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International Dental Journal (2005) 55, 6166

Oral aspects of porphyria


M M D Kooijman and H S Brand
Amsterdam, The Netherlands
Porphyria is a diverse group of diseases in which the biosynthesis of heme is disrupted by
either genetic defects or environmental factors. This review gives an overview of the different
types of porphyria and describes possible causes, clinical signs, diagnosis and therapy. In
addition, the oral manifestations of porphyria and the potential implications of the disease
for dental management are discussed.

Key words: Porphyria, oral pathology, dental management

Porphyria is a diverse group of inherited or acquired


disorders of the heme biosynthesis. The name porphyria
is derived from the Greek word porphuros, which
means purple, after the purple-red urine produced by
some porphyria patients during an acute attack1,2.
Heme biosynthesis

A heme molecule is composed of porphyrin, a large


circular molecule with an iron ion at its centre. Heme is
synthesised in large amounts in the bone marrow where
it is incorporated into haemoglobin, an oxygen transport protein. The remainder is produced in the liver
and used for the synthesis of cytochrome P450
enzymes, important in the detoxification of potentially
harmful substances3.
The biosynthesis of heme involves eight steps,
each requiring a specific enzyme. The rate-limiting

enzyme in heme biosynthesis is ALA-synthase, regulated by a negative feedback mechanism (Figure 1).
A deficiency in one of the other seven enzymes results
in porphyria. Affected individuals are unable to
complete heme synthesis and intermediate products,
porphyrin and its precursors, accumulate. Lack of
heme results in an increased activity of ALA-synthase,
further stimulating the accumulation of porphyrin
precursors2.
Porphyrias are classified according to the specific
enzyme deficiency (Table 1). Another classification is
based on the major clinical features. Individuals with
acute porphyrias suffer from episodes with severe
abdominal pain, psychological symptoms and seizures1,2.
Cutaneous porphyrias are characterised by an increased
photosensitivity of the skin4. However, two types of
porphyria show characteristics of both acute and cutaneous porphyria (Table 1).

Figure 1. The heme biosynthetic pathway. ALA= d-aminolevulinic acid; PBG= porphobilinogen; HMB= hydroxymethylbilane; Uro-3 =
uroporphyrinogen III; Copro-3= coproporphyrinogen III; Proto-9= protoporphyrinogen IX ( Modified from 7).
2005 FDI/World Dental Press
0020-6539/05/02061-06

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Table 1

Some characteristics of the different types of porphyria

Porphyria

Deficient enzyme

Acute or cutaneous

Inheritance

ALADD (ALA Dehydratase-Deficient Porphyria)


AIP (Acute Intermittent Porphyria)
CEP (Congenital Erythropoietic Porphyria)
PCT (Porphyria Cutanea Tarda)
HCP (Hereditary Coproporphyria)
VP (Variegate porphyria)
EPP (Erythropoietic Protoporphyria)

ALA dehydratase
PBG deaminase
Uro synthetase
Uro decarboxylase
Copro oxidase
Proto oxidase
Ferrochelatase

Acute
Acute
Cutaneous
Cutaneous
Acute & cutaneous
Acute & cutaneous
Cutaneous

Unknown
Autosomal
Autosomal
Autosomal
Autosomal
Autosomal
Autosomal

Acute porphyrias

Acute Intermittent Porphyria (AIP)

