Acute Intermittent Porphyria: The Right Clinical Information, Right Where It's Needed

Acute intermit tent
porphyria
The right clinical information, right where it's needed
Last updated: Jan 12, 2017

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Classification 5
Prevention 6
Primary prevention 6
Screening 6
Secondary prevention 6
Diagnosis 7
Case history 7
Step-by-step diagnostic approach 7
Risk factors 8
History & examination factors 9
Diagnostic tests 11
Differential diagnosis 12
Treatment 14
Step-by-step treatment approach 14
Treatment details overview 15
Treatment options 16
Emerging 20
Follow up 21
Recommendations 21
Complications 21
Prognosis 22
Guidelines 23
Diagnostic guidelines 23
Treatment guidelines 23
Online resources 24
References 25
Disclaimer 28
Summary
◊ A rare autosomal dominant inherited disorder characterised by a partial deficiency of

porphobilinogen deaminase (PBGD), the third enzyme in the haem biosynthetic pathway. As a result,
the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) accumulate in
the body.
◊ Most patients remain asymptomatic, but symptoms can be triggered by use of certain drugs or
alteration of nutritional status.
◊ The most common presenting features include pain in the abdomen, extremities, back, and chest;
tachycardia; hypertension; nausea and vomiting; constipation; and peripheral motor neuropathy.
◊ The pain is neuropathic and is not accompanied by inflammation.
◊ Red or brownish urine results from marked increases in urinary excretion of haem pathway
intermediates. Porphyrins are reddish and fluoresce when exposed to long-wave ultraviolet light.
PBG is colourless but degrades on standing to form brownish pigments.
Acute intermit tent porphyria Basics
Definition
Acute intermittent porphyria (AIP) is a rare genetic disorder characterised by a partial deficiency of
porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase, the third enzyme in
BASICS
the haem biosynthetic pathway. As a result, the porphyrin precursors porphobilinogen (PBG) and delta-
aminolevulinic acid (ALA) accumulate in the body. Urinary excretion of ALA, PBG, and porphyrins is
increased. Most patients remain asymptomatic with little or no elevation in ALA, PBG, and porphyrins, but the
condition can be activated after puberty by some drugs and corticosteroid hormones or by reducing dietary
intake.
Epidemiology
The combined prevalence of the acute porphyrias is approximately 5 per 100,000 population.[3] It is more
common in women than in men. AIP is especially prevalent in northern Sweden (approximately 100 per
100,000 population) due to a founder effect.
Aetiology
AIP results from an autosomal dominant inheritance of a deficiency in porphobilinogen deaminase (PBGD),
also known as hydroxymethylbilane synthase (HMBS), the third enzyme in the haem biosynthetic pathway.
The PBGD/HMBS gene is located on chromosome 11. Many different mutations of this gene have been
identified in different AIP families. These mutations include missense, nonsense, and splicing mutations, and
insertions and deletions.[4]
AIP remains latent in most heterozygotes. These people can usually be identified in family studies by
measuring erythrocyte PBGD activity or, more reliably, by DNA studies. Some heterozygotes may develop a
variety of non-specific symptoms after puberty. This can occur following nutritional alterations (e.g., fasting,
dieting), intercurrent illness, or exposure to certain drugs or hormones.[5] [6] [7] These factors induce
the housekeeping form of delta-aminolevulinic acid synthase (ALAS1), the rate-limiting enzyme for haem
biosynthesis in the liver, and cytochrome P-450 (CYP) enzymes. CYPs are haem proteins and require most
of the haem synthesised in the liver. With induction of ALAS1, the deficiency of PBGD becomes significant
and large amounts of the porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG)
accumulate in the body.[2]
Pathophysiology
With the block in haem synthesis at the PBGD reaction stage, the resulting increases in ALA and PBG
synthesis lead to marked increases in urinary excretion of both porphyrin precursors, which are colourless,
and porphyrins. Porphyrins are reddish in colour and PBG degrades to form porphobilin, a brownish
pigment, often resulting in deep red urine, a hallmark of AIP. About 80% of those who inherit AIP remain
asymptomatic, and others may have only a single attack or a few acute attacks during their life.[3]
Symptoms are due to:
• Effects on the nervous system

