96 terms

Porphyria 2

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What's the other name for heme?
--Ferrous protoporphyrin IX
What is used to start the synthesis of heme?
--Succinyl CoA, glycine
--Form ALA
--Rate limiting
What stimulates heme synthesis in erythroid cells?
--Erythropoietin
What organ releases erythropoietin and when?
--Kidney and low oxygen tension
What regulates heme synthesis in erythroid cells?
--Intracellular iron
--NOT HEME
Acute Intermittent P. Dfx?
Porphobilinogen deaminase (PBG)
What P if uroporphyrinogen III synthase is deficient?
CEP
What does a deficiency of vitamin B6 lead to?
--Needed as coenzyme for ALA synthase
--Heme synthesis CANNOT START EFFICIENTLY
Describe ALA synthase
1° regulator of Heme Synth Pthwy by changes in its activity:
^Heme = Not active
vHeme = Active
Describe uroporphyrinogen decarboxylase
enzyme that converts Uor III to Copro III
Describe ferrochelatase
--Mito
--Protoporphyrin IX + Fe2+ --> Heme
--Needs Zn as cofactor
What's found in the urine and blood in acute intermittent porphyria?
ALA, porphobilinogen
What's deficient in acute intermittent porphyria?
--HMB synthase (hydroxymethylbilane)
What's the defect in congenital erythropoietic porphyria?
--Uroporphyrinogen III synthase
--Erythroid cell specific
What accumulates in the blood and urine in CEP?
--Uroporphyrin I (URO)
--Coproporphyrin I (COPRO)
What's the color of the urine in CEP?
--Red/Pink on excretion
What are the clinical symptoms of CEP?
--PHOTOSENSITIVITY
--Onset in childhood
--"werewolf" features: hairy front+ arms -- red urine
What's the deficiency in porphyria cutanea tarda?
--Uroporphyrinogen III decarboxylase
What accumulates in PCT?
--Uroporphyrin III
What color is the urine in a patient with PCT?
--Red on excretion
What are the clinical symptoms of PCT?
Photosensitivity - blister formation
Does not usually appear until adulthood; may remain dormant until liver dysfunction develops (e.g. alcoholic liver disease)
What's the most common porphyria?
--PCT
What can cause PCT?
--Liver damage (hepatitis, EtOH abuse, alcoholic liver disease)
What accumulates in the blood with ALA dehydratase porphyria?
--ALA
Which deficiencies do NOT lead to photosensitive patients?
--ALA dehydratase porphyria
--Acute intermittent porphyria
Which diseases lead to photosensitive patients?
--Congenital erythropoietic porphyria
--Porphyria cutanea tarda
Which deficiency is the MOST SEVERE photosensitive?
--Congenital erythropoietic porphyria
What's the first porphyrin ring leading to heme?
--Uroporphyrinogen III
Porphyria
Congenital disorders with abn porphyrin synthesis due to enzyme/s defect in heme synth pathway.
Coproporphyria (CP)
1/3 have photosensitivity
Deficiency of coproporphyrinogen oxidase
Variegate Porphyria (VP)
Neurological problems, mechanical trauma, and skin sensitivity to sunlight
Deficiency of protoporphyrinogen oxidase
Heme and ALA corelation?
Excess heme inhibits ALA activity
Decreased amounts of heme stimulate ALA activity
Porphyrinogens
Carbon atoms are fully reduced
All four N atoms are protonated - no alternating single and double bonds
Colorless and nonfluorescent
What happens to unused Porphyrinogens?
Porphyrinogens NOT used are spontaneously oxidized to corresponding porphyrin
Oxidized products of the ff?
Uroporphyrinogen
Coproporphyrinogen
Protoporphyrinogen
Uroporphyrin
Coproporphyrin
Protoporphyrin
Route of Excretion as a function of sollubility for the ff?
PROTO
COPRE
URO
Protoporphyrin - 2 carboxyl grps
feces
Coproporphyrin - 4 carboxyl grps
feces and urine
Uroporphyrin - 8 crbxyl grps urine
Classification based on based on clinical presentation?
Neurologic or cutaneous
Class based on site of production?
