porphyrins ii
DESCRIPTION
Porphyrins II. David Hart Dec 13, 2006. HEME. CH 3 -. Bonkovsky ASH Education Book December 2005. Hentze, Muckenthaler & Andrews Cell, Vol 117, 285-297, April 30, 2004. Hepcidin. Lecture Outline. Heme function Heme synthesis and regulation Iron metabolism Porphyrias - PowerPoint PPT PresentationTRANSCRIPT
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David Hart
Dec 13, 2006
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HEME
CH3-
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BonkovskyASH Education BookDecember 2005
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Hentze, Muckenthaler & AndrewsCell, Vol 117, 285-297, April 30, 2004
Hepcidin
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Lecture Outline
• Heme function
• Heme synthesis and regulation
• Iron metabolism
• Porphyrias
• Heme degradation
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Disorders of Heme Synthesis
• X-linked Sideroblastic Anemia
• Lead Poisoning
• Iron Deficiency Anemia
• The Porphyrias
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Porphyrias
• Inherited defects in heme synthesis– Accumulation and excretion of porphyrins– Pattern depends on which enzyme affected– Decreased heme synthesis derepresses hepatic ALAS
• Most are Autosomal Dominant • Erythropoietic, Hepatic or Mixed• Acute and Chronic
– Acute: Neurovisceral attacks
• Porphyrin accumulation: Photosensitivity– Formation of reactive oxygen species– Damage tissues, Release lysosomal enzymes
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FuseliThree WitchesTate
Gillray 1791Weird Sisters
Tate
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Very Rare Recessive Porphyria
Lead Poisoning
ALA-D Porphyria
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
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AcuteHepatic
PBG and ALA (Neurotoxic)Accumulate in Urine
PBG in Urine: Diagnostic ScreenNeurovisceral Attacks
No Photosensitivity with AIP
Hydroxymethylbilane Synthase
Lead Poisoning
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
ALA-D Porphyria
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Acute PorphyriasClinically indistinguishable (Locus Heterogeneity)
PBG in Urine: Diagnostic Screen• Agents which induce cytochrome P450
– Drugs, Alcohol, Hormones• Precipitated by fasting, treated with glucose • After puberty; more in women• Begin with minor behavioral changes• Proceeds to autonomic and sensomotoric
neuropathy; Convulsions• Pain: Back, Extremities, Abdomen• Hypertension and Tachycardia• Arrhythmias; cardiac arrest
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AcuteHepatic
Erythropoietic
RECESSIVEPorphyrin accumulation: PhotosensitivityPorphyrins are Fluorescent compoundsFormation of reactive oxygen species,
Activate Complement
Lead Poisoning
Hydroxymethylbilane Synthase
ALA-D Porphyria
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
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Clin Med2005:5
Dr. Meyer-Betz1912
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GM Murphy, Dermatologic Therapy, March 2003
CEP
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CEPNEJM9/7/2006
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mccaskey4.home.mindspring.com
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Erythropoietic
AcuteHepatic
Chronic
Lead Poisoning
Hydroxymethylbilane Synthase
ALA-D Porphyria
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
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Porphyria Cutanea Tarda (PCT)
• Most common Porphyria– 80% sporadic
• Hepatic and Erythropoietic• Photosensitivity• Uroporphyrin accumulates in Urine
– Red-Brown in natural light
• Clinical expression in 4th - 5th decade• Decrease in UROD activity by Iron-dependent mechanism
– Alcohol, viruses, drugs, hormones– HFE Hemochromatosis
• Venesection, Chloroquine
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Autosomal Dominant PCT (Hepatoerythropoietic Porphyria)
• Hepatic UROD activity < 50% during symptoms
• Additional decrease from reversible inactivation
• C282Y HFE causes earlier onset
