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Pellagra

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Title: Pellagra


1
Pellagra
  • Presented by
  • Milson Chan ltmilson.chan_at_gmail.comgt
  • Richard Lee ltrch.lee_at_gmail.comgt
  • Richard McLaughlin ltrichard.mclaughlin_at_utoronto.c
    agt
  • Sharjeel Syed ltsharjeel.syed_at_utoronto.cagt
  • Date of Presentation April 9, 2008

2
Pellagra Overview
  • Definition
  • Niacin-deficiency disease
  • History
  • 1900s 87 000 deaths in southern US due to a
    low-protein diet centered on corn
  • Pellagra initially thought to be caused by an
    infectious agent
  • Discovery that disease can be caused by diet
    contradicted commonly held views of the nature of
    disease

3
Niacin
  • What is niacin?
  • Vitamin B3
  • Two inter-convertible forms nicotinic acid (i.e.
    niacin) and nicotinamide (i.e. niacinamide)
  • Heat-resistant
  • Nicotinamide adenine dinucleotides function as
    essential coenzymes or as substrates
  • Hydride acceptors NAD, NADP
  • Hydride donors NADH, NADPH

4
Niacin
  • Sources
  • Protein-rich foods (meat, poultry, fish)
  • Tryptophan precursor, 1 mg niacin from 60 mg
    Tryptophan
  • Enriched and whole grains
  • Mushroom, asparagus and leafy-greens richest
    vegetable sources

5
(No Transcript)
6


PARP, poly-ADP-ribose polymerase PRPP,
phosphoribosyl pyrophosphate.
7
Niacin
  • Redox reactions
  • 200 enzymes use NAD and its derivatives in
    metabolic reactions
  • NAD/NADH important in energy metabolism, esp. of
    glucose, fat alcohol
  • NADP/NADPH important in anabolic reactions i.e.
    macromolecule biosynthesis
  • Non-redox reactions
  • ADP-ribosylation of proteins, via
    mono-ADP-ribosyltransferase (ART) and
    poly-ADP-ribose polymerase (PARP) enzymes
    involved in DNA repair, cell differentiation, and
    gene transcription
  • Cyclic ADP-ribose (cADPR) and nicotinic acid
    adenine dinucleotide phosphate (NaADP) involved
    in cell signaling via Ca2 intracellular release

8
Signs and Symptoms
  • Diverse clinical presentations
  • Affects both males and females
  • Mainly adults
  • Characterized by the four Ds
  • Dermatitis
  • Dementia
  • Diarrhea
  • Death

9
Dermatitis
  • Symptoms
  • Bilateral symmetry at sites with sun exposure
  • The usual sites affected are the face, neck, and
    dorsal surfaces of the hands, arms and feet
  • Dermatitis begins as erythema and resembles
    sunburn initially
  • Skin develops edema and vesicles
  • Skin becomes thickened and scaly with
    hyperpigmentation

10
Dermatitis
11
Dermatitis
1. Viscosity of extracellular matrix
Degradation of glycosaminoglycans
Disturbed redox balance
Skin damage
Release of inflammatory mediators
Viscosity of extracellular matrix
Localization of inflammatory mediators
More severe skin reaction
  • 2. Kynurenic acid synthesis
  • Metabolic by-product kynurenic acid induces
    phototoxic changes when subjected to UV
    radiation.

Phototoxic damage
UV
Kynurenic acid
Tryptophan Kynurenine
Niacin
12
Dementia
  • Degeneration of various parts of nervous system
  • Disorder in cognitive and mental function
  • Symptoms
  • Confusion
  • Memory deterioration
  • Delusions
  • Hallucinations
  • Depression

13
Dementia
  • Serotonin synthesis
  • Niacin is produced from tryptophan
  • Tryptophan is a precursor of serotonin
  • Niacin deficiency causes maximal metabolism of
    the small amount of tryptophan
  • Reduction in tryptophan for serotonin synthesis
  • Impaired cognitive and mental function

14
Dementia
15
Diarrhea
  • Viscosity of extracellular matrix
  • Extracellular matrix viscosity
  • Thickness of the wall in the colon
  • Thickness of submucosal layer
  • Atrophy of submucosal layer
  • Impaired fluid absorption
  • Diarrhea

16
Death
  • Can cause death in 4 to 5 years if left untreated
  • Untreated pellagra results in death from
    multi-organ failure
  • Morbidity of pellagra is related to the various
    organ systems involved
  • Malnutrition, infections, and neurological
    complications

17
Diagnosis - Differential
  • Contact and Atopic Dermatitis
  • Skin inflammation, erythematic lesions
  • No GI or neurological effects
  • Vitamin B2 (riboflavin), B6 (pyridoxine)
    deficiency
  • Cracks and sores concentrated at the area of the
    mouth, tongue and lips

