seen within 8 to 12 weeks.
·         Petechiae (red or purple spot caused by internal bleeding into skin)
·         Anemia, bone-pain, bleeding of gums, swelling, fatigue, perifollicular hemorrhage and easy bruising in lower extremities.
·         Late stages: edema, neuropathy, intracerebral hemorrhage, oliguria (production of abnormally small amount of urine) and death, malaise (uneasiness), lethargy, coiled hairs, poor wound healing, ecchymosis –(discoloration of skin resulting from bleeding underneath).
·         Inability to produce collagen in absence of vit. C leads to breakdown of tissues.
·         Deficiency of iron metabolism leads to anemia.

(2) vitamin B1 (thiamine):
·         Functions: (a) active form is thiamine pyrophosphate (TPP).
·         (b) TPP has a role in nerve conduction (activates a Cl- channel in nerve membrane)
·         (c)in the decarboxylation reactions as coenzyme for e.g., PDH converts pyruvate to acetyl-CoA. And alpha-ketoglutarate dehydrogenase in TCA converts alpha-KG to succinyl CoA.
·         (d) most important to make ATP.
·         Sources: yeast, whole wheat flour, unpolished rice beans, seeds or legumes, nuts etc.
·         Deficiency: (1) dry beriberi: involves both CNS and PNS. Decreased muscle function, mental confusion, involuntary eye movement, muscle paralysis, damaged nerves.
·          (2) wet beriberi: effect heart, marked peripheral vasodilation, tachycardia, cardiomegaly, pulmonary and peripheral edema, right heart is enlarged, increased QT intervals, shortness of breath, rapid heart rate. In extreme cases beriberi is associated with Wernicke-Korsakoff syndrome. This causes brain damage (thalamus and hypothalamus)
·         (3) peripheral nervous system (tenderness and cramping of muscles),
·         (4) CNS: Wernicke's encephalopathy and Korsakoff syndrome that permanently impairs memory.
·         Causes: people on processed white rice diet (low thiamine), alcohol abuse, genetic beriberi (body doesn’t absorb thiamine), hyperthyroidism (overactive thyroid gland).

(3) vitamin B3 (niacin):
·         Synthesized from tryptophan
·         Active form is NAD+ or NADP+  (nicotinamide adenine dinucleotide phosphate)
·         Functions: (a) as coenzyme in oxidation-reduction reactions NAD+ linked enzyme e.g.,  LDH, PDH, KGDH, isocitrate DH, G3PDH, etc.
·         (b) NAD is source of ADP-ribose for ADP-ribosylation of proteins.
·         (c) therapeutic use: niacin is a lipid-modifying drug. i.e., it reduces plasma triglycerides and LDL-C level and increases HDL-C levels.
·         Symptoms: (a) dermatitis around neck called casal necklace. (b) red flaky skin, rashes on body, burning patches, (c)  anorexia, burning sensation, numbness, severe diarrhea leads to malabsorption due to atrophy of intestinal villi, (d) nervous symptom: insomnia, depression.
·         4Ds of pellagra: 1. Dermatitis (photosensitive)  2. Dementia  3. Diarrhea  4. Death.
·         Causes: (1) primary: a diet low in niacin or tryptophan, common in people with staple diet i.e., corn and maize- they contain niacytin, a form of niacin that humans cannot digest or jowar- high leucine content inhibit QPRTase, the rate-limiting enzyme in niacin synthesis.
·         (2) secondary: niacin is not absorbed, Hartnup disease (due to intestinal malabsorption and renal reabsorption of tryptophan), Carcinoid syndrome (overproduction of serotonin leads to the diversion of tryptophan from NAD+ pathway), vit. B6 deficiency, certain medications, liver cirrhosis.

(4) vitamin B12 (cobalamin):
·         Water-soluble vitamin, largest and most structurally complicated contains 4 pyrrole rings coordinated with a cobalt atom.
·         Sources: poultry, eggs, yeast, dairy product, fish, soya milk, meat. Does not present in plant foods.
·         Functions: (a) involved in RBCs formation (b) helps to create and regulate DNA (c) metabolism of each cell (d) synthesis of fatty acid and energy production.
·         Active form is methyl-cobalamine. Coenzyme role with methionine synthase in the formation of methionine from homocysteine.
·         Metabolism of vit.B12 = absorption active mechanism site is ileum. Cobalamine binding protein is intrinsic factor (IF).
·         Vit.B12 associate with IF. Actively absorbed from the ileum by binding to IF receptor. IF-receptor in ileum is called CUBULIN. Transport protein in plasma, transcobalamin II (TCII) transport it to target tissues.
·         Causes of vit.B12 deficiencies: (a) only found in animal origin. Hence, strict vegetarians are at risk. (b) malabsorption- pernicious anemia- it is a specific form of megaloblastic anemia caused by autoimmune gastritis and an attendant failure of IF production. (c) gastric causes: congenital absence of IF (d) intestinal causes: Crohn’s disease, IBD, celiac disease, diabetes, gastritis.
·         Deficiencies manifestation: megaloblastic anemia, homocysteinemia (due to the low conversion of homocysteine to methionine), methylmalonic aciduria (due to defective methyl malonyl- CoA mutase which utilize vit.B12 to convert l-methyl malonyl CoA to succinyl CoA), subacute combined degeneration.
·         Megaloblastic anemia is seen in folate and cobalamine deficiency. So, serum methylmalonate test is done to distinguish between the two causes.
·         Symptoms: depression, fatigue, constipation, psychosis, dementia, diarrhea, weight loss, pale skin, sore mouth.

