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RailiKauppinen

Porphyrias

Essentials

  • Porphyrias are hereditary metabolic diseases due to a disorder of haem production in the liver and bone marrow. The symptoms appear either as acute attacks or as photosensitivity of the skin.
  • In the initial phase of an acute attack, most patients have severe abdominal pain and mild mental symptoms, as well as symptoms of autonomic neuropathy, such as vomiting, constipation, palpitations or hypertension.
  • Mild symptoms may be alleviated by symptomatic treatment but severe symptoms should be treated by giving hemin in hospital.
  • Acute attacks can be prevented by avoiding factors that stimulate haem synthesis, such as alcohol, medication and fasting. Any inflammation should be treated well and appropriate nutrition ensured.
  • Blistering and scarring of photosensitized skin are typical skin symptoms of porphyria. Their treatment varies depending on the type of porphyria.
  • Acute porphyrias are rare and usually transmitted as an autosomal dominant condition. Whenever a new case is found, family members should be examined for the disease.
  • Different types of porphyrias exist. This article focuses on the most common types encountered in Finland. Find out about the epidemiology of different porphyria types in your local setting.

Background

  • During an acute attack, the hepatic haem synthesis regulating enzyme ALA synthase-1 is activated by triggering factors, and toxic haem precursors (porphobilinogen and aminolevulinic acid) accumulate in the body. As neurotoxic compounds they cause autonomic and sensomotor neuropathy as well as CNS symptoms.
  • The skin symptoms are due to a phototoxic reaction in the vascular walls of the upper dermis resulting from a combined effect of sunlight and circulatory hepatic or erythropoietic porphyrins. The porphyrin ring is a tetrapyrrole absorbing light energy most intensely at 400-410 nm, i.e. in the purple light range. Its reaction with oxygen leads either to an immediate skin photoreaction, i.e. painful swelling and erythema, or to a slow photoreaction, i.e. fragility, blistering and scarring of the skin depending on the circulating porphyrin complexes.

Classification and heredity

  • Different types of porphyria exist. Table T1 below describes the most common porphyrias occurring in Finland. Acute intermittent porphyria (AIP) causing sudden porphyria attacks and variegate porphyria (VP) are the most common types in Finland. For more complete classification, see e.g. http://porphyria.eu/content/porphyrias.
  • About half of the patients have skin symptoms. These are caused by porphyria cutanea tarda (PCT), variegate porphyria (VP), hereditary coproporphyria (HCP) or erythropoietic protoporphyria (EPP).
  • Porphyrias are usually transmitted by autosomal dominant inheritance. Whenever a new case is found, family members should be examined for the disease by genetic testing in primary health care already.
    • Symptoms suggestive of porphyria in any family member who has undergone genetic testing and been found to have the porphyria gene should be carefully identified at the time of diagnosis already. Porphyrins and their precursors can be assayed to assess disease activity. This can be done in specialized care.
    • Patient guidance will decrease cases of overt disease by making it possible to avoid triggering factors.
    • If the disease has been diagnosed and is appropriately treated, recovery is rapid.
    • For instructions for laboratory tests, see European Porphyria Network http://porphyria.eu/> Porphyria specialist centres http://porphyria.eu/content/specialist-porphyria-laboratory-map: choose on the map > your own location.

Porphyrias occurring in Finland

PorphyriaMain symptomTestDeficient enzymeHeredity and penetranceNumber of patients in Finland (per 5.5 million inhabitants)
Acute intermittent porphyria (AIP)Acute attackUrinary PBG
Urinary ALA
Plasma porphyrins
Eryhtrocyte PBGD
AIP DNA test		PBGDAutosomal dominantApprox. 20-50% of all mutation carriers develop symptoms during their lifetime.Approx. 200
Variegate porphyria (VP)Photosensitivity: fragility, blistering and scarring of the skin
Acute attack		Plasma porfyrins
Faecal porphyrins
Urinary PBG
Urinary ALA
VP DNA test		PPOXAutosomal dominant
Approx. 30-40 % of all mutation carriers develop symptoms during their lifetime.		Approx. 150
Hereditary coproporphyria (HCP)Photosensitivity: fragility, blistering and scarring of the skin
Acute attack 		Plasma porphyrins
Nocturnal urinary porphyrins
Faecal porphyrins
Urinary PBG
Urinary ALA
HCP DNA test		CPOXAutosomal dominant2
Porphyria cutanea tarda (PCT)Photosensitivity: blistering and scarring of the skin
Hepatopathy		Nocturnal urinary porphyrins
Plasma porphyrins
Erythrocyte UROD
PCT DNA test		URODAutosomal dominant or acquired (symptoms triggered by other than genetic factors)Approx. 100
Erythropoietic protoporphyria (EPP)Photosensitivity: painful swelling and erythema of the skin
Microcytic anaemia and acute liver failure		Blood porphyrins
Plasma porphyrins
Ratio of zinc-chelated to free protoporphyrin
Lymphocyte FECH
EPP DNA test		FECHAutosomal recessive or dominant, in which case the phenotype depends on the polymorphisms of the normal allele
Approx. 50% of all mutation carriers develop symptoms.		Approx. 50
X-linked protoporphyria (XLP)Photosensitivity: painful swelling and redness of the skin
Microcytic anaemia and acute liver failure 		Blood porphyrins
Plasma porphyrins
Ratio of zinc-chelated to free protoporphyrin
XLP DNA test		Increased production of ALAS2Linked to X chromosome, males symptomatic and females have symptoms due to inactivation of normal X chromosome So far, no diagnosis has been made in Finland.
About 10% of protoporphyrias of ALAS2 origin
PBG = urinary porphobilinogen
ALA = aminolevulinic acid
PBGD = porphobilinogen deaminase
PPOX = protoporphyrinogen oxidase
CPOX = coproporphyrinogen oxidase
UROD = uroporphyrinogen decarboxylase
FECH = ferrochelatase
ALAS2 = 5'-aminolevulinate synthase 2

