FatSoluble Vitamin Deficiencies

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Fat-Soluble Vitamin Deficiencies

• Andrew Ukleja, M.D., C.N.S.P.
• Assistant Professor of
  Medicine
• Director of Nutrition
  Support Team
• Department of
  Gastroenterology
• Cleveland Clinic
• Weston, FL

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Objectives

• To review
• Functions of fat-soluble vitamins (A,D,E,K)
• Symptoms and signs of vitamin deficiencies
• Treatment of vitamin deficiencies

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Vitamin Deficiencies

• It takes months to years for fat soluble vitamin
  deficiencies to develop because of relatively
  large stores
• Result of
• Decreased intake
• Decreased absorption
• Increased utilization
• Increased loss

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Vitamin A
RETINOL
RETINAL (RETINALDEHYDE)
RETINOIC ACID
BETA-CAROTENE
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Metabolism of Vitamin A

• Absorption proximal small bowel
• Transported by chylomicrons (retinyl ester
  retinol)
• Stored in liver (esters CRBP cellular retinol
  binding protein)
• Stellate cells 80-90
• Hepatocytes 10-20
• Released into plasma as retinol RBP (bound to
  prealbumin)
• From diet 50 stored in the liver
• 20 excreted in feces (from bile)
• 17 excreted in urine
• 10 not absorbed
• 3 CO2

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Functions of Vitamin A

• Vision
• Phototransduction
• Regulation of gene expression
• Immunity
• Maintenance of the integrity of skin, and mucosal
  cells (airways, digestive and urinary tract)
• Differentiation of WBC, activation of
  T-lymphocytes
• Growth and development
• Red blood cell production
• Stem cells differentiation into red blood cells
• Mobilization of iron from storage sites

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Vitamin A and Vision
Photoreceptor (Rod) Cell
Retinal Pigment Epithelium
Capillary
11-cis-retinal
11-cis-retinal
LIGHT
Rhodopsin
11-cis-retinol
Neuronal signaling
Opsin
Opsin

All-trans-retinyl ester
all-trans-retinal
VISION
All-trans-retinol
all-trans-retinol
All-trans-retinol
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Dietary Sources of Vitamin A

• Animal foods Liver, fish oil, kidney, egg yolk,
  butter
• Plants Carrots, dark green leafy vegetables
  (beta-carotene), spinach, broccoli, sweet
  potatoes
• RDA 700-900 mcg
• 1mcg of retinol3.33 IU of vit. A

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Vitamin A Deficiency

• Ancient Egyptians recognized that night blindness
  could be treated by consumption of liver
• 3rd most common nutritional deficiency in the
  world
• Night blindness, complete blindness, and
  xerophthalmia common in malnourished children in
  Asia, Africa, and South America
• Vitamin A deficiency is rarely seen in the United
  States

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Causes of Vitamin A Deficiency

• Inadequate intake (strict vegetarian diet)
• Fat malabsorption
• Crohn's ileitis
• Pancreatic insufficiency
• Cystic fibrosis
• Cholestatic liver disease
• Severely limited protein intake
• Vit. A carried by RBP

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Vitamin A Deficiency Clinical Manifestations

• Night blindness
• Bitot's spots
• - Abnormal squamous cell proliferation and
• keratinization of the conjunctiva
• Xerophtalmia
• 3. Irreversible eye conditions
• Xerosis
• Corneal perforation
• Keratomalacia
• Punctate keratopathy

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Vitamin A Deficiency

• Dermatologic manifestations
• Follicular hyperkeratosis
• (Dry, rough, scaly skin)
• Destruction of hair follicles
• Impairment of the humoral and cell mediated
• immune response
• direct and indirect effects on phagocytes / T
  cells
• ? incidence of respiratory
  disease/diarrhea
• ? rate of mortality from infections in
  children

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Assessment of Vitamin A Status

• Biochemical
• Deficiency serum vit. A level (
• 50 increase in RDR assay - change in serum
  retinol level before and 5 hrs after oral dose of
  450-1000 mcg of retinyl ester
• Histologic (conjunctival impression cytology)
• Physiologic (measurement of dark adaptation)
• Dietary

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Assessment of Vitamin A Status

• Serum retinol levels vary widely
• Serum retinol level is not influenced by dietary
  intake
• ? in serum retinol by 20 after a challenge dose
  indicates limited hepatic stores
• Healthy Ratio of plasma retinol / RBP 1

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Supplementation of Vitamin A

• Tolerable upper level for adult 10,000 IU/d (3
  mg/d)
• MVI supplement - 5,000 IU (1.5 mg) of vitamin A
• Retinol intake of 5,000 IU/day have been
  associated with ? risk of osteoporosis in older
  adults
• Rx of Vit. A deficiency 30 mg of retinol
  palmitate, single IM injection (children)

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Vitamin D
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Vitamin D