1.) Erythropoietic: Congenital Erythropoietic, Protoporphyria
2.)Hepatic:
ALA dehydratase Deficiency, Acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate
Name and enzyme of porphyria that causes anemia
ALA synthase
Name and enzymes of porphyrias that cause Photosensitivity ONLY
Porphyria Cutanea Tarda (Uroporphyrinogen decarboxylase), Protoporphyria (Ferrochelatase)
Name and enzymes of porphyrias that cause abdominal pain and neuropsych symptoms ONLY
ALA dehydratase deficiency (ALA dehydratase), Acute Intermittent Porphyria (Uroporhyrinogen I synthase)
Name and enzyme of porphyria that causes no photosensitivity ONLY
congenital erythropoietic (uroporphyrinogen III synthase)
Name and enzyme of porphyrias that cause Photosensitivity, Abdominal Pain, Neuropsych symptoms
Hereditary Coproporphyria (coproporphyrinogen oxidase), Variegate porphyria (Protoporphyrinogen oxidase)
Symptoms of ALA synthase Def.
anemia
Sx of Uroporphyrinogen I synthase def,
Abd Pain, neuropsych sx
Sx of Uroporphyrinogen III synthase def,
No Photosensitivity
Sx. of Uroporphyrinogen decarboxylase Def.
Photosensitivity
Sx of coproporphyrinogen oxidase Def.
Photosensitivity, Abd Pain, Neuropsych sx
Sx. of protoporphyrinogen oxidase Def.
Photosensitivity, Abd Pain, Neuropsych sx
Sx of ferrochelatase Def.
Photosensitivity
X-linked sideroblastic anemia is
ALA synthase Def.
ALA dehydratase deficiency is
ALA Dehydratase Def.
Acute intermittent porphyria is
Uroporphyrinogen I synthase def,
Congenital erythropoietic Porphyria is
Uroporphyrinogen III synthase def,
porphyria cutanea tarda is
Uroporphyrinogen decarboxylase Def.
hereditary coproporphyria is
coproporphyrinogen oxidase Def.
Variegate Porphyria is
protoporphyrinogen oxidase Def.
Protoporphyria is
ferrochelatase Def.
The most common porphyria
porphyria cutanea tarda
clinical expression of the enzyme deficiency associated with porphyria cutanea tarda is influenced by _____
hepatic iron overload, exposure to sunlight, presence of HAV, HBV, HCV, HIV
Clinical onset of porphyria cutanea tarda
4-5th decade of life
Acute hepatic porphyrias
AIP, HCP, VP
Acute hepatic porphyrias characterized by
acute attacks of GI, Neuropsych, CV sx
Porphyrias leading to the accumulation of ALA and PBG cause_____
abdominal pain and neuropsych sx (AIP)
increasing synthesis of cytP450 -->
decreases available heme--> increased synth of ALA synthase
Erythropoietic porphyrias are characterized by
skin rashes and blisters that appear early in childhood
complications of erythropoietic porphyrias include
cholestatic liver cirrhosis and progressive hepatic failure
major pathophysiology of the porphyrias
accumulation of toxic intermediates prior to the genetic block
Acute Intermittent Porphyria
Most common Neurological P.
Deficient PBG Aminase (porphobiligen decarboxylase)
*(Increased porphobiligen, delta-ALA, uroporphyrin)
a-Thalasemia
Defect in a-globin production (you have 4 gene copies)
prevalent in africa
microcytic hypochromic
Three types:
1. Four deletions: Hg Barts, hydrops fetalis
2. Three deletions: HbH
3. Two or less: no significant disease
b-Thalasemia
Point mutations in B-globin genes (two copies)
increased HbF
microcytic, hypochromic
Two types:
1. B-thal minor: heterozygote
- usually asymptomatic
2. B-thal major: homozygote
- sever anemia requiring transfusions
- 2' hemachromatosis
- skeltal deformaties ("crew cut" and "chipmunk")
Idiopathic Thrombocytopenic Purpura
Autoimmune, ab against GpIIb/IIIa
Presentation:
- decreased PC
- increased megakariocytes (in marrow)
- increased BT
Rx: streroids, IVIG, splenectomy
Thrombotic Thrombocytopenic Purpura
Defective ADAMTS13 > decreased vWF polymer breakdown > excessive plt activation > decreased survival
hemolytic uremic syndrome is a milder form
Presentation:
- Nasty: neuro (headache, seizures)
- Fever: fever
- Torched: thrombocytopenia
- His: hemolytic uremia
- Kidneys: kidney failure
- also ^ LDH
Hemolytic Uremic Syndrome
Caused by e. coli O157
Presentation:
- hemolysis
- uremia
- thrombocytopenia
The feedback inhibitor for dALA is?