This is an autosomal dominant disease, widespread but


especially common in Sweden and probably Great
Britain. In AIP the deficient enzyme is porphobilinogen (PBG) deaminase, also known as uroporphyrinogen
I synthase1,5.
In most cases, attacks of AIP are triggered by
environmental factors like medication, alcohol ingestion, tobacco, fasting, stress and hormonal changes
(menstrual cycle). Usually the first attack occurs after
puberty6. The most frequent symptom during an
acute episode is abdominal pain. Nausea, vomiting,
constipation, malaise, pain in limbs or chest are also
characteristic. Peripheral neuropathy, seizures and
mental symptoms such as depression, confusion and
hallucinations may also occur1,3,7. During an acute
episode of AIP the urine of most patients becomes
purple-red, especially after exposure to sunlight,
because of the excretion of large amounts of porphyrin precursors.
Several authors have suggested that the famous
Dutch painter Vincent van Gogh (18531890) suffered
from AIP. Malnutrition, alcohol abuse (consumption
of absinthe) and the use of turpentine for washing
brushes could have triggered acute attacks with mental
symptoms8,9.
Hereditary Coproporphyria (HCP)

This is an acute porphyria in which the enzyme copro


oxidase is deficient. HCP is an autosomal dominant
disease and considered to be rare. The same factors
that provoke an attack of AIP may also induce an
episode of HCP2. The symptoms of HCP resemble
those of AIP, but are usually less severe5. Besides,
increased photosensitivity of the skin may occur in
patients with HCP. Due to the atypical clinical presentation of HCP, many cases may remain unnoticed or
are attributed to other diseases. Therefore, HCP may
be more prevalent than previously thought10.
Variegate Porphyria (VP)

Also known as South African porphyria, since it is


particularly common in that country. Most patients are
International Dental Journal (2005) Vol. 55/No.2

dominant
recessive
dominant
dominant
dominant
dominant

descendants of a Dutch couple who emigrated to


South Africa in 1688. VP is an autosomal dominant
disease with a defect in the enzyme proto oxidase. The
same factors that precipite acute episodes of AIP and
HCP can also trigger attacks of VP, and the clinical
symptoms also resemble it. VP is called variegate
because of its diverse manifestations. Symptoms can
be acute, cutaneous or both. VP can also be clinically
latent5,10. Cutaneous symptoms appear at a younger
age in contrast with HCP, although many VP patients
with skin symptoms have not (yet) had an acute attack2.
ALA Dehydratase-Deficient Porphyria (ALADD)

Only a few patients with this form have been


described worldwide. The inheritance pattern of
ALADD is still unclear. The clinical presentation of
this acute porphyria, with abdominal pain and neuropathy, resembles that of AIP1.
Cutaneous porphyrias

Congenital Erythropoietic Porphyria (CEP)

Again, this is a rare autosomal recessive disease, also


known as Gunthers disease. In CEP the enzyme URO3-synthetase is deficient. Severe cutaneous photosensitivity begins in early infancy. At sun-exposed areas,
vesicles and bullae develop which are prone to rupture
and infection. Secondary infection can lead to disfiguring of the face and hands. Excessive hair growth, skin
thickening, hypo- and hyperpigmentation in the face
and extremities are characteristic1,11,12. The accumulated
porphyrine precursors are deposited in bones and
teeth. As a result, the dentition can develop a reddishbrown colour1,1113. Because CEP patients have red
teeth, excessive body hair and only venture out at night
to avoid sun-exposure, it has been suggested that CEP
is the origin of the werewolf legend14.
Porphyria Cutanea Tarda (PCT)

PCT occurs when the enzyme URO-decarboxylase is


deficient, and is the most common of the porphyrias1,2.
The major clinical symptom is cutaneous photosensitivity.
Vesicles and bullae develop on sun-exposed areas such
as the face, hands and forearms (Figure 2, 3 and 4). The
bullae heal slowly with crusting and are subject to

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infection. Other cutaneous symptoms are excessive


hair growth, hyperpigmentation, thickening and scarring1,15. A number of factors can contribute to the
development of PCT, including excess alcohol, oestrogens, iron supplements, hepatitis C and some chemicals.
Erythropoietic Protoporphyria (EPP)

Is due to a deficiency of ferrochelatase and is inherited


as an autosomal dominant trait. PCT is the second
most common porphyria1. Cutaneous photosensitivity
usually begins in childhood. The skin manifestations
differ from the other porphyrias. Redness, swelling,
itching and burning can develop within a few minutes
of sun exposure (Figure 5). The pain can last for days.
Chronic changes include skin thickening and nail
deformations. Severe scarring, pigment changes and
hirsutism are rare in EPP1.
Diagnosis