Acute attacks: triggering factors

  • Acute symptoms begin after puberty.
    • For hormonal reasons, most symptoms occur in women from 20 to 40.
    • About 40% of all mutation carriers are symptomatic (women more often than men), and 5-10% have recurrent attacks (more than 4 times a year).
    • The rest of the patients experience milder symptoms or single attacks requiring hospital treatment during their lifetime.
  • The most common triggering factors are premenstruum, fasting, infection, alcohol, and drugs.
    • The most common triggering drugs are sulfa, phenytoin, carbamazepine and its derivatives, valproic acid (valproate sodium) and topiramate.
  • Most current drugs are safe: analgesics, antimicrobial drugs, cardiac and antihypertensive drugs, cytotoxic drugs and sedatives.
    • For more complete information on safe drugs and ones to be avoided, see http://www.drugs-porphyria.org/.
    • If any recently started medication causes symptoms suggesting porphyria, the medication should be interrupted and urinary porphobilinogen (PBG) and aminolevulinic acid (ALA) tested to detect increased haem synthesis. Any other need for treatment should be assessed case by case.
  • Oestrogen products may cause symptoms associated with acute porphyria in about 5% of female patients but they may also decrease symptoms, particularly if attacks are associated with the menstrual cycle or the onset of menopause.
    • Most patients can use current contraceptive products and oestrogen replacement therapy without problems.
  • Symptoms during pregnancy are rare and appear during either the first trimester or the postpartum period, when hormonal and weight changes are greatest.
  • Heavy alcohol consumption is the most common cause of acute attacks in men.
    • Patients can usually tolerate small amounts of alcohol but if alcohol causes symptoms suggestive of porphyria, its use should be avoided.
  • Smoking should be stopped, as it affects disease activity through weight loss.
  • Underweight should be avoided, and regular energy intake ensured. Controlled weight loss is acceptable.

Symptoms of acute attack and diagnosis

  • Attacks often begin with mild mental symptoms (restlessness, sleeplessness) with abdominal pain and autonomic neuropathy (vomiting, constipation, palpitations, hypertension).
  • Nearly all patients have abdominal pain. It is severe (VAS 8-10), and patients seek hospital treatment because ordinary analgesics are no longer effective. The abdomen is often diffusely tender on palpation, but the abdominal wall is soft.
  • If symptoms are prolonged, patients often have back and limb pain, headaches, sensomotor polyneuropathy and CNS symptoms (such as convulsions, confusion, hallucinations, decreased level of consciousness) and hyponatraemia (SIADH). Rhabdomyolysis may occur.
  • CT or MRI during the attack may show the posterior reversible encephalopathy syndrome (PRES) with or without hypertensive crisis.
  • Peripheral motor neuropathy (muscle weakness, paralysis), breathing problems, arrhythmias and bulbar symptoms (dysphagia, dysphonia and dysarthria) suggest progressive neuropathy. 10% of acute attacks are fatal, particularly if the disease has not been diagnosed.
  • Attacks are usually extended and aggravated by the use of porphyrinogenic medication, undernutrition or infections, which should therefore be appropriately treated.
  • Whenever an acute attack is suspected, urinary porphobilinogen (PBG) should be assayed.
    • A rapid test for this exists. If the test is clearly positive, porphyria is likely and treatment can be started.
    • The diagnosis should always be confirmed by a quantitative method, simultaneously assaying urinary aminolevulinic acid (ALA). The urine sample should be carefully protected from light.
  • Typical clinical symptoms and markedly increased porphobilinogen excretion (more than 4 times the reference value) are diagnostic.
    • Other causes of acute abdomen must always be excluded because in patients with AIP, in particular, porphobilinogen and aminolevulinic acid secretion are usually consistently higher than normal even in an asymptomatic stage of the disease.
    • Urinary aminolevulinic acid (ALA) and plasma porphyrin spectrum are slightly better markers of an acute attack than porphobilinogen in AIP patients.

