The porphyrias: clinical presentation, diagnosis and treatment

ARTICLE

Auteur(s) : P Poblete-Gutiérrez¹, T Wiederholt^2,3, HF Merk², J Frank^1,3

¹Department of Dermatology, University Hospital Maastricht, The Netherlands
²Department of Dermatology, University Hospital of the RWTH Aachen, Germany
³Porphyria Center, University Hospital of the RWTH Aachen, Germany

accepté le 29 Septembre 2005

Etiology and mode of inheritance

Almost all types of porphyria show a Mendelian inheritance pattern and result from mutations in the genes outlined in (Table 1), respectively. Porphyria cutanea tarda (PCT), however, occupies an exceptional position among the different types of porphyrias since it is the only porphyria in which an acquired form (PCT type I or sporadic PCT) has to be distinguished from an inherited variant (PCT type II or hereditary PCT) [1, 2].
Table 1 Classification of the acute and non-acute porphyrias highlighting important aspects of each variant

Classification

Non-acute porphyrias

Porphyria cutanea tarda

According to the major site of expression of URO-D, at least two types of PCT can be distinguished: a sporadic (acquired) variant, designated type I PCT, in which the enzymatic deficiency is exclusively expressed in the liver and a familial (hereditary) variant, designated type II PCT, in which the catalytic enzymatic defect is detected in all tissues [1, 2]. Currently, the ratio between type I and type II PCT is estimated to be approximately 3:1 to 4:1 [1-3] although a recent report indicated that, in some countries, the frequency of type II PCT might be much higher than previously estimated [4].

Of note, not every PCT patient with a positive family history will necessarily be suffering from type II PCT. Recently, Elder reported several families in which more than one individual was unequivocally affected with PCT. While these individuals revealed the typical clinical and biochemical characteristics of overt disease, normal URO-D activities were measured in red blood cells. This latter variant of the disease has been designated as type III PCT and, in sum, there is increasing evidence that some facets of the etiology of PCT are not completely elucidated yet [5].

The diagnosis of PCT is made on the basis of cutaneous manifestations, a characteristic urinary porphyrin excretion profile, and, in some laboratories, by measuring URO-D activities in red blood cells. The skin findings include increased photosensitivity due to photosensitization by porphyrins and skin fragility as well as blistering, erosions, crusts, and miliae on the sun-exposed areas of the body (figures 2A, 2B and 2C). Additionally, hyperpigmentation, hypertrichosis, sclerodermoid plaques (figure 2D), and scarring alopecia can be observed.

Histopathological examination commonly reveals subepidermal, cell-poor blisters with a characteristic festooning of dermal papillae that is most likely due to the deposition of PAS-positive glycoproteins in and around the wall of vessels localized in the upper dermis. Upon direct immunofluorescence, immunoglobulins (mainly IgG; less common IgM), complement, and fibrinogen can be detected at the dermal-epidermal junction and around blood vessels of the papillary dermis [6]. Regardless of the aforementioned findings, we would like to emphasize that we consider it unnecessary, and even contra-indicated, to take a skin biopsy if one of the cutaneous porphyrias is suspected. First, simple non-invasive biochemical laboratory techniques can easily prove or exclude the presumptive diagnosis of porphyria and, second, external trauma (such as a biopsy or excision) inevitably constitutes an unnecessary risk for delayed and/or dysfunctional wound healing.

Biochemically, an increased excretion of uroporphyrin (type I isomers > type III isomers), 7-carboxyl porphyrins (type III isomers > type I isomers), and coproporphyrin in the urine and isocoproporphyrin excretion in the feces can be found. Enzymatically, URO-D activity is decreased by approximately fifty percent in red blood cells of individuals suffering from type II PCT.

A wide range of triggering factors has been reported to precipitate the clinical manifestation of PCT, among them alcohol, estrogens, polychlorinated hydrocarbons, hemodialysis in patients with renal failure, iron, inheritance of specific mutations (C282Y and H63D) in the HFE gene underlying classic hemochromatosis, and viral infections such as hepatitis C and HIV [7, 8]. Interestingly, homozygosity for HFE gene mutation C282Y was found to be associated with an earlier onset of cutaneous lesions in both sporadic and familial PCT, the effect being more marked in familial PCT [7]. Further, PCT patients seem to have a higher risk for the development of hepatocellular carcinoma [1, 8].

