Porphyrias: implications for

anaesthesia, critical care

Speaker: Dr Bharani Kumar
Moderator: Dr Sherine Koudaira
 Definition
Porphyrias are a heterogeneous group of
rare, mostly inherited disorders that are
each caused by specific enzyme deficiencies
of haem biosynthesis.
The name porphyria is derived from the
greek word for purple, porphyros.
The disease was probably named porphyria
due to the red discolouration of urine in
affected patients.
 Porphyrin metabolism
Porphyrins are organic cyclical
compounds found in many aspects
of biological life; the most
important in humans is haem.
In biologically active form haem is
bound to various proteins to form
haemoproteins, which inlcude
haemoglobin, myoglobin and all of
the cytochromes (including the
P450 series) together with
numerous other compounds
involved in oxidation and
hydroxylation reactions.
The haem biosynthetic pathway is
most active in the liver and bone
marrow.
 Control of Haem Biosynthesis
The control of haem production is primarly affected
through ALA synthetase.
The formation of ALA synthetase is controlled by the
concentration of haem itself, which forms a negative
feedback loop, thus ensuring that the level of haem
production matches requirements closely.
ALA synthetase is rapidly inducible and can respond
rapidly to increased haem requirements such as those
resulting from the administration of drugs which
require cytochrome P450 for their metabolism.
Thus the availability and activity of ALA synthetase
depends on the intracellular levels of haem, and the
demand for haem by metabolic processes.
 Pathogenesis
The symptoms and signs of acute neurovisceral
crises are thought to result from neurological
dysfunction in motor, sensory, and autonomic
fibres and the central nervous system.
The precise cause remains a matter of debate.
There are two main theories:
The most widely held states that ALA and PBG is
neurotoxic
Other proposes that acute haem deficiency
within nerve cell is responsible
 Classification of the Porphyrias
Multiple classification
systems exist
main site of defect-
hepatic or
erythopoietic
by the enzyme defect
Whether or not they
cause acute symptoms
 Inheritance and Epidemiology
AIP, VP and HCP are all inherited in an autosomal
dominant manner with low clinical penetrance.
ALA dehydratase deficiency is inherited as an
autosomal recessive condition.
The overall prevalence in European counties is 1-
2 in 100,000 with AIP being the most common.
VP is more widespread in the Afrikaner
community in South Africa ( 1 per 250-500)
Attacks are more frequently in women and are
more frequent in third or fourth decades.
 Implications of the Acute Porphyrias
Anesthetists may be involved in the care of patients with diagnoses of porphyria in
a number of settings:
during acute crisis;
during incidental surgery;
for acute or chronic pain management.

Drugs may trigger an acute attack of porphyria in many ways:

Induce the transcription of ALA synthetase directly through mRNA
Interfere with the negative feedback control which haem exerts
Increase demand for haem by increasing utilization
It is of interest that it is only the acute forms of the disease that are affected by
enzyme induction, so this is the only form of disease of Pharmacogenetic
importance.
Presentation of an Acute crisis
Crisis are 4-5 times more
common in women and usually
occur in their early 30s.
A family history may not be
present, due to previously
undiagnosed disease in
asymptomatic carriers.
Acute crises may vary from a
single attack that aborts quickly
to those that go on to have
frequent life threatening
attacks with multisystem
involvement, respiratory and
bulbar paresis.
Diagnosis by urine PBG and
ALA levels
 Management of an acute crisis
Remove precipitating factors: review medication, look for and treat
infection
Consider other causes of symptoms
Human haemin:
Intravenous haem arginate (Normosang / Panhematin)
Somatostatin : decreases the rate of formation of ALA synthetase and
together with plasmapheresis has been used succesfully to reduce pain
and produce complete remission of symptoms.
Analgesia: morphine, diamorphine and fentanyl are safe
Other medications
Nausea and vomiting can be treated with prochlorperazine, promazine
or ondansetron
Severe agitation and anxiety can be treated with chlorpromazine
Hypertension and tachycardia may be cautiously treated with atenolol,
propranolol or labetolol
Convulsions can be terminated with IV diazepam, clonazepam or
magnesium sulphate.
 Management of an acute crisis
Carbohydrate administration: glucose has a repressive effect on ALA
synthase. IV glucose in water solutions, such as dextrose 5% or 10%
should be avoided as they may aggravate hyponatremia.
Fluid balance: IV fluid replacement with 0.9% sodium chloride may
be required to correct dehydration or electrolyte imbalance
Chronic hyponatremia should be corrected slowly
Evidence of respiratory insufficiency may require respiratory
support
Progressive neuropathy: treated with haem arginate as soon as
possible
Neuropathic pain: gabapentin and opiate patches
Safe medication
Nutritional support
 Management of recurrent acute
attacks
General measures and avoidance of
precipitating factors
GnRH analogues
Prophylactic haem arginate
Liver transplantation
 Implications for anaesthesia
General principles:
1. Identification of susceptible individuals: Full medical history
including detailed family history, and a thorough physical
examination, along with a careful neurological assessment paying
particular attention to presence of peripheral neuropathy and
autonomic instability.

Acute crisis: muscle strength and cranial nerve function, CV

examination for hypertension and tachycardia and should be
treated. Postoperative ventilatory support may be required.

2. Identification of drugs:
Far from clear cut
Labelling of drugs as safe or unsafe is from anectodal experience ,
cell cultures and animal model experience
2015 Porphyria safe list WMIC
 Premedication
Anxiolysis : benzodiazepines , phenothiazines
Antacid administration : sodium citrate ,
ranitidine [ cimetidine has been recommended in
the treatment of acute porphyric crises, since it
may decrease haem consumption and inhibit ALA
synthetase activity]
Preoperative starvation should be minimised:
dextrose saline infusion
IV fluids containing dextrose alone are avoided as
hyponatremia is frequently encountered in acute
attacks
 Regional anaesthesia
No absolute contraindication
Thorough neurological and cardiovascular
examination to diagnose pre-existing neurological
deficits and the presence of autonomic
neuropathy.

http://www.porphyriafoundation.com/drug_database/print.php
 General Anesthesia
The total dose
of drug
administered
and the length
of time for
which the
patient is
exposed to
the drug may
influence the
probability of
triggering a
crises.

http://www.porphyriafoundation.com/drug_database/print.php
 Analgesics
Acute crisis
Chronic neuropathic
pain: gabapentin,
pregabalin and
amitryptilline

2015 Porphyria safe list WMIC

 Conclusion
Although relatively uncommon, anesthetists may be
involved with the care of patients with porphyria during
elective or emergency surgery, supportive treatment in
critical care during an acute crisis or for pain management.
The variable and non specific symptoms and signs of the
condition require clinicians to actively consider the
diagnosis and to have a low threshold for checking urinary
PBG levels.
Anesthetists should be aware of the perioperative factors
that may trigger or worsen an acute crises.
Management with IV haem arginate together with
supportive measures can improve outcome
 Sources for further information
www.wmic.wales.nhs.uk
www.drugs-porphyria.org
www.porphyria-europe.com
www.porphyria.org.uk
www.porphyriafoundation.com