Treatment of an acute attack Hemiarginate in Acute Porphyria

  • Triggering factors should be eliminated and adequate nutrition ensured (minimum requirement 1 500 kcal/day).
    • Mild symptoms often subside with symptomatic treatment, and some patients treat them at home.
  • Hospitalized patients are given 3 mg/kg hemin (Normosang® ) for 3-4 days unless the attack subsides with analgesics and fluid administration within a couple of days.
    • Patients with severe symptoms should immediately be given hemin (Normosang® ).
    • The biochemical response to hemin appears in 1-2 days but the alleviation of neuropathy takes an average of one week.
  • The diet should include plenty of carbohydrates or, alternatively, if the patient is vomiting, 400 g glucose/day i.v. because fasting should be avoided.
  • Hyponatraemia should be considered.
  • Weekly hemin infusions (Normosang® ), GnRH analogues or oestrogen-progesterone combination therapy has been used to prevent recurrent attacks, but only liver transplantation can cure acute porphyria. Treatment by inhibition of hepatic ALA synthase-1 with givosiran (Givlaari® ) has also proved effective but expensive.

Symptomatic treatment and follow-up of an acute attack

  • Pain: for mild symptoms an NSAID, for hospitalized patients usually an opioid
  • Palpitations: beta-blocker
  • Hypertension: beta-blocker and clonidine
  • Mental symptoms: 5-10 mg diazepam
  • Hyponatraemia: for patients with SIADH (inappropriate ADH secretion) NaCl infusion or fluid restriction. Dehydration should be avoided because of the risk of acute renal damage.
  • Convulsions: diazepam, correction of hyponatraemia and hypomagnesaemia
  • Urinary retention: catheterization
  • Respiratory paralysis: respirator treatment
  • Pareses: effective physiotherapy, active rehabilitation
  • Monitoring on the ward
    • Pulse and blood pressure (reflecting disease activity quite well)
    • Pain (VAS)
    • Muscle strength
    • Level of consciousness
  • Arrhythmias, respiratory difficulty and bulbar symptoms predict a poor prognosis, and the patient should be transferred to a surveillance unit.

Liver cancer and other late complications

  • Acute intermittent porphyria (AIP) carries a more than 60 times increased risk of liver cancer, and about 10% of patients die of liver cancer.
    • If a patient over 50 with acute porphyria has abdominal pain, the possibility of liver cancer should be considered.
    • Follow-up by annual imaging is recommended for patients over 50 with AIP.
    • In patients with variegate porphyria (VP) or porphyria cutanea tarda (PCT), liver cancer is distinctly rarer and no follow-up is not necessarily needed.
  • In patients with acute porphyria, hypertension and renal failure appear at a younger age and are more common than in the average population.

Diagnosis and treatment of porphyrias with skin symptoms

  • In patients with variegate porphyria (VP), skin symptoms begin after puberty and are milder than in patients with porphyria cutanea tarda (PCT), in whom skin symptoms begin at an average age of 50 years.
    • Typical symptoms include blistering and susceptibility to ulceration in areas exposed to light, such as the face, lower arms, backs of the hands, and lower legs (picture ).
    • The symptoms only appear late in the summer or in the autumn, and the ulcers heal slowly with scarring.
    • Milia, increased facial hair and pigmenting may be the only findings at the time of diagnosis.
  • The skin symptoms of VP, HCP and PCT cannot be clinically differentiated. It is important to define the type of porphyria because the treatment of PCT is completely different from the treatment of HCP and VP patients.
  • In patients with VP, skin symptoms are more common than acute attacks, and these do not usually coincide. In patients with VP, the restrictions to medication are the same as for other patients with acute porphyria.
  • HCP does not differ in clinical symptoms and treatment from porphyria variegata (VP).
  • Patients with PCT do not have acute attacks, and they have no restrictions to medication other than oestrogen and iron products.
  • In erythropoietic protoporphyria (EPP), burning pain, swelling and erythema appear immediately on sun exposure, often already during the first years of life. Children may refuse to go out for fear of pain.