• Peripheral and autonomic neuropathies
• Psychiatric manifestations
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 12, 2017.
BMJ Best Practice topics are regularly updated and the most recent version
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subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
Acute intermit tent porphyria Basics
• Syndrome of inappropriate ADH secretion (SIADH), which causes hyponatraemia.
The mechanisms of neurological manifestations of AIP are not well known, but it seems likely that a haem
pathway intermediate or product is neurotoxic, and ALA seems the most likely candidate.[2]
BASICS
Classification
Clinical definitions[1] [2]
• Clinically expressed AIP: heterozygotes with symptoms and increased porphobilinogen (PBG).
• Biochemically expressed AIP: heterozygotes with increased PBG but no symptoms.
• Latent AIP: heterozygotes without symptoms or increased PBG.
• Homozygous AIP: rare cases that present in childhood with severe neurological symptoms and
delayed development.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 12, 2017.
5
Acute intermit tent porphyria Prevention
Primary prevention
Identification of a known porphobilinogen deaminase (PBGD) mutation is possible in utero, but interruption
of pregnancy is seldom indicated because most heterozygotes do not have severe or life-long symptoms and
most (approximately 80%) remain asymptomatic.[3] To prevent attacks, known heterozygotes should avoid
harmful drugs and other triggers (e.g., nutritional alterations) whenever possible. Triggers are more likely to
be harmful in patients who have already developed symptoms.[10] Generally, a well-balanced diet containing
enough calories to maintain body weight and 60% to 70% of total calories as carbohydrate is recommended.
Cyclic attacks in women can be prevented by giving a gonadotrophin-releasing hormone (GnRH) analogue,
which should be started during days 1 to 3 of the menstrual cycle.[8] With long-term use, add-back oestrogen
in the form of a low-dose skin patch helps prevent bone loss. Haemin infusions once or twice weekly can
prevent non-cyclic attacks.[11] [3]
Screening
Screening for a known mutation in an AIP family is most effective for detecting asymptomatic relatives.
Measurement of erythrocyte porphobilinogen deaminase (PBGD) activity is less reliable than DNA methods
but can be used if an index case has demonstrated AIP with a decreased enzyme activity. All relatives
PREVENTION
should be screened. Screening of children is less urgent than in adults because clinical expression in
children is very rare.
Secondary prevention
• Prevention of further attacks requires education of patients and their family members and physicians.
• Precipitating factors should be identified and avoided. [British Porphyria Association] [American
Porphyria Foundation] [European Porphyria Network]
• Medical alert bracelets and wallet cards can remind patients and medical personnel of the diagnosis
when other illnesses develop and during emergencies.
Acute intermit tent porphyria Diagnosis
Case history
Case history #1
A 30-year-old woman has severe abdominal pain, nausea, vomiting, and diarrhoea, and is admitted
to hospital for 2 weeks for a suspected intestinal infection. Evaluation, including upper and lower
endoscopies, does not establish a definite cause for her symptoms. She gradually improves and is
discharged after 2 weeks. Symptoms recur 2 years later, leading to multiple emergency department visits.
She is admitted to a psychiatric unit with mental status changes and hallucinations, then transferred
to the emergency department with abdominal pain, a grand mal seizure, and hyponatraemia. On
admission to a medical unit her pulse is 120 bpm and BP is 174/114 mmHg. She is disoriented but
has no focal neurological signs. MRI shows subcortical abnormalities, and the spinal fluid is normal.
After cholecystectomy for a distended gallbladder, she is discharged and stays with a family member in
another city because her symptoms are worse and muscle weakness has developed. She is admitted
to hospital and progresses to quadriparesis, respiratory failure, and aspiration pneumonia. Urinary
porphobilinogen (PBG) is reported as 44 mg/24 hours (reference range 0-4). Following treatment with
intravenous glucose and stopping harmful drugs (including phenytoin), she improves gradually and
is discharged for physiotherapy and rehabilitation. She recovers almost completely over a period of
several months, although residual painful hyperaesthesia of the lower extremities, mild proximal muscle
weakness, and impaired short-term memory are noted. Several attacks occur in the next few years, and
some are premenstrual.
Other presentations
Peripheral motor neuropathy is usually a late manifestation of an AIP attack, especially if the attack
has not been diagnosed or treated. Rarely, a rapidly progressive motor neuropathy can develop in the
absence of more common symptoms, such as abdominal pain.
DIAGNOSIS
Step-by-step diagnostic approach
Acute porphyria is often not considered even when characteristic symptoms, signs, and laboratory findings
suggest the diagnosis. If untreated, motor neuropathy may progress to total body paralysis, requiring
ventilation. Prompt diagnosis followed by optimal treatment greatly improves outcomes. In addition, the risk
of developing renal impairment and liver cancer is increased in AIP.
General history
AIP presents with a variety of neurovisceral symptoms and signs that are non-specific and mimic many
other, more common conditions.[12]
• Abdominal pain is usually steady and diffuse but may be cramping.

• The pain is neuropathic and is not accompanied by inflammation. Pain and other symptoms usually
occur during acute attacks, but may become chronic.
• Abdominal pain in women during the luteal phase of the cycle, a preceding intercurrent illness,
exposure to a harmful drug or dietary restriction, and dark or reddish urine can be clues to AIP
diagnosis.[3]
7
• Nausea, vomiting, constipation (less often diarrhoea), and pain in the back, chest, and extremities
are common. Painful hyperaesthesia of the lower extremities may also be noted.
• The family history may be negative for AIP because most carriers of the trait in affected families are
asymptomatic. However, a known family history of the disease is important.
• Muscle weakness usually develops later, but can be an initial symptom, and usually begins
proximally in the upper extremities.
• Seizures may occur during acute attacks and may be due to hyponatraemia or acute effects of AIP
on the nervous system.
• Anxiety, restlessness, agitation, hallucinations, and other psychiatric manifestations are common
during acute attacks. These may represent a metabolic encephalopathy that can be accompanied
by reversible MRI findings resembling the posterior reversible encephalopathy syndrome.
• Chronic pain and depression may occur long-term, and the risk of suicide is increased.
• These symptoms and signs mimic other diseases, and other causes must be excluded by thorough
clinical evaluation.
Physical examination
• Tachycardia and hypertension are the most common signs.
• Abdominal pain is characteristically out of proportion to the findings on examination.
• Patients may be agitated and disoriented, especially early in an attack.
• Testing for proximal muscle weakness by neurological examination is important for early detection
of motor neuropathy.
• Reflexes may be normal or hyperactive with clonus early in the development of neuropathy, and
absent later.
Laboratory tests
For prompt diagnosis it is essential to test for increased porphobilinogen (PBG), preferably in a single-void
urine sample. Availability of a PBG test kit facilitates rapid diagnosis.[3] [13] For confirmation, the same
urine sample may be used to measure delta-aminolevulinic acid (ALA), PBG, and total porphyrins. If PBG
DIAGNOSIS
is elevated, the type of acute porphyria is established by further testing, including:
• Erythrocyte porphobilinogen deaminase (PBGD) activity