• Vitamin D and its metabolites play an important
  role in calcium homeostasis and bone metabolism
• Vitamin D deficiency (referred to "rickets) was
  first described in the mid 1600s by Whistler and
  Glisson
• Severe bone-deforming disease enlargement of
  epiphyses of long bones, bowing of the legs,
  bending of the spine and toneless muscles

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Vitamin D Metabolism
ultraviolet light
P450
Intestinal absorption
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Functions of Vitamin D
Low Calcium
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Functions of Vitamin D

• Calcium homeostasis
• Immune response
• ? IL4 production, ? T cell activity
• Cell growth and differentiation
• Apoptosis
• Protects against peroxidation

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Sources of Vitamin D

• Vitamin D is found naturally in very few foods
• Dietary source fatty fish (mackerel, salmon,
  sardines), cod-liver oil, eggs yolks
• Fortified milk (vitamin D2/D3), cereals and bread
  products, orange juice
• Infant formula is fortified with vit. D (400 IU
  per quart)

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Causes of Vitamin D Deficiency

• Impaired availability of vitamin D
• Inadequate intake of vitamin D
• Fat malabsorption
• Lack of photoisomerization
• Impaired hydroxylation to 25-hydroxy-vitamin D
• liver disease
• Impaired production of 1,25(OH)2-vitamin D
• kidney disease

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Risk Factors for Vitamin D Deficiency

• Exclusively breast fed infants - human milk 25
  IU/L of vit. D
• Dark skin - ? vit. D synthesis with exposure to
  sunlight
• Fat malabsorption - ? absorption of vit. D
• Elderly - ? synthesis of vit. D in the skin
  stay indoors
• Institutionalized adults
• Obesity - vit. D deposited in body fat stores

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Findings in Vitamin D Deficiency

• ? intestinal absorption of calcium and phosphorus
• Hypocalcemia
• Hypophosphatemia
• Phosphaturia
• Secondary hyperparathyroidism (bone resorption)
• Demineralization of bones
• Osteoporosis/ostoemalacia in adults
• Rickets in children
• Muscle pain/weakness

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Vitamin D Deficiency Children

• Rickets
• Failure of bone mineralization in infants and
  children
• Delayed closure of the fontanels (soft spots) in
  the skull
• Deformed rib cage in infants
• Seizures from hypocalcemia

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Assessing of Vitamin D Status

• Serum 25(OH)D3 level
• Normal level ? 75-125 nmol/L
• Severe deficiency
• Serum 1,25(OH)2 D level
• Undetectable in severe deficiency
• PTH level
• BMD (DEXA scan)

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Vitamin D Supplements

• RDI 400 IU (0.01 mg of vit. D3)
• Multivitamin supplements with vit. D
• Children 200 IU (5 mcg)
• Adults 400 IU (10 mcg)
• Vitamin D (D3) supplement 400-1,000 IU
• Older adults (65 years) those with minimal sun
  exposure should take 800 IU/d of vit. D

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Treatment of Vitamin D Deficiency

• Osteomalacia
• Vit D3 orally 4,000-8,000 IU/d (0.1-0.2 mg)
• If malabsorption up to 50,000 IU/d orally
• Monitor 25-OH-vit. D levels q 3-4 weeks until
  normal
• MVI IV form contains 200 IU of vit. D2
• Sun exposure 10-15 minutes of on the arms and
  legs at least x3 weekly

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Vitamin E

• The name tocopherol came from the Greek word of
  "toc" (child) and "phero" (to bring forth) to
  describe its role as an essential dietary
  substance in normal fetal and childhood
  development

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Functions of Vitamin E

• A free radical scavenger, protects PUFA (a
  structural component of the cell membranes) from
  peroxidation
• Inhibits activity of protein kinase C
• Affects the expression and activity of immune and
  inflammatory cells
• Inhibits platelet aggregation and enhances
  vasodilation

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Vitamin E

• Suboptimal intake of vit. E is relatively common
  in the U.S.
• Food source vegetable oils (olive, sunflower,
  safflower), nuts and seeds, whole grains, green
  leafy vegetables
• Vit. E is destroyed by heat
• The RDA for vitamin E
• Women 8 mg/d
• Men 10 mg/d

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Metabolism of Vitamin E

• Intestine Pancreatic esterases brake down
  tocopheryl-ester bonds between vitamin E and
  fatty acids
• Liver alpha-tocopherol is packaged within VLDL
  molecules
• Blood Transported by A-tocopherol transfer
  protein
• Vit. E is stored in adipose tissue (90)

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Causes of Vitamin E Deficiency

• Severe malnutrition / cirrhosis
• Genetic defects affecting the alpha-tocopherol
• transfer protein/abetalipoptoteinemia
• Fat malabsorption syndromes
• Pancreatic insufficiency
• Celiac disease
• Regional enteritis
• Small bowel bacterial overgrowth
• Cystic fibrosis
• Cholestatic liver disease
• Postgastrectomy syndrome
•  

