12.7.07 AIP Golden

Acute Intermittent Porphyria
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.
Heme Production
 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
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)
 Ccongenital 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.
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.
 The enzyme activity is 50% of normal in those who inherit
the genetic trait.
 There is no difference in PBGD activity between patients
and latent gene carriers.
 An inherited deficiency of PBGD is not in itself sufficient to
cause clinical expression of AIP; the great majority ( 90%)
of individuals who inherit a deficiency of PBGD never
develop porphyric symptoms.
 More than 200 mutations of the PBGD gene have been
described to date in AIP.
Acute intermittent porphyria
 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
 Most patients are completely free of symptoms
between attacks
 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%)
 The abdominal pain is severe and lasts for several days. Severe
abdomen pain of short (<1 d) duration or chronic abdominal pain
is unusual.
 Patients may have CNS signs consisting of seizures
(10–20%), mental status changes, cortical blindness, and
coma.
Symptoms
 Patients often experience peripheral
neuropathies (42–60%) that are predominantly
motor and can mimic Guillain-Barré syndrome.
The weakness usually starts in the lower limbs
and ascends, but neuropathies can be
observed in any nerve distribution.
 Diffuse pain, especially in the upper body, can be
observed (50–52%).
 Patients may develop fever(9–37%),
hypertension (36–54%) and tachycardia (28–
80%).
 Patients can have a wide variety of psychiatric
symptoms (40–58%).
 Depression is very common.
Mechanism
 The exact mechanism underlying these complaints is not yet
well understood, various hypotheses have been put forward:
 Excess amounts of PBG or ALA may cause neurotoxicity

(Meyer et al, 1998)
 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
 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

Diagnosis
 Urinary ALA and PBG are
always markedly increased
in symptomatic patients
with AIP and even in some
asymptomatic individuals
with the inherited enzyme
deficiency
 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’.
Treatment
 Recognition and avoidance of precipitating events

is the first key part of treatment.
 Management of acute attack is essentially the same
for AIP, ADP, HCP and VP.
 IV administration of glucose is given to provide
a minimum of 400 g/day.
 People experiencing severe attacks, especially
those with severe neurologic symptoms, should
be treated with hematin in a dose of 4 mg/kg/d
for 4 days (shown to decrease urinary excretion
of ALA and PBG, acute attacks, and perhaps
the severity of neuropathy).
Treatment
 Haemolytic anaemia in erythropoietic porphyrias

may be treated by blood transfusion.
 Cutaneous photosensitivity may be treated by:
 Photoprotection, e.g. with broad-band
sunscreens and/or protective clothing
 Strict avoidance of sunlight exposure
 Change day-night-rhythmoral
 EEP- B-carotene
 PCT- phlebotomy or oral chloroquine
 Most patients (60-80%) who have an acute

attack of porphyria never have another one
Vampires and werewolves
 “Cutaneous Porphyrias have been suggested as an explanation for the

origin of vampire and werewolf legends, based upon a number of
similarities between the condition and the folklore that was first
speculated upon by biochemist David Dolphin in 1985. His ruminations
gave rise to a popular urban legend which accepts this association as
factual, though it is historically and factually baseless.”

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Acute Intermittent Porphyria

 First and the last 2

 All of the heme pathway

 The prevalence of AIP in the United States is thought to be

 Excess amounts of PBG or ALA may cause neurotoxicity

 Less Useful in acute attacks

 Recognition and avoidance of precipitating events

 Haemolytic anaemia in erythropoietic porphyrias

 PCT- phlebotomy or oral chloroquine

 Most patients (60-80%) who have an acute

 “Cutaneous Porphyrias have been suggested as an explanation for the

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