Figure 2. Skin reaction on the right ear and cheek of a patient with
Porphyria Cutanea Tarda (courtesy of G Smeenk)

In most cases, the medical anamnesis in combination


with a family history will allow the discrimination
between an acute type of porphyria and a cutaneous
type. The final diagnosis of the specific type of
porphyria depends on laboratory tests. Abnormal
concentrations of the specific precursors can be determined in urine, faeces, plasma, bile or saliva1,16. DNA
analysis can contribute to the diagnosis of AIP17.
Medical treatment

Acute porphyrias

Figure 3. Skin reaction on the right index finger of a patient of


Porphyria Cutanea Tarda (courtesy of G Smeenk)

The therapy of acute porphyrias depends on prevention,


suppression the production of porphyrin precursors
and the treatment of symptoms. After porphyria has
been diagnosed, the patient receives a list of factors
that may provoke acute episodes. Patients should be
advised to wear a necklace or bracelet with this medical
information to prevent treatment with contraindicated
medication during emergency situations.
The production of porphyrin precursors can be
suppressed by an increased intake of carbohydrates
and by treatment with heme arginate (Normosang).
Carbohydrate decreases the activity of ALA-synthetase
(Figure 1). The best therapy during an acute episode is
administration of heme arginate. This increases the
heme concentration which, because of the negative
feedback, inhibits the activity of ALA-synthetase (Figure
1). Heme arginate also prevents damage to the nerve
system during the acute episode1,7.
In addition, patients should receive additional
psychological therapy for their mental problems18.
Cutaneous porphyrias

Figure 4. Skin reactions on the left hand of a patient met Porphyria


Cutanea Tarda (courtesy of M K Polano and D Suurmond)

The avoidance of sunlight and protection of the skin


with sunscreens, long sleeves, hats and sunglasses is
Kooijman and Brand: Oral aspects of porphyria

64

Figure 5. Facial reactions after exposure to sunlight of a patient


with Erythropoietic Protoporphyria (courtesy of M K Polano and D
Suurmond)

important. Oral administration of >-carotene may


improve tolerance to light in CEP and EPP patients1.
PCT patients should discontinue the use of alcohol,
oestrogens, iron supplements and drugs that exacerbate the disease. Repeated phlebotomy (blood-letting)
to reduce hepatic iron induces a complete remission in
most PCT patients. PCT can also be treated with
chloroquine to promote the excretion of porphyrins1.
Psychological support is especially important for EPP
patients, as they have an isolated social life19.
Oral manifestations

In patients with cutaneous porphyria, skin lesions with


blistering also occur on the facial skin. The healed
lesions become hyperpigmented and scars can develop
on sun-exposed areas like the external ears. Facial
hirsutism may present as profuse eyebrows, long
eyelashes and facial hair1,10,11.
Recently a patient has been described with PCT of
the lower lip20. The patient had difficulty with eating
and speaking because of a bleeding lower lip, which
showed dryness, oedema and ulceration. The clinical
symptoms worsened with exposure to sunlight. A
biopsy specimen from the lip showed parakeratinised
International Dental Journal (2005) Vol. 55/No.2

