THE PORPHYRIAS

The Porphyrias

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Acronyms: AIP, Acute Intermittent Porphyria; CEP, Congenital Erythropoietic Porphyria; PCT, Porphyria Cutanea Tarda; HEP, Hepatoerythropoietic Porphyria; HCP, Hereditary Coproporphyria; VP, Variegate Porphyria; EPP, Erythropoietic Protoporphyria

Mechanism of porphyrin-induced photosensitivity:

The photosensitivity of the skin in porphyria is due to porphyrins absorbing ultraviolet radiation in the 400 nm range and emitting an intense red fluorescence. Porphyrins, when irradiated with light of the appropriate wavelength in the presence of oxygen, will cause photodynamic effects. Light energy absorbed by the porphyrin raises electrons into an excited state. Energy released on return of the molecule to its original state reacts with oxygen to produce free radicals and singlet oxygen (O) which damages molecules, cells and tissues. Unsaturated lipids are particular targets for activated oxygen species; cell damage results from the resulting plasma membrane and lysosomal membrane injury and also from complement activation. b -Carotene, a known quencher of free radicals and singlet oxygen, has a photoprotective effect in porphyria.

Aetiology, clinical picture and investigation of the different types of porphyria: (see table below)

Histopathology of skin lesions in porphyria:

· Homogenous, pale, eosinophilic deposits (PAS-positive, diastase-resistant) are seen around the blood vessels of the papillary dermis; deeper blood vessels may show similar deposits. In areas of sclerosis, the collagen bundles are thickened.

· The bullae arise subepidermally. Some blisters are dermolytic and arise beneath the PAS-positive basement membrane zone (and thus heal with scarring); others form in lamina lucida and are situated above the PAS-positive basement membrane zone. It is quite characteristic of the bullae of porphyria cutanea tarda that the dermal papillae often extend irregularly from the floor of the bulla into the bulla cavity. This phenomenon referred to as festooning, is explained by the rigidity of the upper dermis induced by the presence of eosinophilic material within and around the capillary walls in the papillae and the papillary dermis. There is no or just a minimal inflammatory cell infiltrate in the dermis.

· On electron microscopic examination, the PAS-positive material in the vessels of the papillary dermis consists of concentric multiplications of the basement membrane around these vessels, i.e. it is not true hyaline. Proof that the perivascular material in porphyria represents excessively synthesized basement membrane material and as such contains type IV collagen is provided by positive immunofluorescence staining with anti-type IV collagen monospecific antibody.

· Direct immunofluorescence testing has revealed in the majority of patients the presence of IgG and occasionally also of complement in the walls of blood vessels and at the dermal-epidermal junction of light-exposed skin. It is unlikely that these deposits indicate an immunological phenomenon; rather, they are the result of "trapping" of immunoglobulins and complement in the filamentous PAS-positive material.

Treatment of porphyria:

· AIP: It is important that attacks are prevented if at all possible. Patients with AIP should have medical warning bracelets or carry cards warning of the risks associated with the administration of barbiturates, sulphonamides, sex hormones and other drugs; they should avoid starvation. An acute attack, if severe, is best managed on an intensive care unit. The pain can be controlled with morphine or pethidine. Chlorpromazine is helpful in potentiating these analgesics and in alleviating the psychiatric symptoms. Attention must be paid to electrolyte and fluid balance since inappropriate secretion of antidiuretic hormone can produce hyponatraemia and hypervolaemia. Muscle weakness may result in respiratory failure and intermittent positive pressure ventilation is sometimes required. The control of fits associated with AIP is difficult because many of the anticonvulsants are contra-indicated; intravenous diazepam is probably the best treatment for status epilepticus (although potentially unsafe). The tachycardia and hypertension of the acute attack are thought to be due to sympathetic overactivity and can be controlled using propranolol. Intravenous haematin has been used to reduce the excretion of ALA and PBG, to cut short an acute attack and to reduce the severity of the neuropathy. Carbohydrate loading may reduce the production of porphyrins and their precursors and induce clinical improvement.

· PCT: It is important to identify and avoid precipitating factors; the elimination of alcohol and the withdrawal of prescribed oestrogens and of iron supplements can, in time, induce a remission. Patients should be advised about sun avoidance measures and prescribed an adequate sunblock cream. The removal of iron by venesection is effective and at present the treatment of choice in PCT: 500 ml of blood are removed at intervals of 2 weeks until clinical remission is induced or the haemoglobin falls below 12g/dl; removal of 2-4 litres of blood is normally effective. Low-dose chloroquine, given in the dose of 125 mg twice a week, is an alternative and recommended by some as first line treatment; however, higher doses may exacerbate the symptoms or produce hepatotoxicity. Other treatments suggested for PCT include iron chelating agents (desferrioxamine) and plasmapheresis.