• Urine porphyrins
• Plasma porphyrins
• Faecal porphyrins.
After biochemical confirmation, it is important to carry out DNA studies to identify a mutation of the PBGD/
HMBS gene (which is often family-specific) for confirmation and to facilitate family studies. Complete
medical evaluation in these acutely unwell patients should include measurement of serum sodium levels,
because hyponatraemia may be present due to syndrome of inappropriate ADH secretion (SIADH)
provoked by AIP.
Risk factors
Strong
family history
• AIP results from an autosomal dominant inheritance of a deficiency in porphobilinogen deaminase
(PBGD), the third enzyme in the haem biosynthetic pathway. Very rarely, a more severe and distinct
form of the disorder is inherited from both parents (homozygous disease).
female gender
• Symptoms develop more commonly in women than in men.[2]
drugs
• Certain drugs (e.g., barbiturates, phenytoin, progestins, metoclopramide, sulfonamide antibiotics)
exacerbate AIP, and most are inducers of delta-aminolevulinic acid synthase, and cytochrome P-450
enzymes in the liver.[2]
elevated progesterone levels

• Elevated progesterone levels during the luteal phase appear to be correlated to cyclic attacks. Some
metabolites of progesterone and testosterone are also implicated in causing attacks.[8]
decreased caloric or carbohydrate intake

• Restriction of calories and carbohydrate can exacerbate acute porphyrias. The mechanistic link
is through hepatic delta-aminolevulinic acid synthase. Induction of this rate-controlling enzyme is
enhanced by fasting and repressed by carbohydrate loading.[5] [6] [7]
smoking
• Smoking induces haem synthesis and cytochrome P-450 enzymes in the liver, and heavy smoking in
patients with AIP is related to more frequent attacks.[9]
age >13 years

• Symptoms of this inherited disease are rare before puberty.[1] [2]
Weak
DIAGNOSIS
alcohol
• Alcohol intake may exacerbate AIP though induction of delta-aminolevulinic acid synthase.
History & examination factors

Key diagnostic factors
presence of risk factors (common)
• Key risk factors include family history of acute porphyria, female gender, nutritional alterations (e.g.,
fasting, dieting), intercurrent illness, and exposure to drugs or hormones known to provoke attacks of
AIP.
abdominal pain (common)

• Symptoms out of proportion to the physical examination and not explained by common causes.
tachycardia (common)
9
• Common physical finding.
hypertension (common)
• Common physical finding. Sometimes becomes chronic.[3]
dark or red urine (common)

• Urinary excretion of porphyrins and degradation products of porphobilinogen (PBG).
Other diagnostic factors

nausea (common)
• Accompanies abdominal pain and ileus.
vomiting (common)
abdominal distension (common)

constipation (common)
urinary hesitancy and dysuria (common)

• Reflects neurological bladder dysfunction.
pain in extremities, back, and chest (common)

• Reflects peripheral nerve involvement.
proximal muscle weakness (common)

• In severe attacks. Early motor neuropathy.
DIAGNOSIS
painful hyperaesthesia (common)

• Reflects sensory involvement, and may be manifested especially by pain in the extremities.
mental symptoms (common)

• May range from minor behavioural changes and insomnia to depression, agitation, and confusion.
seizures (common)
• CNS manifestation of porphyria or due to hyponatraemia, which results from syndrome of
inappropriate ADH secretion (SIADH) provoked by AIP.
diarrhoea (uncommon)
• Occurs in 5% to 12% of patients.[3]
quadriparesis (uncommon)
• May occur during a severe and prolonged attack, especially if diagnosis and treatment are delayed.
respiratory failure (uncommon)
• May occur in severe, prolonged attacks due to advanced motor neuropathy and respiratory muscle
weakness. Early detection of respiratory impairment and monitoring in intensive care is often
recommended.
Diagnostic tests
1st test to order
Test Result
urinary porphobilinogen (PBG) reddish colour
• Presence of PBG can be confirmed in a single-void urine specimen
using a PBG test kit.[13] This is the most useful single screening test
for acute porphyrias, with high sensitivity and specificity during or
soon after acute attacks.
• Results should be confirmed by later measurement of delta-
aminolevulinic acid (ALA) and PBG and total porphyrins in the same
sample.
quantitative measure of urinary porphobilinogen (PBG) increased (20-200 mg/L)
• Single-void specimen or 24-hour collection used.
urinary total porphyrins increased
• Quantitative assessment.
• Less specific than urinary porphobilinogen (PBG).
• May remain increased after delta-aminolevulinic acid (ALA) and PBG
become normal.
serum porphobilinogen (PBG) increased
• This is an initial test ordered in patients with advanced renal disease
and suspected AIP.
• Quantitative measurement of serum PBG.
• Less sensitive than urinary porphobilinogen in patients with normal
DIAGNOSIS
renal function.
Other tests to consider
Test Result
delta-aminolevulinic acid (ALA) increased
• Quantitative assessment.
• Less sensitive than urinary porphobilinogen (PBG).
plasma total porphyrins normal or slightly
increased in AIP
• Performed in patients with increased porphobilinogen to differentiate
AIP from variegate porphyria, in which plasma porphyrins are
substantially increased.
urinary porphyrins using high-performance liquid increased
chromatography (HPLC)
• Helps differentiate AIP (predominantly uroporphyrin) from hereditary
coproporphyria and variegate porphyria (both predominantly
coproporphyrin).
11
Test Result
faecal total porphyrins normal or slightly
increased in AIP
• Performed in patients with increased porphobilinogen to differentiate
AIP from hereditary coproporphyria and variegate porphyria, in which
faecal porphyrins are substantially increased.
faecal porphyrins using high-performance liquid normal or slightly
chromatography (HPLC) increased in AIP
• Helps differentiate AIP (normal or slightly elevated) from hereditary
coproporphyria (markedly elevated and predominantly coproporphyrin
III) and variegate porphyria (markedly elevated and predominantly
both coproporphyrin III and protoporphyrin).[14]
erythrocyte porphobilinogen deaminase (PBGD) activity reduced by approximately
50% in most patients
• Helps in confirming a diagnosis of AIP and in differentiating AIP from
other acute porphyrias.
• Also useful in identifying carriers of an AIP trait in families where the
index case has demonstrated AIP and decreased enzyme activity.[4]
[15]
porphobilinogen deaminase (PBGD) gene sequencing identifies a known
AIP mutation or a
• More useful in screening family members with latent AIP.
new mutation that
• Sequencing may not detect some cryptic mutations and complete or
requires further study to
large deletions.
demonstrate functional
significance
serum sodium levels below the reference range

