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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

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slide1

Porphyrins II

David Hart

Dec 13, 2006

slide2

HEME

CH3-

slide3

Bonkovsky

ASH Education Book

December 2005

slide4

Hentze, Muckenthaler & Andrews

Cell, Vol 117, 285-297, April 30, 2004

Hepcidin

lecture outline
Lecture Outline
  • Heme function
  • Heme synthesis and regulation
  • Iron metabolism
  • Porphyrias
  • Heme degradation
disorders of heme synthesis
Disorders of Heme Synthesis
  • X-linked Sideroblastic Anemia
  • Lead Poisoning
  • Iron Deficiency Anemia
  • The Porphyrias
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
slide8

Fuseli

Three Witches

Tate

Gillray 1791

Weird Sisters

Tate

slide9

X-linked

Sideroblastic Anemia

Lead Poisoning

ALA-D Porphyria

Very Rare Recessive Porphyria

slide10

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

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
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
slide12

X-linked

Sideroblastic Anemia

Lead Poisoning

ALA-D Porphyria

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

RECESSIVE

Porphyrin accumulation: Photosensitivity

Porphyrins are Fluorescent compounds

Formation of reactive oxygen species,

Activate Complement

slide13

Dr. Meyer-Betz

1912

Clin Med

2005:5

slide14

CEP

GM Murphy, Dermatologic Therapy, March2003

slide15

CEP

NEJM

9/7/2006

slide18

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

Chronic

porphyria cutanea tarda pct
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
Autosomal Dominant PCT (Hepatoerythropoietic Porphyria)
  • Hepatic UROD activity < 50% during symptoms
  • Additional decrease from reversible inactivation
  • C282Y HFE causes earlier onset
slide22

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

Chronic

Acute

Hepatic

Photosensitivity

(Unlike AIP)

slide23

Normal

Liver

medlib.med.utah.edu

slide24

Granular, Dark Reddish Brown

Surface of Liver in Hemochromatosis

www.med.niigata-u.ac.j

slide25

Hepatic

Porphyria

Lecha, Herrero, Ozalla, Dermatologic Therapy, March2003

slide26

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

Chronic

Acute

Hepatic

Acute

Hepatic

Photosensitivity

slide27

Hair Analysis

Lancet

July 2005

lancet july 23 29 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
slide29

Lancet

July 2005

Color of Urine

“Alicante Wine”

slide30

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

slide31

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

Chronic

Acute

Hepatic

Acute

Hepatic

Erythropoietic

http://www.photodermatologie.de

Photosensitivity

erythropoietic protoporphyria
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
slide34

EPP

GM Murphy, Dermatologic Therapy, March 2003

slide35

EPP

GM Murphy, Dermatologic Therapy, March2003

slide37

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

Chronic

Acute

Hepatic

Acute

Hepatic

No Photosensitivity

With Lead

Erythropoietic

Lead Poisoning

Photosensitivity

slide38

X-linked

Sideroblastic Anemia

ALA-D Porphyria

Lead Poisoning

Acute

Hepatic

Hydroxymethylbilane Synthase

Erythropoietic

Chronic

Acute

Hepatic

“Free” Erythrocyte

PPIX accumulates

in Lead Poisoning

and Iron Deficiency

Acute

Hepatic

Erythropoietic

Iron Deficiency

http://www.photodermatologie.de

Photosensitivity

porphyrias genetics epigenetics
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
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
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
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
slide43

