Transcript Porphyrins II - NYU School of Medicine Educational Technology

David Hart
Dec 13, 2006
HEME
CH3-
Bonkovsky
ASH Education Book
December 2005
Hentze, Muckenthaler & Andrews
Cell, Vol 117, 285-297, April 30, 2004
Lecture Outline
• Heme function
• Heme synthesis
and regulation
• Iron metabolism
• Porphyrias
• Heme
degradation
Disorders of Heme
Synthesis
•
•
•
•
X-linked Sideroblastic Anemia
Lead Poisoning
Iron Deficiency Anemia
The Porphyrias
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
Fuseli
Three Witches
Tate
Gillray 1791
Weird Sisters
Tate
X-linked
Sideroblastic Anemia
Lead Poisoning
ALA-D Porphyria
Very Rare Recessive Porphyria
X-linked
Sideroblastic Anemia
Lead Poisoning
Acute
Hepatic
ALA-D Porphyria
Hydroxymethylbilane Synthase
PBG and ALA (Neurotoxic)
Accumulate in Urine
PBG in Urine: Diagnostic Screen
Neurovisceral Attacks
No Photosensitivity with AIP
Acute Porphyrias
Clinically 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
X-linked
Sideroblastic Anemia
Lead Poisoning
Acute
Hepatic
ALA-D Porphyria
Hydroxymethylbilane Synthase
Erythropoietic
RECESSIVE
Porphyrin accumulation: Photosensitivity
Porphyrins are Fluorescent compounds
Formation of reactive oxygen species,
Activate Complement
Dr. Meyer-Betz
1912
Clin Med
2005:5
CEP
GM Murphy, Dermatologic Therapy, March 2003
CEP
NEJM
9/7/2006
mccaskey4.home.mindspring.com
X-linked
Sideroblastic Anemia
Lead Poisoning ALA-D Porphyria
Acute
Hepatic
Erythropoietic
Chronic
Hydroxymethylbilane Synthase
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
Autosomal Dominant PCT
(Hepatoerythropoietic Porphyria)
• Hepatic UROD activity < 50% during
symptoms
• Additional decrease from reversible
inactivation
• C282Y HFE causes earlier onset
PCT; www.Utah.edu
X-linked
Sideroblastic Anemia
Lead Poisoning ALA-D Porphyria
Acute
Hepatic
Hydroxymethylbilane Synthase
Erythropoietic
Chronic
Acute
Hepatic
Photosensitivity
(Unlike AIP)
Normal
Liver
medlib.med.utah.edu
Granular, Dark Reddish Brown
Surface of Liver in Hemochromatosis
www.med.niigata-u.ac.j
Hepatic
Porphyria
Lecha, Herrero, Ozalla, Dermatologic Therapy, March 2003
X-linked
Sideroblastic Anemia
Lead Poisoning
Acute
Hepatic
ALA-D Porphyria
Hydroxymethylbilane Synthase
Erythropoietic
Chronic
Acute
Hepatic
Acute
Hepatic
Photosensitivity
Hair Analysis
Lancet
July 2005
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
Lancet
July 2005
Color of Urine
“Alicante Wine”
Introduction of Fe2+ into PPIX
Occurs spontaneously, but
Enhanced by FERROCHELATASE
An enzyme which is inhibited by LEAD
http://www.aw-bc.com/mathews/GH/HEME.GIF
X-linked
Sideroblastic Anemia
Lead Poisoning ALA-D Porphyria
Acute
Hepatic
Hydroxymethylbilane Synthase
Erythropoietic
Chronic
Acute
Hepatic
Acute
Hepatic
Erythropoietic
Photosensitivity
http://www.photodermatologie.de
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
www.immunochemistry.com
EPP
GM Murphy, Dermatologic Therapy, March 2003
EPP
GM Murphy, Dermatologic Therapy, March 2003
www.goa-world.ne
X-linked
Sideroblastic Anemia
Lead Poisoning ALA-D Porphyria
Acute
Hepatic
Hydroxymethylbilane Synthase
Erythropoietic
