INTRODUCTION

The porphyrias represent a heterogenous group of inherited errors of metabolism of the heme biosynthesis pathway. Both loss-of-function (LOF) and gain-of-function (GOF) mutations have been identified. Porphyrias may present with neurovisceral symptoms, cutaneous lesions or a combination of both (Table 1) [1–3].

Pseudoporphyrias are missing enzyme deficiencies but share photosensitivity and cutaneous blistering. They have been observed in association to certain drugs (e.g. diuretics) or food components such as chlorophyll. Porphyrins contain chlorophyll [4].

Cutaneous porphyrias, which are more common among adults, present either acute painful photosensitivity or skin fragility and blisters.

PORPHYRIA CUTANEA TARDA

Porphyria cutanea tarda (PCT) is the most common porphyria with an incidence of 40 cases per 1 Mio inhabitants [5]. The prevalence of Scotland has been estimated as 1 case per 13,000 people [6]. Three subtypes are known: Type I is the sporadic PCT accounting for 80% of all PCT cases. The enzyme uroporphyrinogen decarboxylase (UROD) activity is decreased in the liver by development of an UROD inhibitor due to iron overload and susceptibility factors [alcohol, hepatitis C, human deficiency virus (HIV) disease, estrogens, smoking]. It can also be an initial manifestation of hemochromatosis caused by mutations of the High FE2+ (HFE) gene encoding for human homeostatic iron regulator protein and resulting in an iron-overload [4,7].

PCT type II is an autosomal dominant disorder and constitutes 1/5 of PCT cases. UROD activity is reduced in all cells by 50% due to mutations. Susceptibility factors decrease UROD activity further and lead to typical symptoms (see below).

PCT type III has a normal UROD gene like type I but a possible genetic background since it occurs in several family members. This type is rare.

Vulnerable skin is an early symptom of PCT. Clinical findings include blisters and pain after sun-exposure (Fig. 1). Wounds heal slowly leaving scars and milia (Fig. 2). Post-inflammatory hyper- or hypopigmentation and hypertrichosis may develop. An uncommon manifestation is scleredema-like cutaneous fibrosis [8].

PCT-patients with active disease are characterized by marked porphyrinuria – mainly uroporphyrin and 7-carboxylate porphyrin [1–3]. Typical cutaneous findings in hemochromatosis consist of hyperpigmentation, hypertrichosis and resistant pruritus. Since both disorders are often reported together, these symptoms overlap to PCT [9].

Most important in treatment is avoidance of triggers such as certain medical drugs (sexual hormones etc. see: www.drugs-porphyria.org) or alcohol. Mainstay of treatment consists of sun-protection, low-dose oral chloroquine/hydroxychloroquine and phlebotomy. Chloroquine diphosphate is used at doses of 125 mg to 250 mg twice a week. The treatment improves liver enzyme activities, decreases serum iron markers, and transiently increases urinary porphyrin excretion in patients with HFE wild type or HFE heterozygous mutations. Eventually, urinary porphyrins become markedly reduced [10]. In a study with 89 PCT patients, low-dose chloroquine improved liver pathology in 45 patients (81%) after 12 months of treatment [11]. Alternatively, 100 to 200 mg hydroxychloroquine can be used twice weekly. This low-dose regimen is no concern for ocular toxicities [12].

Phlebotomy is essential in case of PCT with homozygotic hemochromatosis to reduce the iron-overload [10,11].

A meta-analysis compared oral antimalarials with phlebotomy for PCT. Relapse rates were lower for phlebotomy, but antimalarials are more comfortable for the patients and less time consuming [13].

In early hepatitis C-induced PCT antiviral treatment seems to be effective in some cases [14,15]. Glycyrrhizin is a triterpene saponin isolated in licorice extract. The substance has been shown to inhibit and/or neutralize proinflammatory mediators such as various interleukins, chemokines, inducible nitric oxidase, tumor necrosis factor-alfa or Toll-like receptors [16]. Recently, glycyrrhizin has been used successfully in PCT in a single patient [17].

Ledipasvir/sofosbuvir (Harvoni™, Gilead Sciences, Foster City, CA, USA) is a direct-acting antiviral used for treatment of chronic hepatitis C. The drug is under investigation for relief of PCT symptoms and lowering porphyrin levels in a phase 2 clinical trial (NCT 03118674) [18].

VARIEGATE PORPHYRIA AND HEREDITARY COPROPORPHYRIA

The prevalence of variegate porphyria (VP) is 1 in 240,000 people in Scotland [6]. Among patients with either VP or hereditary coproporphyria (HCP) extracutaneous manifestations are potentially life-threatening. Cutaneous findings and their treatment resemble PCT: bullae, blisters or vesicular lesions limited to sun-exposed skin, skin fragility, hypertrichosis, and hyperpigmentation of sun-exposed areas. Cutaneous manifestations change seasonally. They can be found in about 20% of VP patients, while they are uncommon among HCP patients [19,20].

Elimination of exogenous triggers and pain relief with parenteral opiates are essential in acute attacks. Intravenous glucose administration terminates the mild episode of acute porphyria, while intravenous panhematin is used for moderate to severe episodes. In contrast to hemin applied by intraperitoneal injections, panhematin represents a water-soluble hemin formulation that induces and activates hemeoxygenase-1 [21–23].

