Disorders of Heme synthesis
HEME-CONTAINING PROTEINS
 Hemoglobin
 Myoglobin
 Cytochromes
 Catalase
 Some peroxidases
STRUCTURE OF HEME
Ferrous iron (Fe2+)
Protoporphyrin IX:
contains 4 pyrrole
rings linked
together by
methenyl bridges

The two major cell types that are active in heme synthesis
are hepatocytes and bone marrow erythroblasts

85% of total synthesis occurs in erythroid cells

80% of liver production is used for cytochromes
Heme Synthesis
Disorders of Heme metabolism
Heme biosynthesis
Porphyrias
Heme degradation
Jaundice
BLOOD
CELLS
Stercobilin
excreted in feces
Urobilin
excreted in urine
Hemoglobin
Heme
O2
Globin
Heme oxygenase
Urobilinogen
formed by bacteria
INTESTINE
CO
Biliverdin IX
NADP
Biliverdin
H
reabsorbed
into blood
via bile duct to intestines
Bilirubin diglucuronide
(water-soluble)
reductase
NADP
Bilirubin+
(water-insoluble)
KIDNEY
2 UDP-glucuronic acid
via blood to
the liver
Bilirubin
(water-insoluble)
LIVER
Figure 2. Catabolism of hemoglobin
The
Porphyrias

Group of inherited
or acquired
disorders of heme
production

8 enzymes in
heme biosynthetic
pathway

First and the last 2
are mitochondrial,
while the other five
are in the cytosol.
Classification of the Porphyrias

Multiple ways to categorize porphyrias:
 Hepatic vs. Erythropoietic: Organ in which
accumulation of porphyrins and their precursors
appears
 Cutaneous vs. Non- cutaneous
 Acute and non-acute forms

Acute:
 Aminolevulinate dehydratase deficiency porphyria
(ALA-D)
 Acute intermittent porphyria (AIP)
 Hereditary coproporphyria (HCP)
 Variegate porphyria (VP)

Chronic:
 Porphyria cutanea tarda (PCT)
 Erythropoietic protoporphyria (EPP)
 Congenital erythropoietic porphyria (CEP)
 Hepatoerythropoietic porphyria (HEP)
Enzymatic
Deficiencies

All of the heme pathway
intermediates are
potentially toxic.

Their overproduction
causes the characteristic
neurovisceral and/or
photosensitizing
symptoms.
PORPHYRIA CUTANEA TARDA
Most common porphyria
Hepatic, autosomal dominant
Disease is caused by a deficiency in uroporphyrinogen
decarboxylase, which is involved in the conversion of
uroporphyrinogen III to coproporphyrinogen III
 Uroporphyrinogen accumulates in urine
 Patients are photosensitive (cutaneous photosensitivity)
Accumulation of porphyrinogens results in their
conversion to porphyrins by light
Porphyrins react with molecular oxygen to form
oxygen radicals
Oxygen radicals can cause severe damage to the
skin
PORPHYRIA
CUTANEA TARDA
Acute intermittent porphyria
Van Gogh
King George III
Mary Queen of Scots
Acute intermittent porphyria

The prevalence of AIP in the United States is thought to be 5–10
per 100 000.
 It is more common in northern European countries, such as
Sweden (60–100 per 100 000), Britain and Ireland.

Acute intermittent porphyria PBGD gene mutation is inherited in
an autosomal dominant fashion.

Affects women more than men, with a ratio of 2:1.
Most patients become symptomatic at age 18-40 years.
 Attacks occurring before puberty or after age 40 years are
unusual unless a major provocation
Most patients are completely free of symptoms between attacks.
Course of the neurological manifestations is highly variable.
 Acute attacks of porphyria may resolve quite rapidly.
 Sudden death may occur, presumably due to cardiac
arrhythmia.



Symptoms

Attacks involve neuro-visceral symptoms but no skin
manifestations:
 The sequence of events in attacks usually is (1) abdominal pain, (2)
psychiatric symptoms, such as hysteria, and (3) peripheral
neuropathies, mainly motor neuropathies.

Gastroenterological Symptoms most common:
 Constipation (48–84%), colicky abdominal pain (occurring in 85–95%
cases), vomiting (43–88%), diarrhea (5–12%)
Patients may have CNS signs consisting of seizures (10–20%), mental
status changes, cortical blindness, and coma.


Patients often experience peripheral neuropathies (42–60%) that are
predominantly motor and can mimic Guillain-Barré syndrome.

Patients may develop fever(9–37%), hypertension (36–54%)
tachycardia (28–80%).
and
Mechanism

The exact mechanism underlying these complaints is
not yet well understood, various hypotheses have
been put forward:

Excess amounts of PBG or
neurotoxicity (Meyer et al, 1998)
ALA
may
cause

Increased ALA concentrations in the brain may inhibit
gamma-aminobutyric acid release (Mueller & Snyder,
1977; Brennan & Cantrill, 1979)

Heme deficiency may result in degenerative changes in
the central nervous system (Whetsell et al, 1984)

Decreased heme synthesis in the liver results in
decreased activity of hepatic tryptophan pyrrolase (TP),
a heme-dependent enzyme, possibly resulting in
increased levels of serotonin
Precipitants

Drugs: most common precipitate of acute attacks :
 Barbiturates and sulphonamides being most common

Reduced energy intake: even brief periods of starvation
during dieting, postoperative periods, or concurrent illness.