• Hyponatraemia may be present due to syndrome of inappropriate
ADH secretion (SIADH) reflecting hypothalamic involvement.
MRI brain may be abnormal during
acute at tacks
• Reversible MRI changes that resemble the changes of the posterior
reversible encephalopathy syndrome may accompany periods of
psychiatric manifestions, such as anxiety, restlessness, agitation, or
DIAGNOSIS
hallucinations, which are common during acute attacks.
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Other conditions that • AIP symptoms are • FBC to eliminate
cause abdominal pain neurological rather than leukocytosis.
inflammatory, so peritoneal • Presence of urinary
signs, fever, and leukocytosis porphobilinogen (PBG)
are usually not as prominent confirms porphyria.
as in other abdominal
conditions.
Delta-aminolevulinate • Symptoms similar to AIP but • Delta-aminolevulinic acid

dehydratase deficiency extremely rare condition.[16] (ALA) and coproporphyrin
porphyria III are markedly increased in
urine, and PBG is normal or
slightly increased.
Condition Differentiating signs / Differentiating tests

symptoms
Hereditary • Presentation the same • Faecal total porphyrins are
coproporphyria as AIP, but occasionally substantially increased with
associated with blistering a marked, isolated increase
skin lesions. in faecal coproporphyrin III
by high-performance liquid
chromatography (HPLC).[14]
Variegate porphyria • May present as in AIP • Increased plasma

but often associated with porphyrin with a diagnostic
blistering skin lesions. fluorescence maximum at
neutral pH.
• Faecal porphyrins are
substantially increased
with a predominance of
coproporphyrin III and
protoporphyrin by HPLC.[17]
[18]
DIAGNOSIS
13
Acute intermit tent porphyria Treatment
Step-by-step treatment approach

The aim of treatment is to hasten recovery from acute attacks and prevent complications. Delayed treatment
may result in progression of neurological damage and even death.[3]
Acute at tacks
Acute attacks are treated with supportive care and observed closely. Patients usually require admission to
hospital and monitoring for respiratory depression and other complications.[3] Admission to an intensive
care unit is indicated, especially if respiration is impaired. Factors that may have precipitated the attack
are identified and removed whenever possible.
Giving intravenous haemin represses synthesis of hepatic delta-aminolevulinic acid (ALA) synthase
(ALAS1), and so decreases the overproduction of ALA and porphobilinogen (PBG). It should be the initial
treatment for most acute attacks.[12] Haemin is available in the US as lyophilised haematin. It should
be reconstituted with human albumin, rather than sterile water, to enhance stability[19] and to prevent
adverse effects of haemin degradation products (e.g., phlebitis at the site of infusion and a transient
anticoagulant effect). Haem arginate is a more stable preparation of haemin, and is available in Europe
and South Africa. Clinical improvement is often within 1 to 2 days if haemin is started early in an attack.[3]
Glucose loading may benefit some patients.[3] It is less effective than haemin, and recommended
only in patients with mild pain (not requiring opioid analgesics) and without hyponatraemia, paresis or
other complications. When tolerated, glucose may be given orally as sucrose, glucose polymers, or
carbohydrate-rich foods. However, most attacks are accompanied by nausea, vomiting, or abdominal
distension, so giving at least 300 g of dextrose (10% glucose) intravenously is recommended. Large
volumes of intravenous glucose increase the risk of hyponatraemia. In severe attacks, intravenous
haemin is started without an initial trial of carbohydrate. Glucose is not recommended as first-line
treatment, except for mild attacks. It is not contraindicated but is not as effective as haemin, and delay in
starting haemin treatment should be avoided.
Intravenous fluid replacement using 0.9% saline or 5% dextrose with normal saline may be required to
correct dehydration, hyponatraemia, and other electrolyte imbalances. Symptomatic treatment is provided
for pain, nausea, vomiting, tachycardia and hypertension, depression, or seizures. Drugs and doses
should be under consultant advice, especially to avoid drugs that are harmful in acute porphyrias.
Prevention of recurrent acute at tacks

