LECTURE 8 (Fat soluble vitamins + B12, B9) Flashcards
Which vitamins are Non-B Vitamins?
Vitamins A, C, D, E & K
[all fat soluble except for Vitamin C)
Which vitamins are fat soluble?
Vitamins A, D, E & K
Describe the absorption of Non-water soluble vitamins
- Together with other lipids, fat-soluble vitamins form MICELLES in JEJENUM
[hydrophobic groups inside + hydrophilic groups outside] - Absorbed by ENTEROCYTES -> packaged into CHYLOMICRONS -> secreted into LYMPH
Describe Fat Malabsorption
Leads to deficiencies of fat-soluble vitamins
CAUSES:
- Abnormal bile/pancreatic secretions
- Disease/resection of intestine
MANIFESTATIONS:
- Cystic fibrosis (lack of pancreatic enzymes)
- Celiac sprue
- Crohn’s disease
- Primary biliary cirrhosis
- Primary sclerosing cholangitis
What are the properties of Vitamin A?
- Includes retinal, retinol and retinoid acid
- Found in liver and leafy vegetables
- Stored in liver -> it takes years to develop deficiency
What is the function of Vitamin A?
- Antioxidant
- Constituent of visual pigments (retinal)
- Essential for normal differentiation of epithelial cells into specialised tissues
- Prevents squamous metaplasia
What is the importance of Retinoic acid?
Acts like a hormone -> binds receptors in nucleus -> regulates/controls protein synthesis
Describe the important examples of Retinoic acid
KERATIN (important for maintenance of healthy skin)
- Limit/control keratin production
- Retinoic acid used in treatment of PSORIASIS
MUCOUS
- Limit/control production in epithelial cells
Describe Vitamin A deficiency
Vitamin A deficiency is when your body lacks the amount of vitamin A it needs to function properly
MANIFESTATIONS:
- Night blindness (NYCTALOPIA)
[often the first sign]
- Dry, scaly skin (XEROSIS CUTIS)
- Dry eyes (XEROPHTHALMIA)
[Keritinisation of cornea -> blindness]
- Corneal degeneration (KERATOMALACIA)
- Corneal squamous metaplasia -> Bitot spots (keratin debris + foamy appearance on conjunctiva)
- Immunosuppression
- Growth failure in children
In which disorders is Vitamin A therapy used?
- Measles
(used in resource-limited countries) - Psoriasis (skin disorder)
- Severe cystic acne (skin disorder)
- Acute promyelocytic leukaemia
What are the properties of Vitamin A therapy used in Acute promyelocytic leukaemia?
- All-trans-retinoic acid (ATRA/tretinoin) = synthetic derivative of retinoic acid
- Induced malignant cells to complete differentiation
Describe Hypervitaminosis A (Vitamin A excess)
Usually occurs from chronic, excessive supplements
ACUTE TOXICITY SYMPTOMS:
- nausea/vomiting
- Increased intracranial pressure (vertigo, blurred vision)
CHRONIC TOXICITY SYMPTOMS:
- Alopecia
- Dry scaly skin
- Hepatic toxicity and enlargement
- Arthralgias (joint pain)
Why is Accutane not prescribed to pregnant women?
Isotretinoin (Accutane) is a TERATOGEN (substances that cause congenital disorders in a developing embryo or fetus) -> A negative pregnancy test and 2 forms of contraception is required before it is prescribed
SIDE EFFECTS ON FETUS:
- Cleft palate
- Cardiac abnormalities
- Ear deformities
- Microcephaly
- Brain fluid accumulation
- Abnormal immune system development
- Learning disabilities
- Facial deformities
What are the two forms of Vitamin D?
- D3 (CHOLECALCIFEROL) from exposure of skin to sun, ingestion of fish, fortified milk & plants
- D2 (ERGOCALCIFEROL) from ingestion of plants, fungi and yeasts
What happens to both of the forms of Vitamin D?
Both are converted to 25-OH D3 (CALCIDIOL - storage form) in liver to the active form 1,25-(OH)2 D3 (CALCITRIOL) in kidney PCT
What is I alpha-hydroxylase regulated by?
