Justin Mak

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Porphyrias and errors in heme metabolism

• Justin Mak
• Rubeena Patil
• Jonathan Mak
• Aisha Shoaib
• SEPTEMBER 28TH 2012

PHM142 Fall 2012 Instructor Dr. Jeffrey
Henderson
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Outline

• Introduction
• Signs, Symptoms and Treatments
• Pathway of Heme Synthesis
• Emphasis on Porphyria cutanae tarda (PCT)

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Introduction

• Porphyrias are a set of diseases that result from
  enzyme deficiencies in the heme synthesis
  pathway.
• Heme is mostly used for its incorporation into
  hemoglobin and role in red blood cells, but is
  also needed for cytochrome P450 function.
• Each disease is associated with a deficiency in
  one of the eight enzymes in the pathway.
• They fall under two categories
• based on their clinical symptoms
• acute hepatic and erythropoietic
• porphyrias.

Heme
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Overall Pathway
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Disease Mechanism

• Generally, the disease mechanism for porphyrias
  is that their respective enzymatic deficiencies
  lead to the accumulation of porphyrins and
  porphyrin precursors that ultimately produce free
  radicals.
• For acute hepatic porphyrias, delta-aminolaevulini
  c acid (ALA) and porphobilinogen (PBG) accumulate
  and produce free radicals via autoxidation.
• For erythropoietic porphyrias, uroporphyrins,
  coproporphyrins, and protoporphyrins accumulate
  and produce free radicals via the absorption of
  visible light.
• The generated free radicals participate in
  oxidative stress reactions, such as lipid
  oxidation and protein crosslinking, that lead to
  membrane and mitochondrial damage, ultimately
  promoting cell death.
• Loss of negative feedback of heme leads to
  further accumulation of porphyrins.

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Genetics

• Enzyme deficiencies in porphyrias are inherited
  acute intermittent porphyria (AIP), hereditary
  coproporphyria (HCP), variegate porphyria (VP),
  and erythropoietic protoporphyria (EPP) are
  autosomal dominant.
• ALA dehydratase deficiency porphyria (ADP) and
  congenital erythropoietic porphyria (CEP) are
  autosomal recessive.
• Porphyria cutanea tarda (PCT) can be autosomal
  dominant, but is mostly sporadic.

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Environmental Factors

• Due to incomplete penetrance, inheritance of an
  enzyme deficiency of an autosomal dominant
  porphyria does not necessarily lead to clinical
  symptoms. Symptoms of acute porphyrias tend to
  come in the form of "attacks" which may be
  induced by other genetic factors or environmental
  factors, such as agents that promote porphyrin
  and porphyrin precursor synthesis and/or agents
  that induce cytochrome P450s.

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Signs and Symptoms of Porphyrias
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Symptoms of Cutaneous Forms

• Occur most commonly with exposure to sunlight
• Mainly skin symptoms that occur
• Due to excess poryphorins that accumulate in
  surface of skin
• Symptoms
• Fluid filled blisters
• Changes in pigmentation
• Breakdown (necrosis) of the skin
• when exposed to sunlight
• Overall skin can become scarred,
• brown, blotchy and fragile

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Symptoms of Acute Forms

• Originate mainly in nervous system
• Symptoms last around 1-2 weeks
• Possible mechanisms include damage by free
  radicals, direct neurotoxicity of ALA acid, and
  the deficiency in nervous tissue
• Symptoms
• Severe abdominal pain
• Muscle weakness and pain, tingling, or numbness
  and possibly paralysis
• Pain in arms, legs, back
• Constipation
• Vomiting
• Diarrhea
• Insomnia
• Seizures and Confusion
• Anxiety and paranoia
• Fever

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Treatments of Porphyrias
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Treatment for Cutaneous Forms

• Avoiding sunlight
• Attention to skin care
• Beta-carotene supplements
• Function to neutralize the effects of reactive
  protoporphyrins

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Treatment for Acute Forms

• Several treatments can be used to control
  neurological symptoms and defective heme
  production
• Carbohydrate such as glucose
• To help limit the synthesis of porphyrins
• Phlebotomy (removal of blood)
• To reduce excessive iron stores which improves
  heme synthesis
• Sedatives to help with anxiety
• Pain medications such as opiates
• Hematin given intravenously
• Hematin are heme-like substances that inhibit ALA
  synthase and the accumulation of toxic precursors

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Heme Metabolism pathway
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Overall Pathway
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Overall pathway
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ALA Synthetase

• Most important rate limiting enzyme
• Deficiency may cause Sideroblastic anemia
• Bone marrow produces ringed sideroblast?
• X-linked
• Respond to pyridoxine treatment

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Overall pathway
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ALA dehydratase deficiency porphyria(DOSS
porphyria)
ALA dehydratase
Aminolevulinic Acid
Porphobilinogen

• Autosomal recessive
• Very rare
• Symptoms Abdominal pain, neuropathy

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Overall pathway
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Acute intermittent porphyria (AIP)
PGB deaminase
Hydroxymethylbilane
Porphobilinogen (PGB)

• 2nd most common form of porphyria
• Caused by deficiency of PGB deaminase
• Metabolite porphobilinogen accumulates in
  cytoplasm
• Symptoms
• Localized abdominal pain
• Urinary symptoms
• Peripheral nerutopathy
• raised concentration of urinary porphyrins
• Treatment
• Hematin, Heme arginate
• Do not cure but reduces symptoms
• Inhibit ALA synthase which occurs at the
  beginning of heme biosynthesis

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Overall pathway
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Congenital erythropoietic porphyria (CEP)
Uroporphyrinogen III synthase
Hydroxymethylbilane
Uroporphyrinogen III

• Deficiency of Uroporphyrinogen III synthase
• Rare autosomal recessive (1 in 1,000,000)
• Severe photosensitivity

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Overall pathway
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Porphyria cutanae tarda (PCT)
Uroporphyrinogen decarboxylase
Coproporphyrinogen III
Uroporphyrinogen III

• Most common porphyria
• Classified as such when Uroporphyrinogen
  decarboxylase activity lt20
• Hepatic disorder
• Inherited or obtained through Hepatitis C, drugs,
  alcohol, poisons
• Treatment discourage risk factors and treat
  symptoms
• can draw blood to reduce iron in the liver until
  the serum ferritin reaches normal iron levels.
• Chloroquine or hydroxychloroquine can move excess
  porphyrins from the liver and promote excretion.
  Can be used when drawing blood is not
  recommended.
• Avoid causes of PCT

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Overall pathway
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Hereditary coproporphyria

• Deficiency of Coproporphyrinogen III Oxidase
• Autosomal dominant
• No cure exists

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Overall pathway
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Variegate porphyria

• Deficiency in protoporphyrinogen IX-oxidase
• Autosomal dominant

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Overall pathway
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Erthropoietic Protoporhyria

• Caused by deficiency of Ferrochelatase
• Autosomal dominant
• Photosensitivity- can be managed by limiting
  exposure

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Summary Slide A

• Porphyria is caused by a deficiency in any of the
  8 enzymes of heme synthesis.
• Leading to the build up of heme precursors
• Divided into two categories based on clinical
  symptoms acute hepatic and erythropoeitic.
• Enzymatic deficiencies are inherited, but
  symptoms may not appear unless induced by
  environmental agents.
• Main symptoms associated porphyrin accumulation
  in various locations, photosensitivity, pain,
  numbness, vomiting, and seizures.
• Treatment
• Reduce symptoms with related drugs
• Encourage excretion or removal of heme precursors

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Summary Slide B
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References

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References

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