Further intervention is needed for a few patients who continue to have frequent attacks after known
inciting factors are removed. Haemin infusions once or twice weekly can prevent frequently recurring non-
cyclic attacks.[11] [3] Serum ferritin levels should be monitored in these patients, because there is some
risk of iron overload.
Frequent, cyclic attacks in women can be prevented by long-term administration of a gonadotrophin-

releasing hormone (GnRH) analogue, which should be started during days 1 to 3 of the menstrual
cycle.[8] If a GnRH analogue is effective, bone loss during long-term treatment can be prevented by
TREATMENT
oestrogen add-back using a low-dose skin patch.
Ongoing symptoms unresponsive to medical therapy
Liver transplant is an option for severe cases that do not respond to established therapies. Marked clinical
and biochemical improvement has been reported in several severe cases after liver transplantation.[20]
[21] An increased incidence of hepatic artery thrombosis has been reported in acute porphyria patients
undergoing liver transplantation.[22]
Treatment details overview

Consult your local pharmaceutical database for comprehensive drug information including contraindications,
drug interactions, and alternative dosing. ( see Disclaimer )
Acute ( summary )
Patient group Tx line Treatment
mild acute at tack 1st haemin
plus supportive care
adjunct glucose
severe acute at tack 1st haemin
Ongoing ( summary )
recurrent non-cyclic at tacks 1st preventative haemin
women with frequent recurrent 1st preventative GnRH analogue

cyclic at tacks
non-responsive to medical therapy 1st liver transplant

TREATMENT
15
Treatment options
Acute
mild acute at tack 1st haemin

» Intravenous haemin should be the initial
treatment for most acute attacks.[12] Haemin
is available in the US as lyophilised haematin
and should be reconstituted with human albumin
rather than sterile water to enhance stability.[19]
Haem arginate is more stable, and is available in
Europe and South Africa.
» Clinical improvement is rapid, often within 1

to 2 days, when haemin is started early in an
attack.[3]
» Symptomatic treatment for accompanying

pain, nausea, vomiting, tachycardia and
hypertension, depression, or seizures should be
given under consultant advice.
Primary options
» haem arginate: 3 mg/kg intravenously once

daily for 4 days
» Patients with acute attacks usually require
admission to hospital for treatment and
monitoring.[3]
» Intravenous fluid replacement may be required

using 0.9% saline or 5.0% dextrose with normal
saline.
» Factors that may have precipitated the attack

adjunct glucose
» May benefit some patients.[3]
» Glucose loading is recommended only for mild

attacks (i.e., not requiring opioid analgesics,
and without paresis, hyponatraemia, or other
complications).[3]
TREATMENT
» Giving at least 300 g of dextrose (10%

glucose) intravenously is recommended.
» However, large volumes of intravenous glucose

increase the risk of hyponatraemia.
Acute
severe acute at tack 1st haemin

» Intravenous haemin should be the initial
treatment for most acute attacks.[12] Haemin
is available in the US as lyophilised haematin
and should be reconstituted with human albumin
rather than sterile water to enhance stability.[19]
Haem arginate is more stable, and is available in
Europe and South Africa.
» Clinical improvement is rapid, often within 1

to 2 days, when haemin is started early in an
attack.[3]
» Symptomatic treatment for accompanying

pain, nausea, vomiting, tachycardia and
hypertension, depression, or seizures should be
given under consultant advice.
Primary options

daily for 4 days
» Patients with acute attacks usually require
admission to hospital for treatment and
monitoring for respiratory depression and other
complications.[3]
» Admission to an intensive care unit is indicated

if respiration is impaired.
» Intravenous fluid replacement may be required

using 0.9% saline or 5.0% dextrose with normal
saline.
» Factors that may have precipitated the attack

Ongoing
recurrent non-cyclic at tacks 1st preventative haemin

TREATMENT
» Further intervention is needed for a few

patients who continue to have frequent attacks
after known inciting factors are removed.
17
Ongoing
» Haemin infusions once or twice weekly
can prevent frequently recurring non-cyclic
attacks.[11] [3] Haemin is available in the US as
lyophilised haematin and should be reconstituted
with human albumin rather than sterile water to
enhance stability.[19] Haem arginate is more
stable, and is available in Europe and South
Africa.
» Serum ferritin levels should be monitored in

these patients, because there is some risk of
iron overload.
Primary options

or twice weekly
women with frequent recurrent 1st preventative GnRH analogue

cyclic at tacks
» Attacks can be prevented by long-term
administration of a gonadotrophin-releasing
hormone (GnRH) analogue, which should be
started during days 1 to 3 of the menstrual
cycle.[8]
» If a GnRH analogue is effective, bone loss

during long-term treatment can be prevented by
oestrogen add-back using a low-dose skin patch.
» There is little evidence of the use of

leuprorelin, gonadorelin, nafarelin, and goserelin
in AIP. Treatment should be under the guidance
of a specialist.
Primary options
» leuprorelin: refer to consultant for guidance

on dose
OR
Primary options
» gonadorelin: refer to consultant for

guidance on dose
OR
Primary options
TREATMENT
» nafarelin: refer to consultant for guidance

on dose
OR
Ongoing
Primary options
» goserelin: refer to consultant for guidance

on dose
non-responsive to medical therapy 1st liver transplant

» Liver transplant is an option for severe cases
that do not respond to established therapies.
» Marked clinical and biochemical improvement

has been reported in several severe cases after
liver transplantation.[20] [21]
» An increased incidence of hepatic artery

