Porphyria cutanea tarda

doi:10.1016/j.bpg.2010.07.002

Best Practice & Research Clinical Gastroenterology

Volume 24, Issue 5, October 2010, Pages 735-745

Best Practice & Research Clinical Gastroenterology

https://doi.org/10.1016/j.bpg.201007002 Get rights and content

Porphyria cutanea tarda (PCT) is the most frequent type of porphyria worldwide and results from a catalytic deficiency of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in heme biosynthesis. At least two different types of PCT are currently distinguished: an acquired variant, also referred to as sporadic or type I PCT, in which the enzymatic deficiency is limited to the liver; and an autosomal dominantly inherited form, also known as familial or type II PCT, in which there is a decrease of enzymatic activity in all tissues. The cutaneous findings include increased photosensitivity , skin fragility , blistering, erosions, crusts, and miliae on the sun-exposed areas of the body. Additionally, hyperpigmentation , hypertrichosis, sclerodermoid plaques, and scarring alopecia might be observed. In patients with type I PCT, there is a significant association with liver disease that can be triggered by genetic and environmental factors , such as alcohol abuse, iron overload , haemochromatosis, polychlorinated hydrocarbons, and hepatitis C virus infection. The diagnosis of PCT can be made based on the skin symptoms, a characteristic urinary porphyrin excretion profile, and the detection of isocoproporphyrin in the feces. In red blood cells of individuals with type II PCT, UROD activity is decreased by approximately 50% due to heterozygous mutations in the UROD gene. Here we provide an update on clinical, diagnostic and therapeutic aspects of PCT, a disorder that affects both skin and liver.

Introduction

The porphyrias are a clinically and genetically heterogeneous group of metabolic diseases, which arise from a predominantly inherited dysfunction of specific enzymes in the heme biosynthetic pathway [1], [2]. Porphyria cutanea tarda (PCT; OMIM 176100) was described for the first time by Waldenström in 1937 [3]. It is the only type of porphyria that is not exclusively inherited as a monogenetic trait since an acquired and a hereditary form can be distinguished. The disease is due to a decrease in the activity of uroporphyrinogen decarboxylase (UROD; E.C.4.1.1.37), the fifth enzyme in heme biosynthesis that catalyzes the conversion of uroporphyrinogen to coproporphyrinogen (Fig. 1). As a consequence, impaired UROD activity leads to an accumulation of uroporphyrin and other highly carboxylated porphyrins in various organs, including the skin and liver [1], [2], [4].

Section snippets

Epidemiology

PCT is the most common type of porphyria worldwide. It has an estimated prevalence of 1:10,000 and the sex ratio is approximately equal [5]. The disease usually becomes clinically manifest in middle-aged individuals but can also develop earlier [1], [2], [4]. Prior to the widespread use of oral contraceptives, PCT was seen predominantly in males. The ingestion of oestrogens in oral contraceptives or hormone supplements, however, could explain the rising incidence of PCT in females [2]. In line

Classification

PCT belongs to the group of the cutaneous and chronic hepatic porphyrias (Table 1, Table 2). At least two clinically similar forms of the disease can currently be distinguished, both associated with decreased UROD activity: (i) acquired PCT, also referred to as sporadic or type I PCT; and (ii) hereditary PCT, also known as familial or type II PCT [1], [2], [4].

In type I PCT, UROD deficiency is restricted to the liver only. By contrast, type II PCT is an autosomal dominant disorder with

Aetiology and pathogenesis

Clinically overt PCT is due to hepatic accumulation of uroporphyrin, the oxidized substrate of UROD, which circulates in plasma and is finally excreted in the urine. Uroporphyrin is the agent responsible for the photochemical skin reaction on the sun-exposed areas of affected individuals. For clinical symptoms to manifest, the residual UROD activity must be ∼25% of the normal level [2]. Recent studies have shown that this substantial decrease in enzyme activity is caused by oxidation of

Genetics

The human UROD gene has been mapped to chromosomal region 1p34 and spans approximately 3.6 kb [12]. The gene contains a single promoter and 10 exons, which encode a polypeptide of 367 amino acids with a molecular weight of approximately 41 kD [13]. The active human UROD protein is a homodimer that belongs to the (α/β)₈ barrel family [14]. To date, more than 100 mutations in the UROD gene have been identified in patients with type II PCT or HEP, reflecting the high degree of molecular

Clinic – the skin

Clinically, type I and type II PCT are indistinguishable. Symptoms exclusively manifest on the sun-exposed areas of the body and predominantly comprise cuaneous photosensitivity, increased skin fragility, vesicles, bullae, erosions and crusts, which occur predominantly in areas subject to repeated trauma, e.g. the back of the hands (Fig. 2a). As the lesions resolve, hyper- or hypopigmented scars (Fig. 2b) and milia (Fig. 2c) can develop. Hypertrichosis of the non-virilizing type is more

Differential diagnosis

Classic PCT must be distinguished in the first place from other types of cutaneous porphyrias that manifest with blistering. These include variegate porphyria, hereditary coproporphyria, mild variants of HEP and congenital erythropoietic porphyria, and pseudoporphyria cutanea tarda [2], [4]. The latter has a well-established association with the ingestion of specific drugs, including non-steroidal anti-inflammatory drugs (e.g. naproxen, nabumetone, and ketoprofen), furosemide, antibiotics (e.g.

Associations and complications – the liver

A variety of triggering factors has been reported to precipitate the clinical manifestations of PCT, among them alcohol, iron, inheritance of specific mutations in the HFE gene which underlie classic haemochromatosis, oestrogens, polychlorinated hydrocarbons, and hepatitis C virus infection [1], [2], [4].

Laboratory diagnostics

Historically, a presumptive clinical diagnosis of PCT was followed by an examination of the patient’s urine, both under Wood’s lamp illumination in the dark and after exposure to natural light. Due to the excessive excretion of porphyrins, the urine of PCT patients turns red to brown after several hours of exposure to natural light and it has a pink to red fluorescence when exposed to a UVA light source. However, these historic bedside observations are neither sensitive nor specific diagnostic

Therapy

The avoidance of UV light exposure, sun-protective clothing, and regular application of broad-spectrum sunscreens is crucial, both prophylactically and therapeutically. However, the wavelengths inducing porphyrins are in the range of 400–410 nm range and, thus, most sunscreens are limited in their therapeutic effectiveness, with the exception of titanium dioxide and zinc oxide. Beside the avoidance of well-known triggering factors as, e.g. alcohol and oestrogens, there are two main therapeutic

Conclusions

PCT has to be considered as a multi-factorial disease in which visible clinical symptoms can manifest on the skin and characteristic metabolic and histopathological alterations are observed in the liver. The complex interplay of both genetic and environmental factors confers susceptibility to iron overload and subsequent hepatic disease.

Practice points

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Most frequently occurring type of porphyria worldwide.
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At least three different forms of the disease must be differentiated.
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The sporadic variant

Acknowledgements

JF is a board member of the European Porphyria Initiative (EPI) and is, in part, supported by grant number A04155HS, GIS-Institut des Maladies rares: Network on rare diseases to the EPI, a grant from the European Union to the European Porphyria Network (EPNET), Program of Community Action in the Field of Public Health, project no. 2006107, and a grant from the Research Committee of the Heinrich-Heine University Düsseldorf, Germany, project no. 9772425.

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