12.3.3 The porphyrias

The porphyrias are metabolic diseases resulting from deficiency, or in one disease, an increase in the activity, of specific enzymes in the haem biosynthetic pathway (1, 2). Each of the eight main types of porphyria is defined by the association of characteristic clinical features with a specific pattern of excess production of pathway intermediates. Each pattern indicates the site of the underlying enzymatic abnormality (Fig. 12.3.3.1).

The porphyrias can therefore be defined clinically as either an acute porphyria, characterized by acute neurovisceral attacks that are associated with the overproduction of the porphyrin precursor, 5-aminolaevulinic acid (ALA, OMIM 125270), usually accompanied by porphobilinogen, or a nonacute porphyria in which these attacks are absent and photocutaneous symptoms due to excess formation of porphyrins are the main clinical manifestation. Other classifications include division into erythropoietic or hepatic, depending on the principal site of expression of the specific enzymatic defect.

Clinically identical acute neurovisceral attacks occur in four porphyrias: acute intermittent porphyria (OMIM 176000), hereditary coproporphyria (OMIM 121300), variegate porphyria (OMIM 600923), and 5-aminolaevulinate dehydratase porphyria (ADP EC 4.2.1.24). Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria are autosomal dominant disorders while the very rare condition ADP is autosomal recessive. Acute attacks can be life threatening if not recognized and appropriately treated.

In most countries, acute intermittent porphyria affects about 1 in 75 000 of the population, variegate porphyria about 1 in 1 50 000 and hereditary coproporphyria about 1 in 1 000 000. Acute intermittent porphyria is more common in Sweden and variegate porphyria in South Africa due to founder effects. Acute neurovisceral attacks are the main clinical feature of acute intermittent porphyria; photocutaneous symptoms do not occur. In variegate porphyria, 40% of patients present with acute attacks, of whom about half also have skin lesions, but 60% present with skin lesions alone. Hereditary coproporphyria presents with acute attacks that are accompanied by skin lesions in about 30% of patients; photocutaneous symptoms in the absence of an acute attack are rare and usually provoked by intercurrent liver disease. The skin lesions of variegate porphyria and hereditary coproporphyria are identical to those of porphyria cutanea tarda (OMIM 176090) and other bullous nonacute porphyrias.

The inherited defect in each of the autosomal dominant acute porphyrias is a mutation leading to inactivation of one of the allelic genes that encode the enzyme whose partial deficiency causes the disorder. Enzyme activities are therefore half of normal in all tissues in which they are expressed. Haem supply is maintained in the liver and other nonerythroid tissues by up-regulation of 5-aminolaevulinate synthase (ALAS1), the rate-controlling enzyme of the pathway, with a consequent increase in the substrate concentration of the affected enzyme. This compensatory change varies between tissues and between individuals. Thus, some individuals show no evidence of overproduction of haem precursors, while others have biochemically manifest disease with or without clinical symptoms.

Low clinical penetrance is a prominent feature of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Many of those who inherit the gene for one of these disorders remain asymptomatic throughout life. For all three disorders, the gene frequency in the general population is sufficiently high for rare ‘homozygous’ variants of acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria (3) to occur in individuals who are homozygotes or compound heterozygotes for disease-specific mutations and for the same person to have two separate types of porphyria. About 25% of patients with symptomatic acute porphyria have no family history of overt disease—another reflection of the high prevalence and low penetrance of these mutations; acute porphyria caused by de novo mutation is uncommon.

All three diseases show extensive allelic heterogeneity, most mutations being present in only one or a few families except in countries where founder effects occur (Human Gene Mutation Database (http://www.hgmd.org)). No clear genotype–phenotype correlation has been identified. About 3% of families with acute intermittent porphyria have hydroxymethylbilane synthase (HMBS, EC 2.5.1.61) gene mutations that impair expression of the ubiquitous isoform and therefore do not decrease activity in erythroid cells. All other mutations in the autosomal dominant acute porphyrias affect all tissues.

The symptomatology of acute attacks is principally due to neurological dysfunction affecting autonomic, motor, and central nervous system (CNS) neurons. The exact pathogenesis is not fully understood although ALA toxicity is currently the leading hypothesis (2).