CH=CH2

CH3

HEME

-CH=CH2

H3C-

N

HN

Fe2+

NH

N

-CH3

H3C-

CH2

CH2

COOH

CH2

CH2

COOH

slide44

Heme Oxygenase

is Inducible by a

variety of agents

MACROPHAGE

takes up

HEME

CH=CH2

CH3

-CH=CH2

H3C-

N

HN

Inhibited by Tin

Protoporphyrin

Fe2+

NH

N

-CH3

H3C-

CH2

CH2

COOH

CH2

CH2

COOH

slide45

MACROPHAGE

Heme

Oxygenase

Step 1

NADPH

O2

CH=CH2

CH3

OH

-CH=CH2

H3C-

N

HN

Fe3+

NH

N

-CH3

H3C-

CH2

CH2

COOH

CH2

CH2

COOH

slide46

MACROPHAGE

Heme

Oxygenase

Step 2

Fe3+

CO

Released

CH=CH2

CH3

O

O

-CH=CH2

H3C-

N

HN

BILIVERDIN

NH

N

-CH3

H3C-

HO also has

Cytoprotective

effects

CH2

CH2

COOH

CH2

CH2

COOH

slide48

M

M

P

P

M

M

V

V

N

H

N

N

H

N

H

CH

CH

CH

O

O

BILIVERDIN

slide49

M

M

P

P

M

M

V

V

N

H

N

N

H

N

H

CH

CH

CH

O

O

BILIVERDIN

BILIVERDIN REDUCTASE

+ NADPH

M

M

P

P

M

M

V

V

N

H

N

H

N

H

N

H

CH

CH2

CH

O

O

BILIRUBIN

slide51

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

slide52

BILIRUBIN

ALBUMIN

LIVER

LIGANDIN

BILIRUBIN

CONJUGATION with

2 Molecules

Glucuronic Acid from

UDP-glucuronic acid

Bilirubin

Glucuronyltransferase

Active

Transport

Bilirubin Diglucuronide

BILE

slide53

VAN DEN BERGH COLORMETRIC REACTION

TOTAL BILIRUBIN: Soluble in Methanol

BILIRUBIN: Unconjugated (Indirect)

Less Soluble in Aqueous Solution, reacts more slowly

LIVER

Bilirubin

Glucuronyltransferase

CONJUGATION

Bilirubin Diglucuronide:

Conjugated (Direct) Bilirubin

More Soluble, reacts more quickly

slide54

Bilirubin

Bilirubin

Diglucuronide

Enterohepatic

Circulation

KIDNEY

Active

Transport

LIVER

Urobilinogen

UROBILIN

Urobilinogen

GALL

BLADDER

BILE

UROBILINOGEN

STERCOBILIN

Bilirubin

Diglucuronide

INTESTINAL BACTERIA

slide55

HEMOLYSIS: Unconjugated

(Indirect) Hyperbilirubinemia

BILIRUBIN

Enterohepatic

Circulation

KIDNEY

Bilirubin

Diglucuronide

Active

Transport

LIVER

Urobilinogen

UROBILIN

Urobilinogen

GALL

BLADDER

BILE

UROBILINOGEN

STERCOBILIN

Bilirubin

Diglucuronide

INTESTINAL BACTERIA

slide56

NEONATAL JAUNDICE:

Unconjugated Hyperbilirubinemia

BILIRUBIN

Enterohepatic

Circulation

KIDNEY

Bilirubin DG

Active

Transport

LIVER

Urobilinogen

UROBILIN

Urobilinogen

GALL

BLADDER

BILE

UROBILINOGEN

STERCOBILIN

Bilirubin

Diglucuronide

INTESTINAL BACTERIA

slide59

OBSTRUCTIVE JAUNDICE

Direct (Conjugated) Bilirubin

Bilirubin

Bilirubin

Diglucuronide

KIDNEY

Active

Transport

LIVER

UROBILIN

GALL

BLADDER

BILE

INTESTINAL BACTERIA

slide60

HEPATOCELLULAR JAUNDICE:

Unconjugated Hyperbilirubinemia

BILIRUBIN

ENTEROHEPATIC

CIRCULATION

KIDNEY

Bilirubin DG

LIVER

Active

Transport

Dark Urine

Urobilinogen

GALL

BLADDER

BILE

STERCOBILIN

UROBILINOGEN

Bilirubin

Diglucuronide

INTESTINAL BACTERIA