stratified squamous epithelium with acanthosis. One


area showed ulceration covered with a fibrinous
exudate. In the connective tissue an intense lymphocyte
infiltrate with increased collagen fibres and nodule
formation was present. Topical treatment with steroids in combination with the use of a sunscreen
achieved complete remission within 15 days.
Accumulated porphyrin precursors make the oral
mucosa extremely vulnerable to mild trauma. A patient
developed bullae and erosive lesions in the mucobuccal
fold and at the palatal side of premolars after routine
dental treatment13. The lesions were very painful when
eating and attempting to perform dental hygiene. A
biopsy from the palatal lesion showed parakeratotic
squamous epithelium with acanthosis. The epithelium
had local necrotic areas with focal aggregates of
leukocytes. These findings are similar to those in skin
lesions of cutaneous porphyria. Dental treatment was
discontinued, resulting in a complete resolution of the
lesions within one week. When dental treatment was
resumed six months later, the lesions reappeared. This
patient illustrates that porphyria should be included in
the differential diagnosis in patients with oral bullae of
unknown aetiology13.
Oral treatment with >-carotene may induce carotenaemia, resulting in a mild yellow-orange colour of the
oral mucosa and tongue in CEP and EPP patients1.
Paleness of the oral mucosa may occur in CEP. CEP
patients can also have a bluish purple discolouration of
the mucosa in the alveolar bone region, probably
reflecting discolouration of the underlying bone11.
In the primary dentition of CEP patients, accumulation of porphyrin precursors induces a deep redbrown or yellow-brown discolouration (erythrodontia).
Usually discolouration of the permanent dentition is
less intense. The coloured teeth fluoresce in near-ultra
violet light with a wavelength of 365nm, so called
Woods light. The discolouration is most marked
cervically and reduces towards the occlusal surface.
The concentration of porphyrin is much higher in
dentine than in enamel, which may be caused by the
affinity of porphyrins for calcium phosphate11-13,21.
Most case reports of porphyria describe extensive
periodontal disease and a high caries incidence, probably related to the increased consumption of carbohydrates of patients with acute porphyria 10,11,13,22,23.
Bitewing radiographs showed marked thinning of the
enamel in a CEP patient, which may also increase the
caries risk11.
A patient with AIP was identified after placement
of a mandibular fixed partial prosthesis containing
76% palladium, 2% gold and 10% copper. Besides
severe abdominal pain, diarrhoea and epileptic episodes,
the patient also developed a metallic taste and drooling. The symptoms disappeared almost immediately
following removal of the prosthesis24.
Saliva of patients with porphyria can be analysed

65

for specific porphyrin precursors. This non-invasive


method is used for diagnosis of PCT16.
Dental treatment

In addition to obtaining a general medical history from


a patient with porphyria, several specific questions
should be asked:
Who is your doctor or specialist?
Do you know factors that precipitate attacks?
How are your attacks usually managed?
And, in the case of a patient with acute porphyria:
How often do you suffer from acute episodes?
When was your last attack?
Have you ever been hospitalised because of your
disease? (Modified from10).
The dentist should consult the physician of the
patient before starting dental treatment. The intended
dental treatment should be discussed, including the use
of local anaesthetics, antibiotics, analgesics, anti-inflammatory drugs and/or sedatives. In addition, information should be obtained on the emergency treatment
of acute episodes during dental treatment10.
An increased consumption of carbohydrates reduces
the risk of an acute attack of porphyria, but increases
the risk of developing caries. Frequent dental check-ups
with extensive oral hygiene instructions are indicated11,22.
Application of fluoride varnishing every six weeks or
daily use of a 0.05% sodium fluoride mouthrinse is
recommended. Chloorhexidine gluconate mouthwashes
can also be used, provided they are ethanol-free10.
Prevention of oral infections and maintenance of the
masticatory function are important factors since
malnutrition is a precipitating factor for attacks of
acute porphyria7.
Dental treatment of patients with CEP is concerned
with improving the aesthetics of the discoloured teeth
with crowns, facings and/or laminated veneers11.
Heavy metals, including copper, have been docu-