Factors implicated in precipitating attacks either individually or in combination include: hormonal fluctuations (particularly menstrual), certain prescribed and illicit drugs, excessive alcohol intake, calorie restriction, systemic illness, and stress. Attacks are therefore more common in women than men, rare before puberty and unusual after the menopause. Although attacks can occur during pregnancy, they are unusual and complicate less than 10% of pregnancies in patients. A clear precipitant is not always identified (4).

Pain is virtually always the initial symptom of an acute attack (95–100%) and is usually abdominal, but can also affect the lower back, buttocks, and thighs (4). It is frequently associated with nausea, vomiting, and constipation. Abdominal pain can mimic an acute surgical abdomen, and may lead to inappropriate laparotomy. Diminishing pain in the absence of treatment can indicate worsening neuropathy. Hypertension and tachycardia due to autonomic dysfunction are common.

Hyponatraemia is common and can be severe, leading to seizures. Seizures may also be secondary to the porphyric encephalopathy. Despite inappropriate elevated urine sodium excretion patients are usually dehydrated and fluid restriction is not usually effective, implying renal sodium wasting rather than inappropriate antidiuretic hormone secretion.

A symmetrical, distal peripheral motor neuropathy can occur particularly where the attack is severe or treatment is delayed. This can progress rapidly to a complete motor paralysis mimicking Guillain–Barré syndrome. Other neurological signs include cranial nerve involvement and sensory changes in the same distribution as the motor neuropathy. CNS involvement may cause behavioural changes such as confusion, anxiety, hallucinations and paranoia. Chronic psychiatric illness is not a feature of the acute porphyrias. The urine may appear ‘port-wine red’ due to the high content of porphobilin, an auto-oxidation product of porphobilinogen, and some porphyrins.

A small minority of patients, usually female, have repeated acute attacks. These may be premenstrual and occur as frequently as every month. They are more likely to occur in acute intermittent porphyria and hereditary coproporphyria than in variegate porphyria. Chronic complications can include hypertension, impaired renal function, and hepatocellular carcinoma. Patients with active porphyria appear to be most at risk.

Patients should be advised about known precipitating factors and how they can reduce the risk of acute attacks. This should include written information as follows:

The diagnosis of an acute porphyria provides an opportunity to investigate family members and diagnose presymptomatic relatives and provide them with similar advice on reducing the risk of an acute attack. Presymptomatic diagnosis usually requires DNA analysis to identify mutations. Patients should be referred for genetic counselling and family studies arranged.

ADP is an exceedingly rare autosomal recessive porphyria that results from an almost complete deficiency of 5-aminolaevulinate dehydratase (ALAD) activity with consequent overproduction of ALA. Only six cases have been reported (7). Clinically it is indistinguishable from acute intermittent porphyria and requires the same treatment. Diagnosis depends on demonstration of markedly increased urinary ALA excretion without an increase in PBG, increased erythrocyte zinc-protoporphyrin concentration and very low erythrocyte ALAD activity. Similar abnormalities occur in lead poisoning and hereditary tyrosinaemia type I; the former can be excluded by measurement of blood lead and the latter by measurement of succinylacetone, a potent inhibitor of ALAD, in urine.

In the nonacute porphyrias, symptoms are produced by photosensitization of the skin by porphyrins to sunlight mainly in the UVA range (∼410 nm) that can pass through plate glass. The symptoms are caused by porphyrin-catalysed photodamage mediated mainly by singlet oxygen. The skin reacts to photodamage in two different ways which are determined by the physical properties and cellular location of the porphyrins.

Accumulation of protoporphyrin in erythropoietic protoporphyria (OMIM 177000) and X-linked dominant protoporphyria (XLDPP, OMIM 300752) causes acute painful photosensitivity without skin fragility, erosions, or bullae. Accumulation of less hydrophobic porphyrins in porphyria cutanea tarda, congenital erythropoietic porphyria (OMIM 236700) and other bullous porphyrias, causes fragility of sun-exposed skin with erosions and sub-epidermal bullae. Painful photosensitivity is usually absent in bullous porphyrias.

Porphyria cutanea tarda is the most common type of porphyria with an annual incidence in the UK of between 2 and 5 in 1 000 000.

