Pellagra

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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

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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

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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

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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

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PARP, poly-ADP-ribose polymerase PRPP,
phosphoribosyl pyrophosphate.
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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

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Signs and Symptoms

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

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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

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Dermatitis
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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
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Dementia

• Degeneration of various parts of nervous system
• Disorder in cognitive and mental function
• Symptoms
• Confusion
• Memory deterioration
• Delusions
• Hallucinations
• Depression

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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

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Dementia
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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

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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

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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

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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

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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

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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

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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.

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