PTH (Parathyroid hormone)
EXPLANATION: 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-hydroxylase) plays an important role in calcium homeostasis by CATALYSING SYNTHESIS of the active form of vitamin D, 1,25-dihydroxyvitamin D(3), in the kidney.
What is the difference between 1,25(OH)2 D3 formed in the kidneys and in the tissues in the body?
KIDNEYS:
- Endocrine
- Maintains calcium economy
TISSUES IN THE BODY:
- Autocrine
- Prevent and/or treat Viral respiratory disease, Cancer, Osteoporosis, Heart disease, Multiple sclerosis, Diabetes, Hypertension
What is the best indicator of Vitamin D status?
Serum 25-OH vitamin D
Explanation: Long half-life + liver production not regulated
What is the function of Vitamin D?
- Ca2+ and PO4 3- absorption in GI tract
- Raises Ca2+ -> increases bone mineralisation
- Bone mineralisation at low levels
- Bone resorption at higher levels
Describe Vitamin D Deficiency
DISEASES:
- RICKETS in children
[decreased vit D -> growth plate thickens without mineralisation -> can be eliminated by eating vitamins]
- Osteomalacia in adults (bone pain + muscle weakness)
- Hypocalcemic tetany (involuntary muscle contractions)
CAUSES:
- Malabsorption
- Decreased sun exposure
- Poor diet
- Chronic kidney disease
- Advanced liver disease
TREATMENT:
- Give oral vitamin D to breastfed infants (breast milk low in vitamin D)
Darker skin + prematurity make someone more susceptible to deficiency
What is seen in Excess Vitamin D (Hypervitaminosis D)?
- Hypercalcemia
- Hypercalciuria
- Loss of appetite
- Confusion
- Seen in GRANULOMATOUS DISEASES -> Granulomatous epitheloid macrophages express I alpha-hydroxylase
What are the properties of Vitamin A?
- Includes Tocopherol + Tocotrienol
- Deficiency is very rare
- Function = Antioxidant (protects RBCs and membranes from free radical damage)
What are the symptoms of Vitamin E deficiency?
- Haemolytic anemia
- Acanthocytosis (spur cells)
- Muscle weakness
- Demyelination of posterior column and spinocerebellar tracts (decreased proprioception and vibration + ataxia)
- Neurologic presentation may appear similar to vitamin B12 deficiency but WITHOUT megoblastic anemia, hyperhsegmented neutrophils or increased methylmalonic acid levels
Describe what is seen with excess Vitamin E
- Least toxic of fat-soluble vitamins
- Very high dosages reported inhibiting Vitamin K metabolism -> enhanced anticoagulant effects of warfarin
What are the properties of Vitamin K?
- Includes Phytomenadione, Phylloquinone, Phytonadione and Menaquinone
- FUNCTION = activates clotting factors in liver (post-translational modification)
- Synthesised by intestinal flora (K2 form) + found in green, leafy vegetables, egg yolk and liver (K1 form)
What are the Vitamin K-dependent clotting factors?
Factors II, VII, IX, X and proteins C and S
What does Warfarin do?
Inhibit Vitamin K-dependent synthesis of factors and proteins
Describe Vitamin K deficiency
- Results in bleeding
- Neonatal haemorrhage - neonates have sterile intestines and are unable to synthesise vitamin K -> Neonates given intramuscular vit K injection at birth to prevent haemorrhagic disease of newborn
- Can occur after prolonged use of broad-spectrum antibiotics
- Dietary deficiency is rare since GI bacteria produces sufficient quantities
Which vitamins does Breastmilk not contain?
Vitamins D and K
What are the properties of Zinc?
- Essential for activity of 100+ enzymes
- Important in formation of ZINC FINGERS (transcription factor motif)
- Found in meat + chicken (absorbed mostly in duodenum)
Describe Zinc deficiency
A rare autosomal recessive disease where Zn absorption is impaired and is associated with ACRODERMATITIS ENTEROPATHICA
CAUSES:
- Alcoholism (low zinc associated w cirrhosis)
- Malabsorption
DEFICIENCY IN CHILDREN
- Poor growth + impaired sexual development (male hypogonadism + decreased adult hair)
DEFICIENCY IN ADULTS
- Delayed wound healing, suppressed immunity (required for cytokine production), dysgeusia (zn required by taste buds), anosmia, dermatitis (red skin + pustules) - can be caused by patient on TOTAL PARENTERAL NUTRITION without supplement
SYMPTOMS:
- Dermatitis - hyper pigmented (red) skin + classically perioral and perianal
- Loss of hair
- Diarrhoea
- Poor growth
- Immune dysfunction
What are the properties of Vitamin B9 and B12?