18
Diagnosis Lab Values
  • Confirmation of diagnosis
  • Low serum niacin, tryptophan, NAD, and NADP
    levels
  • Low urine levels of N-methylnicotinamide and
    pyridone
  • Excretion of N-methylnicotinamide and pyridone
    levels less than 1.5 mg over 24 hours indicates
    severe deficiency
  • Therapeutic response to niacin confirms diagnosis

19
Prevention and Treatment
  • Non-pharmacological (Dietary)
  • Meat (poultry, fish, lean meats)
  • Milk
  • Nuts
  • Green leafy vegetables
  • Whole/enriched grains
  • Long term inclusion of milk, meat, and eggs in
    diet are essential for recovery

20
Prevention and Treatment
  • Pharmacological
  • Niacinamide effective in reversing symptoms and
    the condition of pellagra
  • Give oral dose of 300-500mg daily until
    resolution of acute symptoms
  • Give intravenous dose of 100-250mg BID or TID
  • Maintenance dose of niacin based on individual
  • High protein diet and B-complex vitamins for
    complete restoration

21
Summary
  • Pellagra A niacin-deficiency disease.
  • What is niacin? - Vitamin B3.
  • Two inter-convertible forms nicotinic acid and
    nicotinamide.
  • Niacin functions in body as coenzymes NAD and
    NADP.
  • Functions in Redox reactions Around 200 enzymes
    use NAD/NADP to donate/accept electrons in
    metabolic reactions.
  • Functions in non-redox reactions ADP-ribose
    transfer from NAD to proteins by ART and PARP
    enzymes. PARPs Involved in DNA repair, stress
    responses, cell signaling and differentiation,
    transcription, apoptosis, and chromatin
    structure, suggesting a possible role for NAD in
    cancer prevention. ADP-ribosyl cyclase catalyzes
    the formation of cyclic ADP-ribose ? release of
    Ca2 from intracellular compartments, involved in
    cell signaling
  • Niacin can be found in enriched whole grains,
    mushrooms, leafy-greens, and protein-rich foods.
  • Tryptophan is a precursor for niacin.
  • Signs and Symptoms the four Ds (Diarrhea,
    Dermatitis, Dementia, Death)
  • Dermatitis - Pellagra causes skin damage in the
    face, neck, dorsal surfaces of the hands, arms
    and feet. The disturbance in the redox balance
    decreases the degradation of glycosaminoglycans,
    which increases the viscosity of the
    extracellular matrix. This releases inflammatory
    mediators which cause skin damage. Also, the
    metabolic by-product kynurenic acid induces
    phototoxic changes when subjected to UV
    radiation.
  • Dementia - Dementia can result, as various parts
    of the nervous system are degenerated.
  • There is also a reduction in tryptophan for
    serotonin synthesis. This impairs cognitive and
    mental function, (RECALL - Niacin is produced
    from tryptophan, and tryptophan is a precursor to
    serotonin).
  • Diarrhea - Gastrointestinal symptoms always
    precede dermatitis. Diarrhea may in turn lead to
    malabsorption, creating a vicious cycle.
  • Death - Untreated pellagra results in death from
    multi-organ failure.
  • Differential Diagnosis Contact and allergic
    dermatitis, vitamin B2 (riboflavin), and B6
    (pyridoxine) deficiency.
  • Lab Values - Low serum niacin, tryptophan, NAD,
    and NADP levels. Low urine levels of
    N-methylnicotinamide and pyridone.
  • Prevention and Treatment Include enriched whole
    grains, mushrooms, leafy-greens, and protein-rich
    foods in your diet. Take Niacinamide 300-500mg
    daily, followed by a lower maintenance dose.

22
Reference
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    Dorrestein P. The biosynthesis of nicotinamide
    adenine dinucleotides in bacteria. Vitam Horm.
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  • Dickerson, J.W. and J. Wiryan, 1978, Pellagra and
    mental disturbance, Proc. Nutr. Soc, 37167-171
  • Hegyi, J. et al, 2004, Pellagra Dermatitis,
    dementia, and diarrhea, International Journal of
    Dermatology, 43(1)1-5.
  • Karthikeyan, K. and D.M. Thappa, 2002, Pellagra
    and skin, International Journal of Dermatology,
    41476481
  • Kurnasov O, Goral V, Colabroy K, Gerdes S,
    Anantha S, Osterman A, Begley TP. NAD
    biosynthesis identification of the tryptophan to
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  • Moroni F. Tryptophan metabolism and brain
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