The Porphyrias
Dr Mike Badminton
Senior Lecturer/Honorary Consultant
Cardiff SAS Porphyria Service (www.cardiff-porphyria.org)
Department of Medical Biochemistry
University Hospital of Wales and Cardiff University
OUTLINE
I Overview and Introduction
II Acute Hepatic Porphyrias
III Cutaneous Porphyria
I. Overview
The porphyrias comprise a group of disorders of the haem
biosynthetic pathway that can present with acute neurovisceral
symptoms, skin lesions or both.
Porphyrias result from partial deficiencies of one of the
enzymes of haem biosynthesis and most are inherited.
There are 8 different types
4 Acute Hepatic porphyrias
4 Cutaneous Porphyrias
They are identified by analysing porphyrins and their
precursors in urine, blood & faeces
Haem Biochemistry
Haem is synthesised in all tissues and cells
– 80% for haemoglobin
– 20% for enzymes, the majority for liver enzymes
(CytP450, catalase)
There are 8 enzymes in the pathway: including
mitochondrial and cytosolic locations.
The intermediates (porphyrinogens) are unstable and
rapidly oxidise to the equivalent porphyrins which are
fluorescent
Pathway intermediates are III isomers but I isomers can
form spontaneously from the linear tetrapyrrole by nonenzymatic cyclisation.
The rate limiting step is ALA synthase and is regulated by
haem in non-erythroid tissue and iron in erythroid cells.
Glycine
+
Succinyl CoA
PORPHYRIA
GENE
X-linked dominant
Protoporphyria (XLDPP)
ALA Synthase
(Liver & Erythroid Specific Forms)
ALA
ALA dehydratase
Porphyria (ADP)
ALA Dehydratase
Acute Intermittent
Porphyria (AIP)
Hydroxymethylbilane
synthase
Acute attacks
(ALAD, AIP, HCP, VP)
PBG
HMB
Congenital Erythropoietic
Porphyria (CEP)
Uroporphyrinogen
Synthase
Uroporphyrinogen III
Porphyria Cutanea Tarda
(PCT)
Uroporphyrinogen
Decarboxylase
Hereditary
Coproporphyria (HCP)
Coproporphyrinogen
Oxidase
Variegate Porphyria (VP)
Protoporphyrinogen
Oxidase
Erythropoietic
Protoporphyria (EPP)
Ferrochelatase
Bullous Skin lesions
(CEP, PCT,HEP, HCP,
VP)
Coproporphyrinogen III
Protoporphyrinogen IX
Protoporphyrin IX
Fe2+
Haem
Red denotes those porphyrias that may present with skin lesions,
essentially those after the formation of the linear tetrapyrrole hydroxymethylbilane (HMB)
Acute
photosensitivity
(EPP)
Clinical Overview
• Clinical presentation
– Acute attacks only (ADP, AIP)
– Acute attacks and/or skin lesions (HCP, VP)
– Skin lesions only (CEP, PCT, EPP)
• Skin lesions
– Acute photosensitivity (EPP, XLPP)
– Blisters and skin fragility (CEP, PCT, HCP, VP)
Laboratory Investigation of Porphyria
District General Lab (Spectrophotometric Methods)
1)Measurement of urine porphobilinogen in acute attacks ; screening or
quantitative tests are used but there are few false positives.
2)Total urine porphyrin - refer if increased. Correct for concentration by
using a creatinine ratio and beware false positives.
3)Faecal porphyrin is not a screening test. Its main use is to distinguish
between different types of porphyria.
An EQA scheme is provided from WEQAS
Specialist Laboratory (+ Fluorimetric Methods)
Quantitative urine ALA, PBG
Quantitation and separation by HPLC of urine, faecal porphyrins
Plasma and red cell porphyrins (fluorimetric methods)
Enzyme analysis rarely used now. DNA analysis preferred for family
studies
Fluorimetry requires a specific red sensitive photomultiplier detector
Don’t forget to protect samples from light!
II. The Acute Hepatic Porphyrias
The autosomal dominant acute porphyrias are low penetrant,
disorders that are characterised by acute neurovisceral attacks which
may be life threatening. Acute attacks affect <10% of gene carriers.
ALA dehydratase Porphyria (ADP) is a very rare autosomal
recessive disorder that presents with acute attacks. No case has been
reported in the United Kingdom.
The others are:Acute intermittent
Porphyria (AIP)
Commonest
~ 1:5-10,000
Acute neurovisceral attack
Hereditary
Coproporphyria (HCP)
Rarest
<1:30,000
i. Acute attack only (72%)
ii. Skin lesions only (7%)
iii. Both 21%
Variegate porphyria
(VP)
~1:30,000
i. Acute attack only (20%)
ii. Skin lesions only (59%)
iii. Both (21%)
Acute Attacks
Frequency
Patients presenting with acute attacks account for approximately 1:100,000 of the
population. However the low penetrance means gene carriers are much more
common than this would reflect: e.g. the frequency of AIP is actually estimated at 1:510,000.