The primary enzyme defect in all types of porphyria cutanea tarda is decreased activity of uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) in the liver. This leads to the overproduction of uroporphyrin, heptacarboxylate porphyrin, and other porphyrins derived from the intermediate substrates of the UROD reaction. Two main types of porphyria cutanea tarda have been identified. About 80% of patients have the sporadic (type I) in which UROD deficiency is restricted to the liver and the UROD gene is normal. Typically, there is no family history of porphyria cutanea tarda, but rare cases are clustered in families (type III). The rest have familial (type II) porphyria cutanea tarda, in which half-normal UROD activity in all tissues, caused by mutations in the UROD gene, is inherited in an autosomal dominant pattern with low penetrance.

A rare variant of familial porphyria cutanea tarda, hepatoerythropoietic porphyria, in which UROD mutations, some of which are also found in familial porphyria cutanea tarda, are present on both alleles, has been described (3). Porphyria cutanea tarda may also be caused by exposure to certain polyhalogenated aromatic hydrocarbons, notably hexachlorobenzene and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin.

In families with familial porphyria cutanea tarda, half-normal enzyme activity is not by itself sufficient to cause clinically overt disease. Further inactivation of UROD in the liver by a process that is also responsible for inactivation of hepatic UROD in sporadic porphyria cutanea tarda and in porphyria cutanea tarda caused by chemicals appears to be required. Current evidence suggests that hepatic UROD is inactivated by a uroporphomethene inhibitor that is produced by iron-dependent oxidation of a substrate of the UROD reaction, possibly mediated by hepatic CYP1A2 (8).

Porphyria cutanea tarda occurs at all ages in both sexes with onset usually during the fifth and sixth decades. Familial porphyria cutanea tarda tends to occur at a younger age; children with the clinical appearance of porphyria cutanea tarda usually have this form or, rarely, hepatoerythropoietic porphyria. Patients have increased fragility of sun-exposed skin; minor trauma results in erosions from shearing. Sun-exposure may lead to the formation of vesicles and bullae, particularly on the backs of the hands, forearm, and face, which crust over, take weeks to heal, and leave atrophic scars, milia, and patchy depigmentation. Hyperpigmentation, melanosis, and violaceous-brownish discolorations may also develop. Facial hypertrichosis is common and most noticeable in women. Alopecia may develop in sites of repeated trauma, or bullous formation. Patchy or diffuse sclerodermatous changes are less common and, unlike the other skin lesions, may affect areas of the trunk that are not exposed to sun.

The skin lesions are often the first sign of underlying liver cell damage. Overt liver disease is uncommon, but minor alterations in biochemical tests of liver function are present in more than 50% of patients. Needle biopsy of the liver reveals uroporphyrin deposition with hepatic siderosis in most patients, usually accompanied by minor histopathological abnormalities: mild fatty infiltration, focal necrosis of hepatocytes, and inflammation of portal tracts. Cirrhosis is present in less than 15% of patients, but carries a high risk of hepatocellular carcinoma.

This combination of skin lesions with liver damage is strongly associated with alcohol abuse, oestrogen usage, infection with hepatotropic viruses, particularly hepatitis C virus (HCV), and mutations in the hemochromatosis (HFE) gene (9). Porphyria cutanea tarda may also complicate HIV infection. Hepatic iron overload and at least one of the other associated factors are present in almost all patients. Between 8% and 79% of patients have antibodies to HCV, the prevalence being highest in the USA and southern Europe and lowest in Western Europe. About 20% of patients of northern European descent are homozygous for the Cys282Tyr mutation in the HFE gene, but few show clinical evidence of iron overload. Increased serum ferritin concentrations are common irrespective of the HFE genotype, suggesting that the origin of hepatic iron overload is multifactorial. Porphyria cutanea tarda may also occur in association with other disorders, notably chronic renal failure, systemic lupus erythematosus, and haematological malignancies. Rarely, primary hepatomas may secrete porphyrins and simulate porphyria cutanea tarda.