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PCT; www.Utah.edu
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Erythropoietic
AcuteHepatic
AcuteHepatic
Photosensitivity(Unlike AIP)
Lead Poisoning
Hydroxymethylbilane Synthase
Chronic
ALA-D Porphyria
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
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medlib.med.utah.edu
NormalLiver
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www.med.niigata-u.ac.j
Granular, Dark Reddish BrownSurface of Liver in Hemochromatosis
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Lecha, Herrero, Ozalla, Dermatologic Therapy, March 2003
HepaticPorphyria
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AcuteHepatic
Erythropoietic
AcuteHepatic
AcuteHepatic
Photosensitivity
Lead Poisoning
Hydroxymethylbilane Synthase
Chronic
ALA-D Porphyria
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
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Hair AnalysisLancetJuly 2005
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Lancet July 23-29, 2005
• King George III (1738-1820)• Likely diagnosis of Variegate Porphyria
– Proposed 1969 based on family tree
• Lock of hair showed high lead– Widespread use in his era
• Extremely high levels of arsenic– Likely secondary to medications
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LancetJuly 2005
Color of Urine“Alicante Wine”
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http://www.aw-bc.com/mathews/GH/HEME.GIF
Introduction of Fe2+ into PPIXOccurs spontaneously, but
Enhanced by FERROCHELATASEAn enzyme which is inhibited by LEAD
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http://www.photodermatologie.de
AcuteHepatic
AcuteHepatic
Erythropoietic
AcuteHepatic
Erythropoietic
Photosensitivity
Lead Poisoning
Hydroxymethylbilane Synthase
Chronic
ALA-D Porphyria
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
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Erythropoietic Protoporphyria
• Presentation in early childhood• Burning, stinging pain with sunlight• Subsequent skin changes• Expression requires low-expression allele
in trans– 10% of population of France and UK– IVS3-48 alternative splice acceptor– With AD mutation FECH 35% of normal– Homozygosity does not cause disease
• Beta carotene: free radical scavenger
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www.immunochemistry.com
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GM Murphy, Dermatologic Therapy, March 2003
EPP
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GM Murphy, Dermatologic Therapy, March 2003
EPP
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www.goa-world.ne
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AcuteHepatic
AcuteHepatic
Erythropoietic
AcuteHepatic
Erythropoietic
Photosensitivity
Lead Poisoning
No PhotosensitivityWith Lead
Lead Poisoning
Hydroxymethylbilane Synthase
Chronic
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
ALA-D Porphyria
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http://www.photodermatologie.de
AcuteHepatic
AcuteHepatic
Erythropoietic
AcuteHepatic
Erythropoietic
Photosensitivity
Iron Deficiency
“Free” ErythrocytePPIX accumulatesin Lead Poisoning and Iron Deficiency
Lead Poisoning
Hydroxymethylbilane Synthase
Chronic
X-linked Sideroblastic Anemia
X-linked Sideroblastic Anemia
ALA-D Porphyria
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Porphyrias: Genetics / Epigenetics
• 5 out of 7 are Low-penetrance Autosomal Dominant
• Most mutations are restricted to one family
• Rare Homozygotes very severe• No dominant negative mutants described• 50% residual activity is normally sufficient
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Molecular basis of “low penetrance”
• Genotype/phenotype correlations
• Increased demand– Fasting (low Glucose)– Cell, August 26, 2005
• Low expression allele in trans
• Iron / HFE hemochromatosis can directly inhibit enzymes
• Other epigenetic phenomena
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Treatment
• Medical Support during acute attacks• Treatment for pain and vomiting• Glucose infusion until Hemin available• Intravenous Hemin