thrombosis has been reported in acute porphyria
patients undergoing liver transplantation.[22]
TREATMENT
19
Emerging
Enzyme replacement
Intravenous infusion of recombinant human porphobilinogen deaminase (PBGD) has been reported to lower
porphobilinogen (PBG) but lacked clinical efficacy.[23] Enzyme replacement in hepatocytes has not yet been
achieved.
Gene therapy
Gene therapy approaches are being studied in animals.
Cimetidine
This has been proposed as an alternative to haemin or glucose, but the mechanism of action is not clear, and
efficacy is based on uncontrolled observations in small case series.[24] [25] Therefore, it should not be used
instead of haemin or glucose.
TREATMENT
Acute intermit tent porphyria Follow up
Recommendations
Monitoring
FOLLOW UP
Patients with AIP should be evaluated at least yearly.
• Urinary porphobilinogen (PBG) should be followed and may have prognostic value.
• Hypertension should be controlled, and renal and hepatic function followed.
• Chronic, mild increases in ALT are common, but the risk of cirrhosis is not known to be increased.
• Liver imaging is recommended at least yearly after age 50 years in patients who have a history
of symptoms, especially if urinary PBG remains elevated, for early detection of hepatocellular
carcinoma.
Patient instructions
Patients are instructed to inform their physician if they have latent or clinically expressed AIP. They should
maintain copies of medical records and laboratory reports that document the diagnosis, and provide them
to physicians when needed. They should be familiar with harmful and safe drugs, and have access to
recommended websites with pertinent information. [British Porphyria Association] [American Porphyria
Foundation] [European Porphyria Network] A medical alert bracelet may be worn, but any warnings
should not preclude use of drugs that may be life-saving under emergency conditions. Follow-up with a
physician and screening for renal impairment and early hepatocellular carcinoma are recommended.
Complications
Complications Timeframe Likelihood

hypertension long term low
Hypertension is common during acute attacks, but the risk of long-term hypertension also may be
increased. This should be treated to avoid complications, including renal damage.[27]
chronic renal failure long term low
A few patients with AIP develop chronic renal failure. The mechanism is unclear, but chronic hypertension
may contribute. Plasma porphyrins may increase in AIP patients with renal insufficiency and cause
blistering photosensitivity that resembles porphyria cutanea tarda.[28] Some patients with AIP and
renal disease have successfully undergone renal transplantation,[29] or combined liver and renal
transplantation.[30]
hepatocellular carcinoma long term low
The risk of this liver cancer is clearly increased in AIP and other porphyrias, and is usually not associated
with an increased in serum alpha-fetoprotein. Screening by imaging is recommended at least yearly after
50 years of age in patients who have a history of symptoms, especially if urinary porphobilinogen (PBG)
remains elevated.[31]
21
Acute intermit tent porphyria Follow up
Prognosis
FOLLOW UP
Patients with latent AIP

Approximately 80% of heterozygotes remain asymptomatic and never become unwell.[3] For these carriers,
precautions to avoid harmful factors are advised. Knowledge that they are carriers enables prompt diagnosis
and treatment, if porphyric symptoms develop.
Patients with clinically expressed AIP

The mortality from acute attacks is low, and most patients will recover completely, especially if the diagnosis
and treatment are prompt. Advanced motor neuropathy may recover completely over months or several
years, but there may be residual weakness or neuropathic pain.
Most patients who develop symptoms have only a single attack or a few attacks during their lifetime.
However, a few patients have many attacks, even if they avoid harmful factors. Dietary consultation is
recommended to detect unapparent dietary indiscretions. Those who respond to preventive interventions,
such as a gonadotrophin-releasing hormone (GnRH) analogue for frequent cyclic attacks confined to the
luteal phase of the cycle,[8] or prophylactic haemin given weekly or biweekly for non-cyclic attacks,[11] may
also have a good prognosis. Some patients with frequent attacks develop chronic, unremitting symptoms.
Chronic pain
Neuropathic pain becomes chronic in a few patients, especially after many acute exacerbations. These
patients may require long-term pain management, including narcotic analgesics. They are prone to
depression and suicide, and should be actively managed to prevent such outcomes.[26]
Acute intermit tent porphyria Guidelines
Diagnostic guidelines
North America
Emergency room guidelines for acute porphyrias

Published by: American Porphyria Foundation Last published: 2010
Summary: The most common emergency department clinical presentation is acute abdominal pain.
Other features may include seizures, confusion and hallucinations, and a progressive polyaxonal motor
neuropathy, which can progress to paralysis and respiratory failure requiring a ventilator. A high index
of suspicion in the presence of non-specific symptoms is important for diagnosis. A family history of
porphyria, female gender, onset during the luteal phase of the menstrual cycle, or recent use of a
porphyrinogenic drug may be diagnostic clues. A new diagnosis of porphyria as the cause of acute
symptoms must be substantiated by finding a substantial increase in urine porphobilinogen (PBG).
Recommendations for the diagnosis and treatment of the acute porphyrias

GUIDELINES
Summary: Acute porphyrias are rare and therefore evidence is based on case series and clinical
experience rather than controlled studies. This review is based on the recommendations of a panel of
experts on diagnosis and treatment.
Treatment guidelines
North America
Emergency room guidelines for acute porphyrias

Summary: Treatment should start promptly after the diagnosis is made. Mild attacks are sometimes
treated with glucose loading (e.g., 3 litres of 10% glucose daily by vein). Most acute attacks should be
treated with haemin (Panhematin®) 3-4 mg/kg into a large peripheral vein or venous access port daily for
4 days. Reconstituting Panhematin® with human serum albumin rather than sterile water is recommended
before infusion. This helps prevent phlebitis at the site of intravenous infusion. Admission to the hospital
is usually required for symptomatic treatment of pain, nausea, and vomiting, correction of electrolyte
imbalance, and observation for respiratory impairment, either to a general medical service or to the ICU.
Recommendations for the diagnosis and treatment of the acute porphyrias