More common in females than males (5:1): Acute attacks are very rare before
puberty and less common after menopause. The peak incidence is in the 3rd & 4th
decade.
Symptoms/signs
Severe abdominal pain mimicking acute abdomen but without localising features is
almost universal.
Vomiting, constipation
Psychiatric symptoms include anxiety, confusion, hallucinations occur during an
attack but this does not result in chronic psychiatric illness
Hypertension, tachycardia, due to autonomic dysfunction
Convulsions: may be primary or secondary to a rapid onset of profound
hyponatraemia.
Motor neuropathy may progress from a mild initial presentation to progressive,
severe with complete paralysis
Precipitants
Hormonal fluctuations (e.g. menstrual cycle) - particularly the pre
menstrual phase correlating with progesterone levels
Prescription Drugs (e.g. carbamazepine, barbitutates)
Alcohol (particularly binge drinking), smoking, illicit drugs
Infection, dieting, weight loss and stress
Pathophysiology of acute attacks
The release of ALA from liver results in neuronal toxicity.
Neuronal damage to the autonomic, motor and central nervous
system results in axonal degeneration and patchy demyelination
Diagnosis
First Line
Urine porphobilinogen (random urine)
protected from light, preferably first or 2nd
morning sample
Second Line -Establish Type
Total Urine and faecal porphyrin and individual
porphyrins measured by HPLC as well as a plasma
porphyrin scan allows an unequivocal biochemical
diagnosis in symptomatic patients.
Urine
Faeces
Plasma Fluorescence
Emission Peak (nm)
AIP
ALA, PBG
Uroporphyrin
Normal
615-620
HCP
ALA, PBG, Copro (III)
Copro III
615-620
VP
ALA, PBG, Copro (III)
Proto > Copro III
624-627
Management of acute porphyria attack
General
Remove/treat precipitating factors such as drugs, infection
Symptomatic relief with analgesics (opiates), IV fluids (N-saline)
plus dextrose
Specific
IV haem arginate binds albumin, is taken up by liver and
suppresses the metabolic pathway by down regulating ALA
synthase
Management: Prevention
Identify relatives at risk through family studies.
This requires mutation screening of the proband first and then
mutation testing in relatives.
Affected relatives are then advised to avoid known precipitants
III. THE CUTANEOUS PORPHYRIAS
These include Porphyria Cutanea Tarda, Erythropoeitic Porphyria and
the two forms of Erythropoeitic Protoporphyria
Bullous skin lesions occur in: PCT (HEP), CEP
and also the acute porphyrias, HCP and VP
Acute photosensitivity occurs in EPP and XLDP
Pathophysiology
Circulating porphyrins absorb light ( l 400-410nm) within the dermis of
exposed skin and enter an energy enhanced or ‘Excited state’ . The release
of this energy results in the formation of reactive oxygen species which
damages proteins, lipids and DNA
Lipid membrane peroxidation results in release of inflammatory
mediators from mast cells, neutrophils
Bullous Porphyrias: Clinical Manifestations
Chronic damage to the dermal epidermal border by porphyrins absorbing
light (energy) leading to reactive oxygen species
This results in fragile skin, blisters (bullae) which rupture, crust and heal
poorly leaving permanent scarring
Hypertrichosis (excess hair) in areas exposed to the sun and non-androgen
dependent skin.
Other skin features include: Milia (epidermoid cysts),
hyper/hypopigmentation, scarring alopecia and sclerodermoid plaques
which can affect large areas of the skin
Porphyria Cutanea Tarda (PCT)
This is the commonest porphyria (2-5cases per106 per year) or an
incidence of about 1:25,000 of the population
Most patients (80%) have the acquired (Type I) form in which no
mutations are present at the UROD locus
20% have the familial (Type II), autosomal dominant form, with partial
(50%) deficiency of UROD activity in all cells. Clinical penetrance is low
as additional factors (see below) are required for clinical expression.
The clinical presentation results from inhibition of hepatic
uroporphyrinogen decarboxylase to less than 30% activity
Inhibition of the hepatic enzyme involves an iron dependent
mechanism with most patients having evidence of hepatic siderosis on
liver biopsy
Factors which are strongly associated with this hepatic mechanism
include : Alcohol , Prescribed oestrogens, Hepatitis C, HIV, Genetic
haemochromatosis
PCT: Management
Avoid sunlight, skin protection using Dundee Sun Screen (UV
sunscreens are not effective as porphyrins are activated by visible
light (410nm))
Stop oestrogen therapy, stop alcohol (if possible) and test for
haemochromatosis and hepatitis
Two specific treatments are available to achieve remission.