(5) vitamin K :
·         Three forms of vit.K are : vit.K1- phylloquinone-derived from plants (leafy veg like spinach), vitK2- menaquinone-synthesized by bacterial flora in the intestinal tract, vit.K3: menadione, synthetic and water-soluble.
·         Functions: (a) required for post-translational carboxylation of glutamic acid, required for Ca2+ binding. (b) prothrombin (factor II), factor VII, IX, X, Protein C and S, matrix Gla protein, nephrocalcin in the kidney.
·         Deficiencies: (a) drugs like Warfarin (thins blood) competitively inhibit the enzyme required for conversion of vit.K to its active hydroquinone form. (b) low-fat stores or fat malabsorption in babies- celiac disease, cystic fibrosis, liver immaturity, poor placental transport, elevated prothrombin time, bleeding time, antiobesity drugs.
·         Vit.K refers to fat-soluble vit. Play role in blood clotting, bone metabolism and regulating Ca2+ levels.
·         Vit. K is needed for prothrombin production, a protein and clotting factor.
·         Vit. K1 from plants is converted to vit.K2 –storage form in fatty tissue and liver.
·         Sources: fruits and leafy veg,. Meat, dairy products and egg.
·         Secondary vit.K deficiency occur in people with bulimia and those who taking anticoagulants.
·         Vit. K deficiency has been defined as a vit-K responsive hypoprothrombinemia which increases prothrombin time and can result in coagulopathy, a bleeding disorder.
·         Osteoporosis and coronary heart disease is associated with low levels of K2.
·         Symptoms: excessive bleeding, bruising, small blood clots, heavy menstrual periods, blood in urine and stool.
·         Diagnosis: PT test (prothrombin time),
·         Supplements: phytonadione.

(6) vitamin A (retinoids) :
·         Provitamin A is carotene.
·         Cleaved in intestine by dioxygenase.
·         Retinoids: (a) Retinal – 11 cis retinal for normal vision, (b) retinol- reproduction,  (c) retinoic acid- cell differentiation, normal morphogenesis.
·         Metabolism:                          
beta-carotene is absorbed from plants through the action of beta-carotene-dioxygenase it is cleaved to 2 molecules of retinal. by the action of retinol reductase retinal is reesterified to retinol esters amd transported in chylomicrons (apoE receptor) to the liver where it is reduced to retinol and transported to target cells by retinol-binding protein (RBP).
·         Functions: (1) regulation of gene expression and differentiation, act like steroid hormones, bind to nuclear receptors, (2) normal reproduction, (3) normal vision: rhodopsin( formed by covalent association then between 11-cis retinal+ 7-transmembrane rod protein called opsin)
           isomerase                                                          
                                 11-trans retinal binds to opsin and forms rhodopsin and by the action of    Light, it is converted back to  All trans retinal  +  opsin
·         (4) antioxidant properties , (5) host resistant to infection.
·         Deficiency manifestation: (a) eye lesions, loss of sensitivity to green light (b) night blindness (c) impairement in adaptation to dim light (nyctalopia) (d) dryness of Conjunctiva (e) Bitot spots (Conjuctiva keratinizes), (f) Cornea Keratinizes (Corneal Xerosis)
·         All these ocular manifestation are called Xerophthalmia.
·         Skin and mucosa: hyperplasia and hyperkeratinisation of epidermis produce follicular dermatosis. This is called Phrynoderma or toad skin. Mucus secreting epithelium of respiratory and urinary tract.
·         Hypervitaminosis A: lysosomes damaged, decreased cognition, hepatomegaly.
·         Retinoic acid stimulates osteoclast production and leads to increased bone resorption and high risk of fractures.
·         Sources: fish liver oil, egg, butter, cheese, meat, carrot, spinach, papaya, mango.
·         Xerophthalmia: lack of vit. A can dry out tear ducts and eyes. Lead to an ulcer on the cornea or white spots on eyes, conjunctiva dryness.
·         Nightblindness: nyctalopia due to the absence of retinal in the visual pigment, rhodopsin., causes cataract, diabetic retinopathy, inability to adapt to reduced illumination.

(7) vitamin D:

·         Vit. D2 (Ergocalciferol): obtained from fungus.
·         Vit. D3 (Cholecalciferol) : an endogenous synthesis from 7-dehydrocholesterol
·         Metabolism:
·         When Ca2+ levels are high and PTH is absent, kidney produces 24, 25-dihydroxycholecalciferol which is excreted through urine.
·         Functions: (a) regulation of Ca2+ and phosphate homeostasis: vit.D increases Ca2+ absorption in duodenum and phosphate reabsorption in the kidney.
·         (b) it stimulates osteoblasts to synthesize calcium binding protein osteocalcin involved during bone development.
·         Clinical manifestations: (a) Rickets: protruding abdomen, fractures, spine-scoliosis, kyphosis, lordosis, respiratory infections, bone pain, tenderness, bow-legs, enlargement of wrists and ankles.
·         Causes of rickets are : vit.D deficiency, serum Ca2+ and phosphate levels low, this causes secondary hyperparathyroidism, so PTH is high. This increases 1-alpha-hydroxylation so 1,25-D levels increases. Serum Ca2+ increases and thus ca2+ levels is variable but phosphate remains low.
·         Osteomalacia: softening of bones, deficiency of vit.D and Ca2+, easy bone fractures, muscle weakness, dull pain, and numbness.
·         Osteoporosis: the weakening of bones, bones become weak and brittle due to low bone mass and bone tissue loss, bone-density decreases, hormone imbalance (PTH, growth hormone), accelerates after menopause (low estrogen), Ca2+, Phosphate, and vit.D levels decreases.
·         Symptoms: bone fragility, bone demineralization, chronic back pain, rheumatoid arthritis, thyroid problems.
·         Sources: sunlight, liver, egg yolk, fish.
·         Assay: 25-OH D is measured.
                                                                                                                        


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