Porphyria cutanea tarda can be differentiated from variegate porphyria and other porphyrias in which porphyria cutanea tarda-like skin lesions may be the only symptom by demonstrating increased uroporphyrin I and III and heptacarboxylate porphyrin excretion in urine and increased faecal excretion of isocoproporphyrins and heptacarboxylate porphyrin (see Table 12.3.3.1). Plasma fluorescence scanning shows a porphyrin peak at 615–622 nm which distinguishes porphyria cutanea tarda from variegate porphyria but not from other bullous porphyrias.

Urinary and faecal porphyrin excretion is normal in pseudoporphyrias (porphyria cutanea tarda-like skin lesions in patients with renal failure on long-term dialysis or provoked by certain drugs or the use of sun beds). Familial and sporadic porphyria cutanea tarda can be identified by measurement of UROD activity in erythrocytes and by mutational analysis of the UROD gene. These investigations are not usually necessary for the management of porphyria cutanea tarda but are needed to distinguish unequivocally hepatoerythropoietic porphyria from familial porphyria cutanea tarda.

Avoidable risk factors (alcohol, oestrogens) and underlying disorders should be identified and withdrawn or managed appropriately (10). Exposure of the skin to sunlight can be diminished by suitable clothing and reflectant sunscreens that protect against UVA. Acute adverse effects have not been reported for drugs in porphyria cutanea tarda apart from chloroquine and its derivatives which, in antimalarial doses, produce a severe hepatotoxic reaction.

Two specific treatments can produce remission in most patients. Both are similarly effective, typically producing clinical and biochemical remission in 6–12 months.

Phlebotomy should be used for patients with genetic haemochromatosis. Both treatments may be monitored by plasma or urinary porphyrin measurement.

Congenital erythropoietic porphyria or Gunther’s disease is a severe bullous porphyria that usually presents in infancy (11, 12). It affects less than 1 per 1 000 000 of the UK population.

Congenital erythropoietic porphyria is an autosomal recessive disease. Patients are homoallelic or heteroallelic for mutations in the uroporphyrinogen synthase (UROS) gene, or, rarely, the GATA1 gene, which decrease UROS activity. Decreased UROS activity leads to massive overproduction of uroporphyrin-I and other isomer-I series of porphyrins, mainly from the bone marrow. Porphyrins accumulate in erythroid cells and are released into the plasma as these cells die. Porphyrin-laden erythroid cells have a shortened lifespan, leading to haemolytic anaemia and ineffective erythropoiesis. There is some correlation between genotype and severity of disease. In particular, homozygosity for the C73R mutation, which is common in patients of European ancestry, carries a poor prognosis.

Clinical severity varies from nonimmune hydrops fetalis to a mild porphyria cutanea tarda-like syndrome in young adults but the majority of patients present in infancy with red urine, skin lesions, and haemolytic anaemia. The skin lesions are similar in type to those of porphyria cutanea tarda but more persistent and severe. Progression to severe scarring with photomutilation is common. Haemolytic anaemia varies in severity but may require repeated transfusion; splenomegaly is common. Porphyrin accumulates in the bones being visible in the teeth as erythrodontia (brown pigmentation with red porphyrin fluorescence under ultraviolet light).

Expansion of hyperactive bone marrow may result in pathological fractures, vertebral compression or collapse, shortness of stature, and rarely osteolytic and sclerotic lesions in the skeleton. Rare cases of a congenital erythropoietic porphyria-like syndrome developing in adults with myeloid malignancies have been described.

Congenital erythropoietic porphyria is readily differentiated from all other porphyrias by the high concentration of series I isomer porphyrins in urine, faeces, and erythrocytes (see Table 12.3.3.1). Identification of UROS mutations may help to assess prognosis. Although the amniotic fluid from affected fetuses contains large amounts of porphyrin, prenatal diagnosis requires UROS assay or, preferably, mutational analysis for confirmation.

Protection against sunlight and prevention of skin infections are essential. In addition to reflectant sunscreen ointments, rigorous physical avoidance of UVA radiation is usually necessary. Various measures to decrease porphyrin accumulation have been used but none have been shown to be practical, effective or reliable in the long term (11). Haemolytic anaemia may require repeated transfusion and infusion of desferrioxamine or other procedures to prevent iron overload; splenectomy is rarely effective. Bone involvement may require bisphosphonate treatment and patients should monitored for vitamin D deficiency.

The only curative treatment is allogeneic haematopoietic stem cell transplantation. Gene therapy for those without donors or otherwise unsuitable for transplantation is under development.