Erythropoietic protoporphyria

Clinically, EPP is characterized by cutaneous photosensitivity with onset early in life. The acute episodes of cutaneous photosensitivity include burning, stinging, and pruritus in light-exposed skin, particularly of the nose, cheeks, and dorsal aspects of the hands. These are followed by erythema, edema, urticarial lesions, erosions, and wax-like scarring, particularly on the nose (figures 3A and 3B). Skin symptoms can occur within minutes of sun exposure, often starting early in spring time, continuing through the summer, and diminishing in fall and winter [1, 9].

Histological examination in EPP reveals vacuolization of epidermal cells. Further, intercellular edema as well as vacuolization and lysis of endothelial cells of superficial dermal blood vessels can be seen. If disease activity progresses, deposition of PAS-positive hyaline material leads to thickening and degeneration of capillary basement membranes, sometimes resembling the amorphous protein depositions seen in lipoid proteinosis [10]. Still, we consider it unnecessary to perform a skin biopsy if EPP is suspected.

Biochemically, EPP is characterized by an increase of free protoporphyrin in erythrocytes, plasma, feces and other tissues, such as the liver (Table 2)(Table 3)(Table 4) [1, 9, 10].

The most important concern in EPP patients is the development of cholestasis with accumulation of protoporphyrin in hepatobiliary structures and progressive cellular damage resulting in severe liver disease [11, 12]. Although rarely occurring, progressive liver failure is now a well recognized complication in EPP. Still, the pathogenesis of PP-induced hepatic disease is poorly understood and is rarely diagnosed prior to advanced liver damage.

Recently, the genetic mechanisms in EPP that lead to phenotypic disease with cutaneous photosensitivity have been characterized. It is now well understood that only those individuals will develop skin symptoms who not only inherit a heterozygous FC mutation on one parental allele in cis but also an intronic FC polymorphism on the other parental allele in trans [13]. Although these molecular mechanisms explain the development of increased photosensitivity in EPP the molecular mechanisms underlying the phenotype with severe liver injury are still not well understood. Thus, other as yet unidentified factors may contribute to the pathogenesis and development of severe liver failure in EPP [14].
Table 2 Biochemical characteristics of the acute porphyrias in the urine

Congenital erythropoietic porphyria

CEP manifests shortly after birth with severe cutaneous photosensitivity that, as the disease progresses, can lead to blistering, erosions, excoriations, ulceration, and scarring. On the hands, scarring can lead to deformation and movement impairment. In the face, loss of eyebrows and eye-lashes as well as severe mutilation involving cartilage structures, e.g. the nose, is frequently observed (figure 4A). In addition to the cutaneous findings, erythrodontia (figure 4B) and a variable degree of hematological involvement ranging from mild forms of hemolytic anemia to intrauterine hydrops fetalis as well as spenomegaly can be found.

Biochemically, an increased excretion of uroporphyrin I and coproporphyrin I in the urine and elevated levels of coproporphyrin I in the stool can be found. Upon exposure to sun light, the accumulation of uroporphyrin I and coproporphyrin I in the bone marrow, skin, and several other tissues exerts dramatic cytotoxic effects underlying the cutaneous symptoms.

The diagnosis of CEP is made on the basis of the typical clinical manifestations, a characteristic porphyrin excretion profile, and, in some laboratories, by measuring uroporphyrinogen III synthase activity in red blood cells [17].

Hepatoerythropoietic porphyria

The disease is rare and has only been reported in the United States of America and Europe. Clinically, HEP usually manifests in early childhood, with dark urine in the diapers being the most frequently observed first sign. Subsequently, severe cutaneous photosensitivity develops that includes blistering, pruritus, hypertrichosis, hyperpigmentation, and scleroderma-like scarring. If the clinical course is severe, the disease closely resembles CEP.

The diagnosis is based on the excretion of elevated urinary uroporphyrin, hepta-carboxylated porphyrins, elevated fecal coproporphyrin, and isocoproporphyrin as well as increased levels of zinc-chelated protoporphyrin in erythrocytes [1].

Differential diagnosis of the non-acute porphyrias

In EPP, the most important differential diagnoses are dermatitis solaris, solar urticaria, polymorphous light eruption, and lipoid proteinosis [1, 10, 19].