Summary: Acute porphyrias are rare and therefore evidence is based on case series and clinical
experience rather than controlled studies. This review is based on the recommendations of a panel of
experts on diagnosis and treatment.
23
Acute intermit tent porphyria Online resources
Online resources
1. British Porphyria Association (external link)
2. American Porphyria Foundation (external link)
3. European Porphyria Network (external link)

ONLINE RESOURCES
Acute intermit tent porphyria References
Key articles
• Phillips JD, Anderson KE. The porphyrias (chapter 57). In: Kaushansky K, Lichtman MA, Beutler E, et
REFERENCES
al, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill; 2010:839-863.
• Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of
the acute porphyrias. Ann Intern Med. 2005;142:439-450. Abstract
• Deacon AC, Peters TJ. Identification of acute porphyria: evaluation of a commercial screening test for
urinary porphobilinogen. Ann Clin Biochem. 1998;35:726-732. Abstract
• Anderson KE, Bonkovsky HL, Bloomer JR, et al. Reconstitution of hematin for intravenous infusion.
Ann Intern Med. 2006;144:537-538. Abstract
• Jeans JB, Savik K, Gross CR, et al. Mortality in patients with acute intermittent porphyria requiring
hospitalization: a United States case series. Am J Med Genet. 1996;11:269-273. Abstract
• Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria:
frequency of occurrence and related factors. J Hepatol. 2000;32:933-939. Abstract
References
1. Solis C, Martinez-Bermejo A, Naidich TP, et al. Acute intermittent porphyria: studies of the severe
homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch
Neurol. 2004;61:1764-1770. Full text Abstract
2. Phillips JD, Anderson KE. The porphyrias (chapter 57). In: Kaushansky K, Lichtman MA, Beutler E, et
al, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill; 2010:839-863.
3. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of
the acute porphyrias. Ann Intern Med. 2005;142:439-450. Abstract
4. Grandchamp B, Picat C, Mignotte V, et al. Tissue-specific splicing mutation in acute intermittent

porphyria. Proc Natl Acad Sci USA. 1989;86:661-664. Full text Abstract
5. Welland FH, Hellman ES, Gaddis EM, et al. Factors affecting the excretion of porphyrin precursors by
patients with acute intermittent porphyria. 1. The effect of diet. Metabolism. 1964;13:232-250. Abstract
6. Bonkowsky HL, Collins A, Doherty JM, et al. The glucose effect in rat liver: studies of δ-
aminolevulinate synthetase and tyrosine aminotransferase. Biochim Biophys Acta. 1973;320:561-576.
Abstract
7. Handschin C, Lin J, Rhee J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria
through PGC-1alpha. Cell. 2005;122:505-515. Full text Abstract
25
8. Anderson KE, Spitz IM, Bardin CW, et al. A GnRH analogue prevents cyclical attacks of porphyria.
Arch Int Med. 1990;150:1469-1474. Abstract
REFERENCES
9. Lip GYH, McColl KEL, Goldberg A, et al. Smoking and recurrent attacks of acute intermittent
porphyria. Br Med J. 1991;302:507. Full text Abstract
10. Mustajoki P, Heinonen J. General anesthesia in "inducible" porphyrias. Anesthesiology. 1980;53:15-20.