Liver transplantation is curative. It is an option for patients with a life-threatening acute porphyria attack and for patients with recurrent acute attacks, who are refractors to prophylactic therapy [24].

Oral supplementation with 50 mg vitamin E and 150 mg vitamin C for 6 months is capable to reduce oxidative stress in acute hepatic porphyria [25]. Vitamin C Inhibits the catalytic oxidation of CYP1LA2 and can reduce the hepatic accumulation of urinary porphyrins [26]. Both may be used as adjuvant treatment.

Givosiran (Givlaari™, Alnylam Pharmaceuticals, Boston, MA, USA) is an RNA therapy. It has been approved for the treatment of acute intermittend porphyrias in patients aged ≥ 12 years. The drug is administered subcutaneously at a dose of 2.5 mg/kg once per month. The drug prevents recurrent attacks in patients with severe acute intermittent porphyria and it is most effective when given early in the course of the disease. The experience in VP and HCP is limited [27].

CUTANEOUS ERYTHROPOIETIC PROTOPORPHYRIAS

In contrast to PCT, recessive porphyrias usually manifest in early childhood. They are much less common. Patients present with either chronic neurological symptoms with or without photosensitivity or severe cutaneous photosensitivity and chronic hemolysis [1–3].

Congenital erythropietic protoporphyria (CEP) is a very rare disease affecting less than 1 in 1 Mio inhabitants in Scotland [6]. Erythropoietic protoporphyria (EPP) has a prevalence of 3.15 cases per Mio inhabitants in Italy and 2.3 per 100,000 inhabitants in Scotland [6,26]. X-linked protoporphyria (XLP) accounts for about 2% to 10% of cases [28].

The genetics are different (Table 1) but the cutaneous symptoms are shared by CEP, EPP and XLP. They are characterized by severe photosensitivity to visible light resulting in acute burning sensations, edema, bullous or vesicular lesions and crusts of sun-exposed areas. The kinetic of cutaneous reaction after sun-exposure is not uniform among EPP patients and can vary from minute to hours. Teeth may show a reddish-brownish discoloration demonstrated under Wood light known as erythrodontia. Chronically sun-exposed skin develops a pale-yellow discoloration and probably persistent purpura. Later findings are lichenoid, eczematous and waxy skin on the nose and knuckles, perioral and depressed scars (Fig. 3) [29].

In CEP, repeated infections of cutaneous lesions can eventually result in progressive photo-mutilation of face and hands. Other symptoms include post-inflammatory hyperpigmentation, hypertrichosis, and scarring alopecia. Late-onset CEP is a variant with mild cutaneous involvement [30].

Seasonal palmar keratoderma is associated with autosomal recessive inheritance in EPP [31]. Photo-onycholysis presenting with transverse Mees lines is another finding especially seen in EPP [32].

Patients need a strict avoidance of exposure to visible light by sunglasses, wearing protective textiles, and filtered window and car glass. Good wound care and topical antibiotics are necessary to prevent soft tissue infections and osteolysis [30].

Treatment includes cold compresses, topical corticosteroids and oral antihistamines for acute cutaneous symptoms. Preventive measures are protective clothing or high-dose b-carotene, an antioxidant [33]. Oral zinc 200 mg 3 times a day reduced sun-sensitivity and pain in in 71% of patients [34]. Cimetidine has been shown to inhibit heme biosynthesis leading to symptomatic improvement in patients with PCT, acute intermittent porphyria (AIP), and CEP [35].

Afamelanotide (Scenesse™, Clinuvel Pharmaceuticals, Melbourne, Australia) is a melanocyte-stimulating hormone that increases the production of eumelanin. It is applied subcutaneously. The drug has been approved by the European Medicines Agency and in the US by the FDA in 2019 as the first effective medical treatment for EPP. Afamelanotide (Scenesse, Clinuvel Pharma) drug has been shown to increase tolerability of sunlight exposure and to improve quality of life in EPP patients [36]. It has also been used successfully in XLP off label [30].

Bitopertin is an oral selective glycine transport inhibitor undergoing a phase 2 clinical trial for the treatment of EPP (NCT05308472) [37]. Dersimelagon is an orally active small-molecule selective melanocortin-1 receptor agonist that increases the production of eumelanin. In a phase II trial, it significantly increased the mean daily time to the first prodromal symptom associated with sunlight exposure at dosages of 100 mg/or 300 mg/d [38]. There are limited data for XLP [37].

Another treatment option for EPP is narrow-band ultraviolet B (UVB) phototherapy (311–313 nm). It seems to work by epidermal thickening and induction of melanin [39].

In our experience, oral Polypodium leucotomos (PL) extract can be helpful to decrease sun-sensitivity in EPP. PL contains phenolic compounds with antioxidant activity. Furthermore, it prevents direct DNA damage and supports DNA repair, increases the expression of tumor suppressor p53, and inhibits UV-induced COX-2 enzyme [40]. Efficacy has been demonstrated in several photodermatoses, but a controlled study in porphyria patients is missing.

PATIENT PERMISSION

Patient permission for publication was obtained.

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