Tobacco smoke: polycyclic aromatic hydrocarbons, are
known inducers of hepatic cytochrome P450 enzymes and
heme synthesis.
 An association between cigarette smoking and repeated
attacks of porphyria was found in a survey of 144
patients with AIP in Britain (Lip et al, 1991).

Infections, surgery and stress.
Diagnosis
PBG in urine is
oxidized to porphobilin
upon standing, which
gives a dark-brown
color to urine, and
often referred to as
‘port-wine
reddish
urine’.

Demonstration of porphyrin precursors, such
as ALA and/or PBG, is essential for the diagnosis
of acute porphyrias.

Porphyrin analysis is necessary for the
diagnosis of porphyrias with cutaneous
photosensitivity.
 PBG usually is not included in a urine
porphyrin screen and must be ordered
specially

Molecular diagnostic testing:
 Detection of PBGD mutations in AIP provides
95% sensitivity and around 100% specificity
 Possible to screen asymptomatic gene
carriers.
 Less Useful in acute attacks
Erythropoietic Protoporphyria
 It is the most common childhood porphyria.
 It is usually evident by 2 years of age.
Pathogenesis
deficient
activity
of
ferrochelatase enzyme
Lab. finding:
Plasma porphyrin level and fluorescence spectrum
Increased free protoporphyrin in RBCs, stool
CBC, LFTs
Liver/gallbladder imaging
Congenital Erythropoietic porphyria
( Gunther's disease ):
It is a very rare autosomal recessive disorder.
Patients usually present during infancy and rarely present in adult life
with milder forms.
Pathogenesis
It is caused by elevation of both water-soluble and lipid-soluble porphyrin
levels due to deficiency of uroporphyrinogen III synthase enzyme.
Clinical features
Lab. finding
1. Very severe photosensitivity with phototoxic burning
and blistering leading to mutilation of light exposed
parts.
2. Erythrodontia.
3. Scleromalacia perforans.
4. Hypersplenism.
5. Hemolytic anemia.
6. Thrombocytopenia
Uroporphyrin and Coproporphyrin in urine
Corproporphyrin in stool
Hepatoerythropoietic Porphyria
Inheritance/Pathogenesis:
AD
Uroporphyrinogen (UROGEN) decarboxylase deficient
Incidence:
Very rare -Presents at age 1
Prognosis:
Normal life span
Clinical picture:
Skin
Similar to CEP—Severe photosensitivity with burning, edema,
vesicles/bullae, erosions, infection
Late changes—Mutilating scars with deformation of nose, ears,
fingers; scarring alopecia, pigmentary changes, sclerodermoid
changes
Hypertrichosis
Teeth
Red/brown color
Eyes
Photophobia, ectropion, conjunctivitis
Heme
Hemolytic anemia
GI
Splenomegaly
GU
Dark urine at birth
Lab. finding:
Plasma porphyrin level and
fluorescence spectrum
protoporphyrin in RBCs
urinary uroporphyrin
fecal coproporphyrin
CBC
Varigeate Porphyria
Inheritance:
AD
Protoporphyrinogen oxidase gene (PROTOGEN)
Severe forms associated with hemochromatosis gene
Prenatal Diagnosis:
DNA analysis
Incidence:
Most common in South African whites 1:330
Elsewhere is 1:50,000 to 100,000
M=F
Age at Presentation:
Begins after puberty in second and third decade of life
Pathogenesis:
Mutation in PROTOGEN oxidase gene causes a 50% decrease in
PROTOGEN oxidase activity
Acute attacks precipitated by:
Drugs: barbiturates, estrogen, griseofulvin, sulfonamides
Infection
Fever
Alcohol
Pregnancy
Decreased caloric intake
Increase Δ-aminolevulinic acid (ALA) synthetase with attacks

Clinical picture:


Skin:
 Identical to PCT with bullae, erosions, skin fragility, scarring,
hypertrichosis, hyperpigmentation on photodistributed face,
neck and dorsum of hands
Acute Attacks (i.e., Acute Intermittent Porphyria and Hereditary
Coproporphyria):
 Gastrointestinal:
• Colickly abdominal pain, nausea, vomiting, constipation
 CNS:
• Peripheral neuropathy with pain, weakness, paralysis
• Confusional state, anxiety, depression, delerium
• Seizures, coma
 CV:
• Tachycardia, hypertension

Laboratory Data:





Plasma porphyrin level
Plasma porphyrin fluorescence spectrum—626 nm is
diagnostic
24 hour urine porphyrin levels: coproprophyrin = or >
uroporphyrin
Urine ALA and porphobillinogen (PBG) levels increased
during attacks
Fecal prophyrin levels: markedly elevated,
protoporphyrin>coproporphyrin