mented in playing a role in provoking acute episodes


of porphyria. It has also been suggested that mercury
may have an effect on porphyrin metabolism25. Therefore, it has been recommended that amalgam should
not be used for dental restorations in patients with
porphyria10,25. However, restorations of carious lesions
with amalgam in both an AIP and a CEP patient
proceeded uneventfully11,23, which does not support
this recommendation. On the other hand, placing a
frame prosthesis with high levels of copper induced an
acute porphyric attack, indicating that heavy metals,
including amalgam, should be avoided24. At least
dentists should ask porphyria patients about the inability to tolerate certain types of jewellery: This may
indicate the possibility of an existing metal intolerance10.
In several EPP patients, the lights of the operating
room induced severe burns during surgery19. The light
of the dental unit should therefore be considered a
potential danger to EPP patients. A coloured filter
may remove the dangerous part from the spectrum
(400550nm).
Several lists have been published with recommendations of indicated and contraindicated medication
for porphyria patients, especially those with AIP (Table
2). In general, these tables are based on combined data
from cell culture experiments, animal studies and case
reports of porphyria patients. For most medication,
the data are limited to in vitro studies and animal
experiments. However, in vitro studies on the effect of
medication on the porphyrin metabolism are very
sensitive with a relatively high risk of false-positive
results, and the porphyrin metabolism of laboratory
animals differs from that in man. Therefore, it is
possible that some drugs classified as unsafe may be
without negative effects when administered to porphyria
patients23.
Most published recommendations focus on the use
of local anaesthetics in dentistry. Bupivacain is considered to be safe for porphyria patients. Mepivacain,
prilocain and lidocain are frequently considered to be

Table 2 Drug recommendations for dental treatment of


patients with porphyria (modified from 1,7,10,22,23)
Indicated (safe)

Contraindicated (unsafe)

Acetaminophen
Acetylsalicylic acid
Acyclovir
Amoxicillin
Amphotericin B
Bupivacaine
Codeine
Dexamethasone
Gentamicin
Ibuprofen
Naproxen
Nitrous oxide
Penicillins
Streptomycin

Alcohol
Clindamycin
Diclofenac
Erythromycin
Lidocaine
Mepivacaine
Metamizol
Miconazole
Oxazepam
Pyrazolones

Kooijman and Brand: Oral aspects of porphyria

66

unsafe10,23. Nevertheless, a dental abscess in an AIP


patient was treated uneventful after use of prilocain23.
Likewise, a HCP patient received extensive dental treatment without any problem after administration of
mepivacain10. Although local anaesthetics classified as
unsafe have been used without any clinical symptoms
in some patients with acute porphyria, the safe
bupivacain remains the recommended local anaesthetic
for such patients.
Nitrous oxide sedation of porphyria patients is
considered to be safe10,23. Several aspects of general
anaesthesia for oral-maxillofacial surgery need special
attention. Major surgery interferes with nutrition, which
may provoke an attack in patients with acute porphyria. Therefore, the period of starvation before surgery
should be as short as possible and during surgery an
intravenous infusion of glucose is likely to be necessary7. The intravenous anaesthetic propofol is indicated
for the induction of surgical anaesthesia, barbiturates
are contraindicated. To maintain general anaesthesia,
the inhalation anaesthetics isoflurane and enflurane are
considered to be safe26,27.
The antibiotics amoxicillin and penicillin are safe
for porphyria patients, in contrast to clindamycin. The
anti-inflammatory drugs ibuprofen and naproxen can
be prescribed safely to patients with porphyria, but
diclofenac is contraindicated. Postoperative pain of
porphyria patients can be managed with acetaminophen
or acetylsalicylic acid10,22,23.
In summary, porphyria is clinically significant to the
dental practitioner. Medication used in dentistry may
provoke an acute attack that, in extreme cases, could
be fatal. Close collaboration between physician, dentist
and dental hygienist is essential for providing optimal
dental care to porphyria patients.

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Correspondence to: Dr. Henk S. Brand, Department of Basic
Dental Sciences, Section of Oral Biochemistry, Academic Centre
for Dentistry Amsterdam (ACTA), van der Boechorststraat 7,
1081 BT Amsterdam, The Netherlands. E-mail: hs.brand@vumc.nl

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