Erythropoietic protoporphyria is the most common of a group of porphyrias, which also includes XLDPP and rare cases of protoporphyria secondary to myeloid malignancy. All are characterized by acute painful photosensitivity caused by accumulation of protoporphyrin IX in the skin without skin fragility, subepidermal bullae, or hypertrichosis. The prevalence of erythropoietic protoporphyria in western Europe is one per 75 000 to 130 000.

Partial deficiency of ferrochelatase (FECH, EC 4.99.1.1) activity leads to accumulation of protoporphyrin IX in skin, erythroid cells, liver, and other tissues. Although FECH is decreased in all tissues, almost all the excess protoporphyrin is formed during erythropoiesis. Erythropoietic protoporphyria is an autosomal recessive disorder. In more than 90% of families, patients are compound heterozygotes with a FECH mutation that markedly decreases or abolishes activity on one allele and a hypomorphic variant (FECH IVS3-48C) on the other (13), Together these reduce FECH activity to below the level of about 35% at which protoporphyrin starts to accumulate. The prevalence of EPP in a population is directly related to the frequency of the hypomorphic variant allele which ranges from 45% in Japan to less than 1% in West Africa. The frequency in Western Europe is 7–11%, which is sufficiently high for some families to show pseudominant inheritance. About 4% of EPP families have deleterious FECH mutations, other than the hypomorphic variant, on both alleles.

Symptoms usually start between birth and the age of 6 years, the median age of onset being 1 year, and both sexes are equally affected (14). They are exclusively photocutaneous, and occur in light-exposed areas, such as the face and hands. Within an hour of exposure to the sun, stinging or painful burning sensations occur in the skin, and may be followed several hours later by erythema and oedema. Petechiae, or more rarely, purpura, vesicles, and crusting may develop, and persist for several days after sun exposure. Some patients experience burning sensations in the absence of objective signs of cutaneous phototoxicity. Recurrent episodes lead to chronic skin changes; typically, shallow linear scars over the bridge of the nose and elsewhere on the face with thickened waxy skin, especially over the knuckles. Symptoms tend to be more severe during spring and summer and may improve during pregnancy.

Protoporphyrin is hepatotoxic. About 20% of patients have abnormal biochemical tests of liver function and 2–5% of patients develop liver failure (15). Erythropoietic protoporphyria may also increase the risk of cholelithiasis, the formation of gallstones being promoted by high concentrations of protoporphyrin in the bile. Erythropoiesis is impaired in all patients with a downward shift in haemoglobin concentration so that about 50% of women and 30% of men have a mild microcytic anaemia. Biochemical evidence of vitamin D deficiency is present in up to 50% of patients.

Erythrocyte protoporphyrin is markedly increased in erythrocytes and plasma and, in about 60% of patients, in faeces (see Table 12.3.3.1). Erythrocyte protoporphyrin is present as free protoporphyrin in contrast to other conditions, such as iron deficiency and lead poisoning, where zinc-protoporphyrin is increased. Neither FECH assay nor mutation analysis is essential for diagnosis but the latter is necessary to identify the few patients who have deleterious mutations on both alleles and who have a particularly high risk of developing severe liver disease.

About 2% of families with inherited acute painful photosensitivity and raised erythrocyte protoporphyrin concentrations have XLDPP (16). Accumulation of protoporphyrin is secondary to increased activity of the rate-controlling enzyme of erythroid haem synthesis, 5-aminolaevulinate synthase (ALAS2), which leads to formation of protoporphyrin in excess of the amount required for haemoglobinization. Increased activity is caused by gain-of function mutations in the ALAS2 gene on the X chromosome; ALAS2 mutations that decrease activity cause nonsyndromic X-linked sideroblastic anaemia. XLDPP is inherited in an X-linked pattern with expression of disease in males and most females. It carries a higher risk of severe liver disease than erythropoietic protoporphyria. Erythrocyte protoporphyrin concentrations tend to be higher than in erythropoietic protoporphyria and, in contrast to erythropoietic protoporphyria, 20–40% is present as zinc-protoporphyrin. FECH activity is normal. The diagnosis can be confirmed by mutational analysis of ALAS2.