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Vitamin E Deficiency

• Vitamin E deficiency is uncommon due to the
  abundance of tocopherols in our diet
• Divided to
• Subclinical (low serum tocopherol level)
• Clinically evident
• Consequences of vit. E deficiency
• Neuromuscular disorders
• Hemolysis

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Symptoms of Vitamin E Deficiency

• Neurological
• Spinocerebellar ataxia
• Peripheral neuropathy
• Muscle weakness/skeletal myopathy
• Pigmented retinopathy (retinitis pigmentosa)
• Hematologic
• Hemolysis- ? red blood cell life span
• Hemolytic anemia common with vitamin E deficiency
  in premature infants

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Evaluation of Vitamin E Status

• Serum total alfa-tocopherol concentration
• Normal level 0.5 mg/dL
• Tocopherol isomers (by HPLC)
• Peroxide hemolysis test (2 hydrogen peroxide)
• Tocopherol/total lipids ratio
• Normal 0.8mg/g

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Vitamin E Supplementation

• Tolerable upper intake 1,500 IU/d (1,000 mg/d)
• Side effects impaired blood clotting/ ? risk of
  hemorrhage seen in adults with vit. E mg/d
• Large oral supplements of vit. E have been
  associated with
• Necrotizing enterocolitis in infants
• Higher mortality due to hemorrhagic strokes in
  adults
• Impaired absorption of vitamins A and K seen with
  large vitamin E supplements in animals

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Vitamin K
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Vitamin K

• The "K" is derived from the German word
  "koagulation
• Two forms of vitamin K
• Vitamin K1 (phylloquinone) - dietary from plants
• Vitamin K2 (menaquinone) - synthesized by gut
  micro-flora
• Vitamin K is essential for the functioning of
  several proteins involved in blood clotting

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Metabolism of Vitamin K

• Vitamin K is absorbed in the distal small
  intestine
• Dietary vitamin K is protein-bound and requires
  liberation by proteolysis (pancreatic enzymes)
• Bile salts solubilize vitamin K into micelles for
  absorption into chylomicrons (transport via
  portal circulation to the liver)
• Microorganisms of the colon and distal ileum can
  synthesize absorbable vitamin K

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Functions of Vitamin K

• A major role in coagulation pathways
• Essential for activity of carboxylase enzymes
• responsible for carboxylation of glutamate to
  gamma-carboxyglutamate (liver)
• Clotting factors prothrombin, factors VII, IX,
  X
• Anticoagulant proteins C, S
• Osteocalcin
• Hydroxylation of osteocalcin (bone matrix)

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Vitamin K

• Dietary source
• Liver
• Oils (soy, canola, olive)
• Green leafy vegetables (spinach, broccoli)
• Current DV for vitamin K 65-80 mcg/d

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Vitamin K Deficiency

• Vitamin K deficiency is rare in adult
• Factors protecting from vit. K deficiency
• Wide distribution of vit. K in plants and animal
  tissue
• Production of vit. K by gut micro-flora
• Recycling of vitamin K
• ? vitamin K levels seen with prolonged fasting or
  starvation
• Acquired deficiency can occur secondary to
• Long-term use of antibiotics

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Causes of Vitamin K Deficiency

• TPN (no dietary intake)
• Rx Vit.K 1 mg/week
• Malabsorption
• Rx vit.K 1-2mg/d p.o.
• Biliary obstruction
• Liver disease
• Drugs
• Coumarins, salicylates, antibiotics, vit. AE

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Signs and Symptoms of Vitamin K Deficiency

• Mucosal bleeding
• Easy bruisability
• Splinter hemorrhages
• Melena
• Hematuria

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Vitamin K Deficiency Hemorrhagic Disease of the
Newborn

• Causes
• Poor transfer of lipids via placenta
• Immature liver
• Sterile GI tract
• Breast milk low in vit. K
• Infants at risk
• Diarrhea
• Malabsorption
• CF
• Cholestasis
• TPN
• Rx 1mg I.M. of vit. K

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Determination of Vitamin K Status

• Measurements
• Levels of vitamin K-dependent factors
• (prothrombin, factors VII, IX, X, protein C)
• Vitamin deficiency factor levels
• Plasma Vit. K level (normal 0.2-1.0 ng/ml)
• Plasma Des-gamma-carboxyprothrombin (DCP)
• Normal subjects DCP0
• Vitamin K deficiency ? DCP

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Vitamin K

• Treatment of coagulopathy
• Vitamin K in doses 1-25 mg orally, IM, IV, SC
• Vitamin K IV can cause severe anaphylactic-type
  reaction
• Prevention of hemorrhagic disease of the newborn
• Vitamin K 0.5-1 mg IM at birth