In HEP, strict sun avoidance is essential; venesection is not effective.

· VP: The treatment of a patient with an acute attack of VP is identical to that described for AIP. The skin lesions are managed in a similar way to those of PCT. Besides sun avoidance and sunscreens, canthaxanthin, a b -carotene analogue, is reported to be of some benefit although it may cause retinopathy.

In HCP, the treatment of acute attacks is as outlined for AIP.

· EPP: Avoidance of sun is important as is the use of a high protection factor sunscreen. b -carotene in a dose of 50-200 mg daily offers photoprotection in some patients. Cholestyramine has been shown to reduce photosensitivity and to decrease hepatic protoporphyrin content.

· CEP: Rigid protection from sunlight is essential; topical sunscreens are relatively ineffective. b -carotene can improve light tolerance, but it is not as effective as in EPP. Splenectomy may be performed for intractable haemolytic anaemia. Hypertransfusion with packed erythrocytes may be helpful as it suppresses erythropoiesis and depresses the production of porphyrins. Iron overload may be avoided by the concurrent administration of desferrioxamine.

Porphyria

Type; Heredity; Onset

Cutaneous manifestations

Extracutaneous manifestations

Urine

Faeces

Erythrocytes

Congenital Erythropoietic Porphyria (CEP - Gunther's disease)

Erythropoietic; Autosomal recessive; Infancy

Photosensitivity is in some cases almost immediate and so severe that the infant may scream when put in sunlight. Erythema, swelling and blistering occur on exposed sites. Ulceration may follow and healing is slow with scar formation. Repeated episodes of blistering results in mutilation of the ears, nose and fingers. Hypertrichosis, seen in areas of mild involvement, takes the form of lanugo hair over the limbs and coarser hair on the face, but the most severely affected areas show a scarring alopecia often involving the scalp. Irregular hyperpigmentation follows in areas of scarring ± hypopigmentation.

Brown teeth that fluoresce reddish-pink under Wood's light. Haemolytic anaemia and splenomegaly. Eyes: Photophobia is commonly present and patients may develop ectropion (related to facial scarring) or keratoconjunctivitis, up to loss of vision.

Uroporphyrin I; to dark brown staining of the nappies; Urine will fluoresce reddish-pink under Wood's light

Coproporphyrin I

Uroporphyrin I; Stable fluorescence

Erythropoietic Protoporphyria (EPP)

Erythropoietic; Autosomal dominant; Childhood

Symptoms are worst in spring and summer and occur few minutes to 1 hour of exposure to sunlight in light-exposed areas with burning and tingling rather than itching. Oedematous urticaria-like plaques and eczematous areas may appear several hours later at the exposed sites. Rarely, purpra develops. Curious linear crusted and pitted areas are seen sometimes over the nose, the cheeks and dorsa of hands. In remission patients may show pock-like scarring on the nose and cheeks and circumoral linear scars. The skin appears weather-beaten. Hyperkeratosis, thickening and mild scarring are sometimes seen over the dorsa of hands but bullae, skin fragility, pigmentation, hypertrichosis or mutilation are uncommon in EPP. Symptoms often improve spontaneously after the age of 10 years.

Protoporphyrin gallstones; Mild liver dysfunction - rarely, fatal liver cirrhosis

Negative

Protoporphyrin continuously

Protoporphyrin; Transient fluorescence

Acute Intermittent Porphyria (AIP)

Hepatic; Autosomal dominant; Young adulthood

Negative

Periodic attacks of: abdominal colic (usually there is no abdominal wall rigidity, although tenderness and distension are present), peripheral neuropathy, mostly motor, psychiatric disorders and tachycardia. AIP-inducing drugs include: barbiturates, non-barbiturate sedatives, phenytoin, halothane, sulphonamides, sulphonylureas as chlorpropamide, dapsone, griseofulvin, oestrogens, and ergot preparations. Attacks may also follow a febrile illness, alcoholic excess, fasting, surgery (including dental procedures done under a local anaesthetic), or be related to the menstrual cycle or to pregnancy.

ALA, PBG continuously; 75% have port-wine coloured urine

Negative

Negative

Variegate Porphyria (VP)

Hepatic; Autosomal dominant; Young adulthood

Same as PCT

Same as AIP

ALA, PBG during attacks

Protoporphyrin continuously

Negative

Porphyria Cutanea Tarda (PCT)

Hepatic; Autosomal dominant; Sporadic type I (80%): Only hepatic activity of UD is ¯ ; middle age; no clinical evidence of PCT in other members of patient's family; results from an inherited enzymatic defect + acquired damaging factor to liver function (ethanol, oestrogens) Familial type II (20%): In addition to hepatic activity, extrahepatic activity of UD is ¯ to 50% of normal; any age, including childhood; there is often a +ve family history of overt PCT