CEP has to be differentiated from HEP and the rare homozygous variants of variegate porphyria; mild variants can sometimes mimic PCT. Likewise, the most important differential diagnoses of HEP are CEP and severe forms of PCT. Normally, both CEP and HEP can not be easily confused with skin diseases other than the porphyrias [1].

Acute porphyrias

Patients suffering from one of the acute porphyrias might reveal a broad range of often unspecific clinical symptoms, including long-lasting colicky abdominal pain, nausea and vomiting, diarrhea, tachycardia, hypertension, seizures, muscle weakness, paraplegia and tetraplegia as well as a variety of other neurological and psychiatric signs. This broad spectrum of often unspecific clinical symptoms mimicking other diseases demands all diagnostic abilities of the attending physician particularly since the porphyrias are rare disorders and, therefore, rarely considered as differential diagnosis [20, 22].

Acute porphyric attacks can be precipitated by a variety of factors, including porphyrinogenic drugs, alcohol, hormonal changes, recurrent or chronic infection, and reduced caloric intake due to fasting or diets [1, 20, 23].

Apart from the aforementioned neurological findings, individuals suffering from VP or HCP can also present with cutaneous symptoms on the sun-exposed areas of the skin, including increased photosensitivity, abnormal skin vulnerability, blistering, erosions, scars, and post-inflammatory hyperpigmentation. Thus, VP and HCP are also referred to as neurocutaneous porphyrias. By contrast, however, AIP and ALA-D deficiency porphyria do not manifest with cutaneous symptoms [1].

In an effort to set forth standards in diagnosis and management of the acute porphyrias and to provide information and guidelines for patients as well as physicians, a European consortium of expert porphyria specialists from different European porphyria centers founded the European Porphyria Foundation (EPI) in the year 2000. On the EPI web-page (http://www.porphyria-europe.org), which is constantly up-dated, important information is available, particularly if dermatologists and general practitioners are seeking to contact the nearest porphyria center in their country to discuss specific problems encountered in the management of their patients. Furthermore, a comprehensive overview on safe and potentially unsafe drugs that can be administered or should be avoided in patients suffering from an acute porphyria can be found. Motivated by the European expert group, several American porphyria specialists have recently likewise gathered together in a 24-hour meeting and, as a result of their meeting, published recommendations for the diagnosis and treatment of the acute porphyrias [24].

Acute intermittent porphyria

In AIP, no cutaneous symptoms occur. Clinically, the disease usually manifests after puberty with acute porphyric attacks, which comprise a variety of neurological and/or psychiatric symptoms that can mimic many other disorders [22]. Signs and symptoms include abdominal pain, mental disturbances, constipation, diffuse pain, vomiting, muscle weakness, hypertension, tachycardia, fever, convulsions, sensory loss, and respiratory paralysis that can lead to coma and death [1, 25]. These acute attacks might be precipitated by porphyrinogenic drugs, alcohol ingestion, reduced caloric intake due to fasting or dieting, infection, and hormones [23].

Biochemically, elevated urinary levels of the porphyrin precursors ALA and porphobilinogen (PBG) can be found during an acute attack, ALA values ranging from five to twenty-fold the normal levels, and PBG being increased as high as fifty to hundred-fold the normal range.

Variegate porphyria

The clinical picture of VP is variable, since cutaneous and neuropsychiatric symptoms can occur separately or together in affected individuals [1, 26]. Skin findings include increased skin fragility and photosensitivity due to photosensitization by porphyrins. Clinically, these skin findings can not be differentiated from those observed in PCT (figure 5). Likewise, the acute attacks observed in VP totally resemble the clinical symptoms encountered in AIP [20].

The diagnosis is based on elevated urinary levels of ALA and PBG during acute attacks as encountered in AIP. In phases of remission, however, ALA and PBG in the urine may be within normal range. Therefore, additional biochemical analyses of porphyrins in the feces are mandatory to establish the diagnosis of VP. In the stool, elevated levels of protoporphyrin and coproporphyrin can be found, protoporphyrin concentrations usually being higher than those of coproporphyrin. The latter findings can also be observed in the phase of remission in between attacks [1, 26].

Hereditary coproporphyria

The clinical symptoms and biochemical findings are similar to those described in detail for VP. Biochemically, however, the stool porphyrin profile commonly reveals coproporphyrin concentrations higher than those measured for protoporphyrin [28].