Heme
Types of Acute/Neurological Porphyria
Acute Intermittent Porphyria (AIP)
Corproporphyria (CP)
Variegate Porphyria (VP)
This type of of porphyria is chronic in nature?
Cutaneous Porphyrias
Types of Cutaneous Porphyrias
Erythropoietic porphyria (EP)/Congenital erythropoietic porphyria (CEP)
Porphyria cutanea tarda (PCT)
Protoporphyria (PP)
Types of Chronic Symptoms
Peripheral Neuropathies/ weakness/pain
Liver Dysfunction
Emotional distress/mood change
Red colored urine
Photosensitivity
Skin Lesions
Blisters
Acute Intermittent Porphyria enzyme deficiency?
PBG deaminase
Porphobilinogen accumulates
Neurological P. Symptoms
1. Acute Attacks: Abdominal/back pain, Neuromascular signs and sympt, Psychotic behaviour, Constipation
2.^Excretion of PBG & ALA in urine
3. Adolescence or later, wmn>men
4. Attacks precipitated by alcohol, toxins, drugs
Congenital Erythropoeitic Porphyria enzyme deficiency?
Uroporphyrinogen III
Hydroxymethylbilane accumulates
Porphyria Cutanea Tarda enzyme deficiency?
Uroporphyinogen Decarboxylase
Uroporphyrinogen accumulates
Hereditary Coproporphyria enzyme deficiency?
Coproporphyrinogen Oxidase
Coproporphyrinogen accumulates
Hereditary Coproporphyria Symptoms
Mild neural and skin problems
photosensitivity
Ethanol precipitated bullae
Variegate Porphyria enzyme deficiency?
Protoporphyrinogen Oxidase
Protoporphyrinogen IX accumulates
Erythropoietic Protoporphyria enzyme deficiency?
Ferrochetalase
Protoporphyrin IX accumulates
Porphyrias
Congenital disorders with abn porphyrin synthesis due to enzyme/s defect in heme synth pathway.
Coproporphyria (CP)
Coproporphyria (CP)1/3 have photosensitivity
Deficiency of coproporphyrinogen oxidase
Variegate Porphyria (VP)
Variegate Porphyria (VP)Neurological problems, mechanical trauma, and skin sensitivity to sunlight
Deficiency of protoporphyrinogen oxidase
Congenital Erythropoietic Porphyria (CEP): Disorder Mechanism
ONLY porphyria that is autosomal recessive
Rarest and most severe - Bleak prognosis
Disorder: ^levels of series I porphyrins due to either
1.) Deficiency of urophrphyrinogen III cosynthase
2.) Hyperactivity of urophrphyrinogen 1 synthase
Congenital Erythropoietic Porphyria (CEP): Clinicals
CUTANEOUS: Severe scarring and mutilation of fingers, ears and nose due to extreme photosensitivity
Affected people are nocturnal - werewolf legend?
Erythrodontia, HA, splenomegaly
Pink or red urine 2o massive amounts of URO and COPRO (RC fluoresce due to URO/COPRO
Protoporphyria (PP)
Deficiency of ferrochelatase
CUTANEOUS: Photosensitivity - mild scarring, burning itching after sun expsre
FEP greatly elevated
Porphyria Cutanea Tarda (PCT)
MOST COMMON of all porphyrias
Deficiency of uroporphyrinogen decarboxylase
Photosensitivity - blister formation
Does not usually appear until adulthood; may remain dormant until liver dysfunction develops (e.g. alcoholic liver disease)
Porphyrias: pathphys
Porphyrins and/or heme precursors accumulate in tissues
Excretion of these products in urine and/or feces
All but one are autosomal dominant
One functional gene
No heme deficiency; no anemia
Porphyrins
Alternating single and double bonds
Causes them to absorb visible light
Bonds give red color to hemoglobin
Fluoresce a reddish-pink color with UV light
Porphyrins are toxic and cause symptoms characteristic of these disorders
i.e. photsensitivity, abdominal pain, neurologic problems