1) Venesection (450 ml 2-weekly) -the first choice if iron is
overloaded
Treat until there is a borderline iron deficient (e.g. serum ferritin at
the lower limit of normal, Transferrin saturation <16%)
2)Low dose chloroquine (hydroxychloroquine) –a good option for
others 125 (100) mg twice weekly
Treat until the biochemistry normalises
Congenital Erythropoeitic Porphyria
Very rare autosomal recessive porphyria due to a marked deficiency of
uroporphyrinogen III synthase (about 20 cases in UK).
Most cases present soon after birth. However, as with other autosomal recessive
metabolic diseases, phenotype varies with the residual enzyme activity. It can
present as a milder form in adulthood.
Clinical Manifestations include haemolytic anaemia and extreme photosensitivity
and scarring which can lead to photomutilation with loss of digits, ears and nose.
Severity correlates with level of haemolysis
Hypertrichosis (excess hair) and erythrodontia (porphyrin staining of teeth)
common
Treatment
General treatments include sunlight avoidance and active treatment of superficial
infections of skin
Blood transfusions to limit erythroid driven haem synthesis together with iron
chelation therapy.
Bone Marrow Transplantation is curative but is focussed on the most severely
affected patients. Gene therapy has been under investigation and clinical trials are
due to start soon.
Erythropoeitic Protoporphyria
Accumulation of free protoporphyrin in skin, liver and bone marrow results
in acute photosensitivity due to the free protoporphyrin. Pain usually
occurs 20-40 minutes following exposure to sunlight.
It is only relieved by cold water and complete resolution can take several
days following an episode
It also results in itching, redness, swelling
It usually presents in childhood:
Mean age of onset: 1 year
Mean age of diagnosis: 12 years!! This is partly due to inexperience among
clinicians, the often limited clinical signs on presentation (diagnose on
history!) and an inappropriate sample being sent for porphyrin analysis
AN EDTA BLOOD SAMPLE IS ESSENTIAL!
Molecular genetics of protoporphyria
Two distinct causes:
I. Erythropoietic protoporphyria (EPP) due to deficiency of
ferrochelatase
Autosomal recessive, with mutation of both alleles
In 95% of EPP cases one of these mutations is a low expression variant
present in 10% UK population
II. X-linked dominant protoporphyria (XLDPP) due to gain of function
mutations in ALA Synthetase 2 (ALAS2) (the erythroid specific enzyme)
Deletions in the C-terminus appear to interfere with regulation of
enzyme activity
Treatment
Avoid sunlight (Clothing, hats reflectant sunblock cream
NOT UV sunblock)
Beta-carotene is reported to reduce photosensitivity in
some patients probably by acting as energy and oxygen
radical quenching agent.
Narrow band UV therapy (by exposure to light at 311-313
nm which does not activate porphyrins) aims to thicken
skin and increase the melanin pigmentation
Complications
Liver dysfunction with cirrhosis due to protoporphyrin
damage which can progress to liver failure requiring
transplantation.
Self Assessment Questions
Which Clinical Features occur in the following enzyme defects.
Mark Yes or No.
Skin Lesions or Photosensitivity
Ferrochelatase Deficiency
ALA Dehydratase Deficiency
Uroporphyrinogen Synthase
Hydroxymethylbilane synthase
Protoporphyrinogen Oxidase
ALA Synthase (Erythroid Form)
Uroporphyrinogen Decarboxylase
Coproporphyrinogen Oxidase
Acute Neurovisceral Attacks
Self Assessment Questions
•
•
Which Clinical Features occur in the following enzyme defects.
Mark Yes or No.
Skin Lesions or Photosensitivity
Acute Neurovisceral Attacks
Ferrochelatase Deficiency
(Erythropoeitic Porphyria)
Yes
No
ALA Dehydratase Deficiency (ALA
Dehydratase Porphyria)
No
Yes
Uroporphyrinogen Synthase
(Congenital Erythropoeitic
Porphyria)
Yes
No
Hydroxymethylbilane synthase
(Acute Intermittent Porphyria)
No
Yes
Protoporphyrinogen Oxidase
(Variegate Porphyria)
Yes
Yes
ALA Synthase (X-linked
protoporphyria)
Yes
No
Uroporphyrinogen Decarboxylase
(Porphyria Cutanea Tarda))
Yes
No
Coproporphyrinogen Oxidase
(Hereditary Coproporphyria)
Yes
Yes
Specialised Porphyria Services and Support
Cardiff SAS Porphyria Services (www.cardiff-porphyria.org)
Biochemical and genetic testing
Clinical and diagnostic advice
Patient support groups
British Porphyria Association www.porphyria.org.uk/
Drug safety information (searchable database)
www.drugs-porphyria.org
European Porphyria Network
www.porphyria-europe.org