δ-Aminolevulinic acid dehydratase deficiency porphyria

Differential diagnosis of the acute porphyrias

Some of the difficulties and challenges in diagnosis, prevention, and treatment of the porphyrias will now be presented.

Diagnostics

• – an anamnesis including the frequency of clinical symptoms and the family history as well as a thorough physical examination, particularly with regard to skin symptoms on the sun-exposed sites of the body;
• – a biochemical measurement of porphyrins and porphyrin precursors in urine and feces (tables 2 and 3). If the presumptive diagnosis is EPP, the amount of protoporphyrin in erythrocytes has to be determined, too;
• – determination of specific enzymatic activities in fibroblasts or lymphocytes, which is usually only possible in specialized laboratories upon specific indication;
• – mutation analysis using molecular genetic techniques including DNA isolation from peripheral blood followed by polymerase chain reaction (PCR) and automated DNA sequencing, likewise only possible in specialized laboratories.

Difficulties in obtaining a correct diagnosis are primarily due to the fact that the different types of porphyrias often reveal overlapping findings with regard to clinical and/or biochemical features (for diagnostic algorithm see ( figure 6). This is especially true for VP where cutaneous lesions appear similar to those observed in PCT and HCP as well as neurovisceral symptoms similar to those being observed in AIP, HCP, and ALA-D deficiency porphyria. These symptoms do not necessarily occur universally in every patient, but some can often be found together in affected individuals [1, 30].

Concerning biochemical analyses, drastically elevated urinary levels of the porphyrin precursors ALA and PBG can be found during an acute attack. However, asymptomatic mutation carriers are rarely detected by measurement of urinary fecal porphyrin precursors which often display a high variability and can be just slightly elevated or normal in the phase between acute attacks. Thus, these methods, as well as the measurement of enzymatic activities in fibroblasts or lymphocytes, are somewhat imprecise, since a certain overlap between the values measured in patients, clinically unaffected gene carriers (so called “silent” carriers), and normal control individuals could be found, and the results of the analyses were not always conclusive [31].

Therefore, the establishment of molecular genetic laboratory techniques for the identification of underlying mutations on the basis of direct DNA analysis has been an important contribution to the traditional diagnostic procedures employed in the different types of porphyrias [1, 31, 32]. The routine application of such diagnostic techniques are not only important for clinicians in obtaining the most precise confirmation of a presumptive diagnosis but has also enabled molecular biologists and geneticists to learn more about genes and their function as well as to provide affected individuals and their family members with genetic counseling [31, 32]. In conclusion, only the combination of all four aforementioned diagnostic steps will lead to the most accurate diagnosis.

Prevention and therapy

Treatment of the non-acute porphyrias

In PCT, triggering factors as e.g. alcohol ingestion and estrogen therapy should be stopped. Successful treatment can be achieved by repeated phlebotomy (venesection) of approximately 500 mL blood every two weeks. Some authors recommend weekly venesections of 300 mL blood. Phlebotomy usually leads to resolution of skin fragility and blistering within 2-4 months. However, normalization of urinary porphyrin concentrations will usually take longer (about 12 months). Chloroquine is thought to work by accelerating the secretion of porphyrins and may also inhibit porphyrin synthesis, thereby reducing photosensitivity. The standard therapy consists of 125 mg chloroquine twice weekly and complete remission can be expected within 6-9 months (table 4). Chloroquine and phlebotomy can be used in combination to induce faster remission [1, 33]. Of note, a recent report indicates that the genetic background of PCT patients with regard to the presence of HFE gene mutations plays a critical role in the outcome of chloroquine treatment. Whereas heterozygosity for mutation C282Y and compound heterozygosity of HFE mutations did not compromise the therapeutic response to chloroquine, PCT patients homozygous for C282Y seem to retain high serum iron, ferritin, and transferrin saturation and, most importantly, failed to respond to chloroquine therapy [34].