- Both used in synthesis of Thymidine (DNA)
- Both used in metabolism of Homocysteine
Deficiency of either vitamin
- Decreased DNA -> Megaloblastic anemia
- Increased homocysteine
Which enzyme converts DiUridine-MP to Thymidine-MP?
Thymidylate Synthase
What is S-adenosyl Methionine (SAM)?
- Cofactor that donates Methyl groups
- Synthesised from ATP and methionine
What is Megoblastic Anemia?
Megaloblastic anemia is a form of anemia characterized by very large red blood cells and a decrease in the number of those cells.
HISTOLOGICAL FINDINGS:
- Large RBCs
- Hypersegmented neutrophils (6 or more nuclear segments)
CAUSES:
- Defective DNA production
- Folate deficiency
- B12 deficiency
- Orotic aciduria
- Drugs (MTX + 5-FU)
- Zidovudine (HIV medication)
What are the properties of Vitamin B9?
- Also called “Folate”
- Used in synthesis of THYMIDINE (DNA) and metabolism of amino acid HOMOCYSTEINE
- Absorbed in JEJENUM
- Deficiency commonly seen in alcoholics (decreased intake and absorption)
Why is increased amount of folate required during pregnancy and lactation?
Increased cell division -> more metabolic demand -> Lack of folate can lead to NEURAL TUBE DEFECTS
What are the properties of Vitamin B12?
- Also called “cobalamin” (contains element cobalt)
- Presents only in animal products
- Absorbed in terminal ileum
- Stored in high quantity in liver -> development of deficiency needs couple of years
- Used in synthesis of thymidine (DNA) and homocysteine
What is the function of Vitamin B12?
- Required for synthesis of odd-chain fatty acids
- Deficiency will INCREASE levels of METHYLMALONIC ACID (hallmark that distinguishes it from folate deficiency)
- Methylmalonic acid is toxic to myelin -> B12 deficiency leads to PERIPHERAL NEUROPATHY
What is Vitamin B12 Neuropathy?
Peripheral neuropathy is the most common presentation of vitamin B12 deficiency. It involves dorsal spinal columns (pressure, vibration, fine touch, proprioception) and Subacute combines degeneration (SCD)
SYMPTOMS:
- Bilateral symptoms -> Legs + arms
- Paresthesias
- Ataxia -> frequent falls
- Loss of vibration and position sense
Prolonged deficiency -> irreversible nerve damage
What is Cobalamin deficiency?
Vitamin B12 deficiency is a treatable condition that happens if you are not consuming enough vitamin B12 in your diet or if your body is not absorbing it properly
Very large reserve pool stored primarily in liver -> deficiency due to diet is rare
CAUSES:
- Malabsorption
- Lack of intrinsic factor
- Absence of terminal ileum
- Certain drugs
- Insufficient intake
DIAGNOSIS:
- Low serum B12
- High serum methylmalonic acid
- Antibodies to intrinsic factor (pernicious anemia)
- Schilling test
TREATMENT:
- Liquid injection (given subcutaneous/intramuscular) - increase in reticulocytes
B9 supplementation can mask the hematologic symptoms of B12 deficiency but not the neurologic symptoms
What is Pernicious anemia?
Pernicious anemia is a relatively rare autoimmune disorder that causes diminishment in dietary vitamin B12 (cobalamin) absorption, resulting in B12 deficiency and subsequent megaloblastic anemia
Autoimmune destruction of Parietal cells in stomach -> Loss of intrinsic factor which is necessary for B12 absorption in TERMINAL ILEUM -> More common among women + associated with GASTRIC ADENOCARCINOMA
What is the Schilling test?
Classic diagnostic test for pernicious anemia
Oral labelled B12 is given -> IM B12 is given to saturate liver receptors
NORMAL RESULT = Radiolabeled B12 detectable in urine
NEGATIVE RESULT = repeat with oral IF -> Corrected B12 levels if pernicious anemia