Abstract
11. Anderson KE, Egger NG, Goeger DE. Heme arginate for prevention of acute porphyric attacks
(abstract). Acta Haematologica. 1997;98(suppl 1):120.
12. Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects
from porphyrias consortium. Am J Med. 2014;127:1233-1241. Abstract
13. Deacon AC, Peters TJ. Identification of acute porphyria: evaluation of a commercial screening test for
urinary porphobilinogen. Ann Clin Biochem. 1998;35:726-732. Abstract
14. Blake D, McManus J, Cronin V, et al. Fecal coproporphyrin isomers in hereditary coproporphyria. Clin
Chem. 1992;38:96-100. Full text Abstract
15. Anderson KE, Sassa S, Peterson CM, et al. Increased erythrocyte uroporphyrinogen-I-synthetase,
γ-aminolevulinic acid dehydratase and protoporphyrin in hemolytic anemias. Am J Med.
1977;63:359-364. Abstract
16. Akagi R, Kato N, Inoue R, et al. Gamma-aminolevulinate dehydratase (ALAD) porphyria: the first case
in North America with two novel ALAD mutations. Mol Genet Metab. 2006;87:329-336. Abstract
17. Poh-Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol.
1980;116:543-547. Abstract
18. Hift RJ, Davidson BP, Van der Hooft C, et al. Plasma fluorescence scanning and fecal porphyrin
analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity
with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem.
2004;50:915-923. Abstract
19. Anderson KE, Bonkovsky HL, Bloomer JR, et al. Reconstitution of hematin for intravenous infusion.
Ann Intern Med. 2006;144:537-538. Abstract
20. Soonawalla ZF, Orug T, Badminton MN, et al. Liver transplantation as a cure for acute intermittent
porphyria. Lancet. 2004;363:705-706. Abstract
21. Seth AK, Badminton MN, Mirza D, et al. Liver transplantation for porphyria: who, when, and how? Liver
Transpl. 2007;13:1219-1227. Full text Abstract
22. Dowman JK, Gunson BK, Mirza DF, et al. LT-11-056 liver transplantation for acute intermittent
porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl. 2012;18:195-200.
Full text Abstract
23. Sardh E, Rejkjaer L, Harper P, et al. First clinical trial of i.v. rhPBGD in healthy subjects with and
without diagnosed manifest acute intermittent porphyria (AIP). Physiol Res. 2003;52(suppl):23S.
REFERENCES
24. Horie Y, Tanaka K, Okano J, et al. Cimetidine in the treatment of porphyria cutanea tarda. Intern Med.
1996;35:717-719. Full text Abstract
25. Cherem JH, Malagon J, Nellen H. Cimetidine and acute intermittent porphyria. Ann Intern Med.
2005;143:694-695. Abstract
26. Jeans JB, Savik K, Gross CR, et al. Mortality in patients with acute intermittent porphyria requiring
hospitalization: a United States case series. Am J Med Genet. 1996;11:269-273. Abstract
27. Church SE, McColl KE, Moore MR, et al. Hypertension and renal impairment as complications of acute
porphyria. Nephrol Dial Transplant. 1992;7:986-990. Abstract
28. Sardh E, Andersson DE, Henrichson A, et al. Porphyrin precursors and porphyrins in three patients
with acute intermittent porphyria and end-stage renal disease under different therapy regimes. Cell Mol
Biol (Noisy-le-grand). 2009;55:66-71. Abstract
29. Nunez DJ, Williams PF, Herrick AL, et al. Renal transplantation for chronic renal failure in acute
porphyria. Nephrol Dial Transplant. 1987;2:271-274. Abstract
30. Wahlin S, Harper P, Sardh E, et al. Combined liver and kidney transplantation in acute intermittent
porphyria. Transpl Int. 2010;23:e18-e21. Full text Abstract
31. Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria:
frequency of occurrence and related factors. J Hepatol. 2000;32:933-939. Abstract
27
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DISCLAIMER
Contributors:
// Authors:
Gagan Sood, MD
Associate Professor
Department of Medicine and Surgery, Baylor College of Medicine, Houston, TX
DISCLOSURES: GS is an author of a number of references cited in this monograph.
Karl E. Anderson, MD
Professor
Departments of Preventive Medicine and Community Health and Internal Medicine, University of Texas
Medical Branch, Galveston, TX
DISCLOSURES: KEA has received grants from the National Institutes of Health, the US Food and Drug
Administration, and Alnylam Pharmaceuticals; he is an author of a number of references cited in this
monograph.
// Peer Reviewers:
Alexios Carayannopoulos, MD
Medical Director
Spine Center, Interventional Spine Physiatrist, Pain Medicine Specialist, Burlington, MA
DISCLOSURES: AC declares that he has no competing interests.
Kenneth E.L. McColl, MD, FRCP

Professor of Medical Sciences
Gardiner Institute, Western Infirmary, Glasgow, UK
DISCLOSURES: KELM declares that he has no competing interests.
Neville Pimstone, MD
Professor Emeritus of Medicine
Division of Gastroenterology, UC Davis Medical Group GI Unit, Sacramento, CA
DISCLOSURES: NP declares that he has no competing interests.

Acute Intermittent Porphyria: The Right Clinical Information, Right Where It's Needed

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Acute intermit tent

The right clinical information, right where it's needed

Last updated: Jan 12, 2017

◊ A rare autosomal dominant inherited disorder characterised by a partial deficiency of

◊ The pain is neuropathic and is not accompanied by inflammation.

Symptoms are due to:

• Effects on the nervous system

• Abdominal pain is usually steady and diffuse but may be cramping.

is elevated, the type of acute porphyria is established by further testing, including:

• Erythrocyte porphobilinogen deaminase (PBGD) activity

elevated progesterone levels

decreased caloric or carbohydrate intake

age >13 years

History & examination factors

abdominal pain (common)

dark or red urine (common)

Other diagnostic factors

abdominal distension (common)

urinary hesitancy and dysuria (common)

pain in extremities, back, and chest (common)

proximal muscle weakness (common)

painful hyperaesthesia (common)

mental symptoms (common)

respiratory failure (uncommon)

Other tests to consider

serum sodium levels below the reference range

hallucinations, which are common during acute attacks.

Condition Differentiating signs / Differentiating tests

Delta-aminolevulinate • Symptoms similar to AIP but • Delta-aminolevulinic acid

Condition Differentiating signs / Differentiating tests

Variegate porphyria • May present as in AIP • Increased plasma

Step-by-step treatment approach

Prevention of recurrent acute at tacks

Frequent, cyclic attacks in women can be prevented by long-term administration of a gonadotrophin-

oestrogen add-back using a low-dose skin patch.

Treatment details overview

mild acute at tack 1st haemin

plus supportive care

severe acute at tack 1st haemin

plus supportive care

recurrent non-cyclic at tacks 1st preventative haemin

women with frequent recurrent 1st preventative GnRH analogue

non-responsive to medical therapy 1st liver transplant

mild acute at tack 1st haemin

» Clinical improvement is rapid, often within 1

» Symptomatic treatment for accompanying

» haem arginate: 3 mg/kg intravenously once

» Intravenous fluid replacement may be required

» Factors that may have precipitated the attack

» Glucose loading is recommended only for mild

» Giving at least 300 g of dextrose (10%

» However, large volumes of intravenous glucose

severe acute at tack 1st haemin

» Clinical improvement is rapid, often within 1

» Symptomatic treatment for accompanying

» haem arginate: 3 mg/kg intravenously once

» Admission to an intensive care unit is indicated

» Intravenous fluid replacement may be required

» Factors that may have precipitated the attack

recurrent non-cyclic at tacks 1st preventative haemin

» Further intervention is needed for a few

» Serum ferritin levels should be monitored in

» haem arginate: 3 mg/kg intravenously once