Photosensitivity resulting in bullae, especially on sun-exposed areas or areas subject to friction, trauma, or heat ( skin fragility). The bullae rupture easily to form erosions or shallow ulcers. These heal with scarring, milia and dyspigmentation. Lesions on the legs, especially the shins and dorsal feet, occur primarily in young women on birth control pills. There is hyperpigmentation of the skin, especially of the face, neck and hands. Hypertrichosis of the face, especially over the cheeks and temples is seen. The face and neck, especially in the periorbital area, may show a pink to violaceous tint (suffusion). Sclerodermatous thickenings with calcification may develop on cheeks, on the back of the neck, in the preauricular areas, the ears, the chest, the fingers and the scalp. In the latter instance, there may be associated alopecia.

A history of heavy alcoholism is common in the sporadic type (alcohol stimulates ALA synthase and inhibits ALA dehydratase [PBG synthase]; it also iron uptake and non-specifically impairs liver function). Hepatic iron overload is present in nearly every case of PCT (siderosis) and plasma iron is in 50% of patients. Decreased liver function and cirrhosis may be present. Patients with PCT have an increased risk of developing hepatocellular carcinoma and lymphoma, and a PCT-like condition may occur with hepatic tumours, hepatitis and SLE. The use of oestrogens in oral contraceptives and for treatment of prostatic carcinoma may precipitate PCT; pregnancy may induce or aggravate PCT. Other drugs capable of inducing PCT are chloroquine in high doses (low doses are used for treatment of PCT!), tetracyclines, furosemide, nalidixic acid, dapsone, pyridoxine and naproxen. The wheat fungicide, hexachlorobenzene, and chlorinated hydrocarbons as dioxins have caused PCT. A few patients with chronic renal failure on haemodialysis have developed PCT or pseudoporphyria (clinical lesions of PCT with normal¾ instead of raised¾ plasma and urine uroporphyrin levels). Diabetes mellitus is present in 15-20% of PCT patients.

Uroporphyrin III; Continuous fluorescence: coral pink using Wood's light

isocoproporphyrin

Negative

Hepatoerythropoietic Porphyria (HEP): Homozygous form of PCT; UD activity in all organs is ¯ to less than 10% of normal

Erythropoietic and hepatic; Autosomal dominant; Infancy

Extreme photosensitivity is usually evident before the first year of life. Blistering leads to scarring with mutilation, hyperpigmentation, hypertrichosis and sclerodermatous changes.

Liver biopsy may demonstrate mild portal lymphocytic infiltration or micronodular cirrhosis. Red fluorescence of the teeth under Wood's light.

Uroporphyrin I and III; Dark urine is passed from birth

Coproporphyrin I and III

Protoporphyrin

Hereditary Coproporphyria (HCP)

Hepatic; Autosomal dominant; Young adulthood

Same as PCT (in about one third of patients)