Variegate porphyria (VP)

  • Patients with VP and skin symptoms have significantly increased faecal protoporphyrin excretion and a peak in the plasma porphyrin spectrum at 624 nm.
  • Because the mutations in VP families in Finland are known, detection of the PPOX gene mutation is used for diagnosis.
  • To prevent skin symptoms, patients with VP should protect themselves from sun by wearing clothes, a hat and protective gloves because there is no specific treatment for VP. Vitamin D supplementation may be necessary.
  • If there are no skin symptoms, protection is unnecessary.
  • Correct diagnosis is important because of the risk of acute attacks. Instructions for avoiding acute porphyria attacks should be given even if the patient has never had such attacks.

Hereditary coproporphyria (HCP)

  • Patients with cutaneous HCP have significantly increased urinary coproporphyrin excretion (elevated isomers III and I) and higher concentration of faecal coproporphyrins than of protoporphyrins. The ratio of isomers I to III of the faecal coproporphyrins exceeds 1.5. The peak of the plasma porphyrin spectrum is at 619 nm.
  • Since secondary coproporphyrinuria is common in cholestatic conditions, the diagnosis should be confirmed by a mutation detection test for the coproporphyrinogen oxidase gene.

Porphyria cutanea tarda (PCT)

  • Patients with PCT usually have some form of hepatopathy, most commonly alcoholic fatty liver disease.
  • Urinary excretion of uroporphyrins (isomers I and III) and 7-carboxyl porphyrins (nU-Porf) is greatly increased, and the peak in the plasma porphyrin spectrum is at 619 nm. Isocoproporphyrins can be found in feces. Uroporphyrinogen carboxylase activity in erythrocytes may be either normal or reduced but in the liver the enzyme activity is reduced due to iron overload.
  • About 40% of patients with PCT have a mutation of the UROD gene. In such patients who have what is called familial PCT, oestrogen, alcohol or iron therapy may trigger skin symptoms as in the sporadic form of the disease. Mutations associated with haemochromatosis, chronic haemodialysis, HIV and hepatitis C also increase the risk of PCT due to iron overload and should be effectively treated after venesection.
  • Plasma ferritin and transferrin saturation are usually increased in every type of PCT, and venesection is effective in eliminating porphyrins. Patients with milder symptoms can be treated by low-dose hydroxychloroquine after venesection at the early stage.
  • Alcohol consumption should be stopped to prevent the recurrence of PCT. Other predisposing factors should also be eliminated to prevent recurrence.
  • Skin protection is no longer necessary when porphyrin excretion has been normalized by treatment.

Erythropoietic protoporphyria (EPP)

  • Patients with EPP are usually children, as well as their parents and/or grandparents in whom EPP had not been diagnosed earlier. The diagnostic delay is often several decades. The severity of skin symptoms also varies by family, and symptoms often subside with age.
  • The symptoms (skin pain, swelling and erythema) begin after a few minutes of sun exposure and continue for 1-2 days. As the symptoms can usually no longer be observed in the doctor's office, the child or his/her parents should take a picture of the child's skin at the acute stage.
  • In patients with EPP, erythrocyte protoporphyrin levels are greatly increased, and the peak of the plasma porphyrin spectrum is at 634 nm. The ratio of zinc-chelated to free protoporphyrin may help to distinguish between EPP (ratio < 1) and X-linked dominant protoporphyria (XLP; ratio > 1) caused by a genetic defect in ALA synthase-2 and with nearly identical symptoms and biochemical findings.
  • EPP is usually transmitted by autosomal dominant inheritance but to produce the disease phenotype, polymorphism of the same ferrochelatase gene in the allele inherited from the healthy parent is required in addition to the mutation.
  • Patients usually have microcytic anaemia due to ferrochelatase deficiency, and one patient in three has transient liver dysfunction or gallstones already at a young age. 5% of patients show cholestatic liver damage, which may lead to acute liver failure requiring immediate liver transplantation. If bone marrow transplantation is not performed, the disease usually recurs in the transplanted liver.
  • EPP is treated by using clothing and sunscreen for protection. As a yellow film will reduce the amount of visible light exciting porphyrins (350-450 nm), such a film on a visor in front of the face may facilitate staying outdoors. Such a film on windows will reduce the amount of light entering the home or the car. As most patients avoid sunlight meticulously because of its painfulness, vitamin D supplementation is usually necessary.
  • Some patients benefit from beta carotene, some from UVB treatment and afamelanotide (Scenesse® ) that increases the ability to tolerate sunlight. XLP patients have also benefited from iron supplement (which converts protoporphyrinogen into haem). Iron preparations are not recommended for patients with EPP unless there is symptomatic iron deficiency.