Chronic
Acute
Hepatic
Acute
Hepatic
Erythropoietic
Photosensitivity
No Photosensitivity
With Lead
Lead Poisoning
X-linked
Sideroblastic Anemia
Lead Poisoning ALA-D Porphyria
Acute
Hepatic
Hydroxymethylbilane Synthase
Erythropoietic
Chronic
Acute
Hepatic
Acute
Hepatic
Erythropoietic
Photosensitivity
“Free” Erythrocyte
PPIX accumulates
in Lead Poisoning
and Iron Deficiency
Iron Deficiency
http://www.photodermatologie.de
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
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
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
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
HEME
CH=CH2
CH3
-CH=CH2
H3CN
HN
Fe2+
NH
N
-CH3
H3C-
CH2
CH2
COOH
CH2
CH2
COOH
Heme Oxygenase
CH3
is Inducible by a
variety of agents
MACROPHAGE
CH=CH2
takes up
HEME
-CH=CH2
H3CN
HN
Inhibited by Tin
Protoporphyrin
Fe2+
NH
N
-CH3
H3C-
CH2
CH2
COOH
CH2
CH2
COOH
MACROPHAGE CH=CH
2
Heme
OH
Oxygenase
CH3
-CH=CH2
H3C-
Step 1
NADPH
O2
N
HN
Fe3+
NH
N
-CH3
H3C-
CH2
CH2
COOH
CH2
CH2
COOH
MACROPHAGE CH=CH
2
Heme
O O
Oxygenase
CH3
-CH=CH2
H3C-
Step 2
Fe3+
CO
Released
N
HN
BILIVERDIN
NH
N
-CH3
H3C-
CH2
CH2
COOH
HO also has
Cytoprotective
effects
CH2
CH2
COOH
J Cell Mol Med 2006
BILIVERDIN
M
O
V
N
H
CH
M
P
N
P
CH
M
N
H
CH
M
V
N
H
O
BILIVERDIN
M
N
H
O
M
V
P
N
CH
P
M
N
H
CH
M
V
N
H
CH
O
BILIVERDIN REDUCTASE
+ NADPH
M
O
V
N
H
CH
M
P
N
H
P
CH2
M
N
H
BILIRUBIN
CH
M
V
N
H
O
Bilirubin Released from Macrophage,
binds to Albumin in the Plasma
BILIRUBIN ALBUMIN
Low Albumin
Anionic Drugs:
Salicylates
Sulfonamides
BILIRUBIN
ALBUMIN
Unbound Bilirubin
Can enter CNS
Cause Kernicterus in Neonate
BILIRUBIN ALBUMIN
LIVER
BILIRUBIN LIGANDIN
CONJUGATION with
2 Molecules
Glucuronic Acid from
UDP-glucuronic acid
Bilirubin
Glucuronyltransferase
Bilirubin Diglucuronide
Active
Transport
BILE
VAN DEN BERGH COLORMETRIC REACTION
TOTAL BILIRUBIN: Soluble in Methanol
BILIRUBIN: Unconjugated (Indirect)
Less Soluble in Aqueous Solution, reacts more slowly
LIVER
CONJUGATION
Bilirubin
Glucuronyltransferase
Bilirubin Diglucuronide:
Conjugated (Direct) Bilirubin
More Soluble, reacts more quickly
KIDNEY
Bilirubin
Bilirubin
Diglucuronide
Active
Transport
LIVER
Urobilinogen
UROBILIN
BILE
Bilirubin
Diglucuronide
UROBILINOGEN
STERCOBILIN
INTESTINAL BACTERIA
KIDNEY
BILIRUBIN
HEMOLYSIS: Unconjugated
(Indirect) Hyperbilirubinemia
Bilirubin
Diglucuronide
Active
Transport
LIVER
Urobilinogen
UROBILIN
BILE
Bilirubin
Diglucuronide
UROBILINOGEN
STERCOBILIN
INTESTINAL BACTERIA
NEONATAL JAUNDICE:
Unconjugated Hyperbilirubinemia
KIDNEY
BILIRUBIN
Bilirubin DG
Active
Transport
LIVER
Urobilinogen
UROBILIN
BILE
Bilirubin
Diglucuronide
UROBILINOGEN
STERCOBILIN
INTESTINAL BACTERIA
www.mtwthailand.org
home.hawaii.rr.com
KIDNEY
Bilirubin
OBSTRUCTIVE JAUNDICE
Direct (Conjugated) Bilirubin
Bilirubin
Diglucuronide
Active
Transport
LIVER
UROBILIN
BILE
INTESTINAL BACTERIA
HEPATOCELLULAR JAUNDICE:
Unconjugated Hyperbilirubinemia
KIDNEY
BILIRUBIN
Bilirubin DG
Active
Transport
LIVER
Urobilinogen
BILE
Bilirubin
Diglucuronide
UROBILINOGEN
STERCOBILIN
INTESTINAL BACTERIA
Dark Urine
www.privivka.ru
Carotenemia