Same as AIP

Coproporphyrin, ALA, PBG during attacks

Coproporphyrin continuously

Negative

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Porphyria	Type; Heredity; Onset	Cutaneous manifestations	Extracutaneous manifestations	Urine	Faeces	Erythrocytes
Congenital Erythropoietic Porphyria (CEP - Gunther's disease)	Erythropoietic; Autosomal recessive; Infancy	Photosensitivity is in some cases almost immediate and so severe that the infant may scream when put in sunlight. Erythema, swelling and blistering occur on exposed sites. Ulceration may follow and healing is slow with scar formation. Repeated episodes of blistering results in mutilation of the ears, nose and fingers. Hypertrichosis, seen in areas of mild involvement, takes the form of lanugo hair over the limbs and coarser hair on the face, but the most severely affected areas show a scarring alopecia often involving the scalp. Irregular hyperpigmentation follows in areas of scarring ± hypopigmentation.	Brown teeth that fluoresce reddish-pink under Wood's light. Haemolytic anaemia and splenomegaly. Eyes: Photophobia is commonly present and patients may develop ectropion (related to facial scarring) or keratoconjunctivitis, up to loss of vision.	Uroporphyrin I; to dark brown staining of the nappies; Urine will fluoresce reddish-pink under Wood's light	Coproporphyrin I	Uroporphyrin I; Stable fluorescence
Erythropoietic Protoporphyria (EPP)	Erythropoietic; Autosomal dominant; Childhood	Symptoms are worst in spring and summer and occur few minutes to 1 hour of exposure to sunlight in light-exposed areas with burning and tingling rather than itching. Oedematous urticaria-like plaques and eczematous areas may appear several hours later at the exposed sites. Rarely, purpra develops. Curious linear crusted and pitted areas are seen sometimes over the nose, the cheeks and dorsa of hands. In remission patients may show pock-like scarring on the nose and cheeks and circumoral linear scars. The skin appears weather-beaten. Hyperkeratosis, thickening and mild scarring are sometimes seen over the dorsa of hands but bullae, skin fragility, pigmentation, hypertrichosis or mutilation are uncommon in EPP. Symptoms often improve spontaneously after the age of 10 years.	Protoporphyrin gallstones; Mild liver dysfunction - rarely, fatal liver cirrhosis	Negative	Protoporphyrin continuously	Protoporphyrin; Transient fluorescence
Acute Intermittent Porphyria (AIP)	Hepatic; Autosomal dominant; Young adulthood	Negative	Periodic attacks of: abdominal colic (usually there is no abdominal wall rigidity, although tenderness and distension are present), peripheral neuropathy, mostly motor, psychiatric disorders and tachycardia. AIP-inducing drugs include: barbiturates, non-barbiturate sedatives, phenytoin, halothane, sulphonamides, sulphonylureas as chlorpropamide, dapsone, griseofulvin, oestrogens, and ergot preparations. Attacks may also follow a febrile illness, alcoholic excess, fasting, surgery (including dental procedures done under a local anaesthetic), or be related to the menstrual cycle or to pregnancy.	ALA, PBG continuously; 75% have port-wine coloured urine	Negative	Negative
Variegate Porphyria (VP)	Hepatic; Autosomal dominant; Young adulthood	Same as PCT	Same as AIP	ALA, PBG during attacks	Protoporphyrin continuously	Negative
Porphyria Cutanea Tarda (PCT)	Hepatic; Autosomal dominant; Sporadic type I (80%): Only hepatic activity of UD is ¯ ; middle age; no clinical evidence of PCT in other members of patient's family; results from an inherited enzymatic defect + acquired damaging factor to liver function (ethanol, oestrogens) Familial type II (20%): In addition to hepatic activity, extrahepatic activity of UD is ¯ to 50% of normal; any age, including childhood; there is often a +ve family history of overt PCT	Photosensitivity resulting in bullae, especially on sun-exposed areas or areas subject to friction, trauma, or heat ( skin fragility). The bullae rupture easily to form erosions or shallow ulcers. These heal with scarring, milia and dyspigmentation. Lesions on the legs, especially the shins and dorsal feet, occur primarily in young women on birth control pills. There is hyperpigmentation of the skin, especially of the face, neck and hands. Hypertrichosis of the face, especially over the cheeks and temples is seen. The face and neck, especially in the periorbital area, may show a pink to violaceous tint (suffusion). Sclerodermatous thickenings with calcification may develop on cheeks, on the back of the neck, in the preauricular areas, the ears, the chest, the fingers and the scalp. In the latter instance, there may be associated alopecia.	A history of heavy alcoholism is common in the sporadic type (alcohol stimulates ALA synthase and inhibits ALA dehydratase [PBG synthase]; it also iron uptake and non-specifically impairs liver function). Hepatic iron overload is present in nearly every case of PCT (siderosis) and plasma iron is in 50% of patients. Decreased liver function and cirrhosis may be present. Patients with PCT have an increased risk of developing hepatocellular carcinoma and lymphoma, and a PCT-like condition may occur with hepatic tumours, hepatitis and SLE. The use of oestrogens in oral contraceptives and for treatment of prostatic carcinoma may precipitate PCT; pregnancy may induce or aggravate PCT. Other drugs capable of inducing PCT are chloroquine in high doses (low doses are used for treatment of PCT!), tetracyclines, furosemide, nalidixic acid, dapsone, pyridoxine and naproxen. The wheat fungicide, hexachlorobenzene, and chlorinated hydrocarbons as dioxins have caused PCT. A few patients with chronic renal failure on haemodialysis have developed PCT or pseudoporphyria (clinical lesions of PCT with normal¾ instead of raised¾ plasma and urine uroporphyrin levels). Diabetes mellitus is present in 15-20% of PCT patients.	Uroporphyrin III; Continuous fluorescence: coral pink using Wood's light	isocoproporphyrin	Negative
Hepatoerythropoietic Porphyria (HEP): Homozygous form of PCT; UD activity in all organs is ¯ to less than 10% of normal	Erythropoietic and hepatic; Autosomal dominant; Infancy	Extreme photosensitivity is usually evident before the first year of life. Blistering leads to scarring with mutilation, hyperpigmentation, hypertrichosis and sclerodermatous changes.	Liver biopsy may demonstrate mild portal lymphocytic infiltration or micronodular cirrhosis. Red fluorescence of the teeth under Wood's light.	Uroporphyrin I and III; Dark urine is passed from birth	Coproporphyrin I and III	Protoporphyrin
Hereditary Coproporphyria (HCP)	Hepatic; Autosomal dominant; Young adulthood	Same as PCT (in about one third of patients)	Same as AIP	Coproporphyrin, ALA, PBG during attacks	Coproporphyrin continuously	Negative