In EPP, beta-carotene has proven to minimize burning, stinging and photosensitivity reactions in approximately 60% of the patients. Although it has no effect on protoporphyrin levels in erythrocytes it reduces photosensitivity through quenching the formation of free radicals during the cutaneous photoreaction. Beta-carotene should be administered preferably from February to October with a pause between November and January. The doses administered range from 30-90 mg/day in children and 60-180 mg/day in adults with desirable maximum plasma levels of approximately 600-800 μg/dL. Single reports exist on therapeutic attempts with cysteine or narrow-band UVB-phototherapy but the usefulness of these treatment modalities has so far not been convincingly demonstrated [1, 10, 30].

In CEP, surveillance of anemia and skin infections is crucial. Frequent blood transfusions can suppress erythropoiesis thereby decreasing porphyrin production and photosensitivity. Concomittant administration of deferoxamine can reduce the resulting iron-overload. If successful, bone marrow transplantation leads to marked reduction of porphyrin levels and photosensitivity and has been reported to be curative CEP [1, 15, 30].

Apart from thorough photoprotection, no specific treatment options are currently available for HEP. An overview on current therapeutic strategies in the non-acute porphyrias is given in table 4.

Treatment of the acute porphyrias

Therapy of the cutaneous symptoms

Therapy of an acute porphyric attack

Therapy of an acute porphyric attack should comprise three consecutive measures.

• 1. The administration of suspicious porphyrinogenic drugs should be ceased immediately and, if necessary, patients should be admitted to an intensive care unit.
• 2. Neurological symptoms like abdominal pain and vomiting should be treated symptomatically. However, one should keep in mind that any administration of drugs in a patient with acute porphyria certainly carries the risk of triggering or prolonging an acute attack. Thus, several guidelines have been previously published suggesting so called “safe” and “unsafe” drugs to be used or avoided in the treatment of an acute porphyric attack [1, 23]. In addition to guidelines previously published in medical journals and textbooks, extensive information about drugs and their safety in patients with acute porphyria can also be found on the web site of the EPI at http://www.porphyria-europe.org.
• 3. The most important therapeutic step is the early intravenous administration of heme arginate (Normosang^®). Since the early 1970s, acute attacks have been treated with hematin preparations [36]. These hematin preparations had the disadvantage of being very unstable. Further, thrombophlebitis as an adverse effect was reported in a high percentage of patients treated [37, 38].

Heme arginate is composed of human hemin and L-arginine as an additive to increase the solubility and stability of the product. In contrast to the older hematin preparations, heme arginate does not induce any significant changes in coagulation and fibrinolysis and the frequency of thrombophlebitis as well as the overall rate of side effects is markedly reduced [38, 39]. Heme arginate is administered as a short-time (15-20 minutes) infusion in a dosage of 3 mg/kg bodyweight/day over a period of four days. In exceptional cases, heme arginate administration can be prolonged up to seven days if the acute attack does not cease. However, it is not recommended to use heme arginate for more than seven days. In Europe, heme arginate (Normosang^®) is available from Orphan Europe, www.orphan-europe.com, in cases of emergency, usually even within 24 hours, if requested. If heme arginate is not immediately available, the time span can be bridged by initiating adjuvant intravenous glucose infusions.

An overview on current therapeutic strategies in the acute porphyrias is given in table 4.

Conclusions and future prospects

The biggest challenge with regard to biochemical analyses is the identification of clinically asymptomatic mutation carriers, in particular children before puberty. These so called “silent carriers” are only rarely detected by the traditional measurement of urinary and/or fecal porphyrins and porphyrin precursors which often display a high variability. These biochemical methods, as well as the measurement of enzymatic activities in fibroblasts or lymphocytes, are somewhat imprecise, since a certain overlap between the values measured in patients, clinically unaffected silent carriers, and normal control individuals was reported to occur. Thus, these analyses were not always conclusive [31, 40].

However, the recent progress in the field of molecular genetics and the accomplishments of the Human Genome Project have provided clinicians and medical researchers with permanently advancing molecular biological techniques and novel insights into the complexity of genetic disorders. These modern genetic techniques nowadays enable us to transfer our clinical observations and biochemical data to the laboratory bench for diagnostic complementation by PCR based DNA testing. Understanding the molecular basis of the porphyrias is essential for genetic engineering and the development of gene therapy strategies that will not only serve those suffering from porphyria but eventually also be of benefit for patients with different genetic disorders. The advancing progress in basic science has made an invaluable contribution to the rapid translation of discoveries made today in the laboratory into new diagnostics and therapeutics in the near future.

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