– Decreases synthesis of ALAS
• Avoid Sunlight -carotene, a free-radical scavenger• Chronic transfusion for Erythropoietic
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Degradation of Heme
• At end of their 120 day lifespan, red blood cells are taken up and degraded by the reticuloendothelial (RE) system (liver and spleen)
• 85% heme for degradation from RBC• 15% immature RBC, cytochromes
from extraerythroid tissues
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N
NH N
HNH3C-
H3C-
-CH=CH2
-CH3
CH2
CH2
COOH
CH2
CH2
COOH
CH3
Fe2+
CH=CH2HEME
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N
NH N
HNH3C-
H3C-
-CH=CH2
-CH3
CH2
CH2
COOH
CH2
CH2
COOH
CH3
Fe2+
CH=CH2
MACROPHAGEtakes up HEME
Heme Oxygenaseis Inducible by a variety of agents
Inhibited by TinProtoporphyrin
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N
NH N
HNH3C-
H3C-
-CH=CH2
-CH3
CH2
CH2
COOH
CH2
CH2
COOH
CH3CH=CH2MACROPHAGEHemeOxygenase
Step 1NADPH O2
Fe3+
OH
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N
NH N
HNH3C-
H3C-
-CH=CH2
-CH3
CH2
CH2
COOH
CH2
CH2
COOH
CH3CH=CH2MACROPHAGEHemeOxygenase
Step 2Fe3+ COReleased
O O
BILIVERDIN
HO also has Cytoprotectiveeffects
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J Cell Mol Med 2006
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NH
CH
VM
N CH
PM
NH
CH
MP
NH
O
VM
O
BILIVERDIN
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NH
CH
VM
N CH
PM
NH
CH
MP
NH
O
VM
O
NH
CH
VM
NH
CH2
PM
NH
CH
MP
NH
O
VM
O
BILIVERDIN
BILIVERDIN REDUCTASE+ NADPH
BILIRUBIN
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BILIRUBIN ALBUMINLow AlbuminAnionic Drugs:SalicylatesSulfonamides
BILIRUBIN ALBUMIN
Unbound BilirubinCan enter CNSCause Kernicterus in Neonate
Bilirubin Released from Macrophage, binds to Albumin in the Plasma
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BILIRUBIN ALBUMIN
LIVER BILIRUBIN LIGANDIN
CONJUGATION with2 MoleculesGlucuronic Acid fromUDP-glucuronic acid
BilirubinGlucuronyltransferase
Bilirubin Diglucuronide BILEActiveTransport
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BILIRUBIN: Unconjugated (Indirect)
LIVER
CONJUGATIONBilirubinGlucuronyltransferase
Bilirubin Diglucuronide:Conjugated (Direct) Bilirubin
VAN DEN BERGH COLORMETRIC REACTIONTOTAL BILIRUBIN: Soluble in Methanol
Less Soluble in Aqueous Solution, reacts more slowly
More Soluble, reacts more quickly
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GALL
BLADDER
Ac
tiveT
ran
sp
ort
Bilirubin Diglucuronide
LIVER
Bilirubin Diglucuronide
UROBILINOGEN STERCOBILIN
KID
NE
YB
ILE
INTESTINAL BACTERIA
UrobilinogenUrobili
nogen
Enterohepatic
Circulation
UROBILIN
Bilirubin
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GALL
BLADDER
Ac
tiveT
ran
sp
ort
BilirubinDiglucuronide
LIVER
Bilirubin Diglucuronide
UROBILINOGEN STERCOBILIN
KID
NE
YB
ILE
INTESTINAL BACTERIA
UrobilinogenUrobili
nogen
Enterohepatic
Circulation
UROBILIN
BILIRUBINHEMOLYSIS: Unconjugated(Indirect) Hyperbilirubinemia
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GALL
BLADDER
Ac
tiveT
ran
sp
ort
Bilirubin DG
LIVER
Bilirubin Diglucuronide
UROBILINOGEN STERCOBILIN
KID
NE
YB
ILE
INTESTINAL BACTERIA
UrobilinogenUrobili
nogen
Enterohepatic
Circulation
UROBILIN
BILIRUBIN
NEONATAL JAUNDICE: Unconjugated Hyperbilirubinemia
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www.mtwthailand.org
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home.hawaii.rr.com
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GALL
BLADDER
Ac
tiveT
ran
sp
ort
Bilirubin Diglucuronide
LIVER
KID
NE
YB
ILE
INTESTINAL BACTERIA
UROBILIN
Bilirubin OBSTRUCTIVE JAUNDICEDirect (Conjugated) Bilirubin
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GALL
BLADDER
Ac
tive
Tra
ns
po
rt
Bilirubin DG
LIVER
Bilirubin Diglucuronide
UROBILINOGEN STERCOBILIN
KID
NE
YB
ILE
INTESTINAL BACTERIA
Urobilinogen Dark Urine
BILIRUBIN
HEPATOCELLULAR JAUNDICE: Unconjugated Hyperbilirubinemia
ENTEROHEPATIC
CIRCULATION
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www.privivka.ru
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Carotenemia