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A 56-year-old male with porphyria cutanea tarda

Jorge, Emily, MSN, DCNP, FNP-BC

doi: 10.1097/01.NPR.0000554122.31123.78
Department: Dermatology Dilemmas
Free

Emily Jorge is a dermatology certified NP of the Skin Cancer & Cosmetic Dermatology Centers, Dalton, Ga.

The author has disclosed no financial relationships related to this article.

Mr. R, a 56-year-old male, was referred from family practice to the dermatology clinic complaining of itching and burning on sun-exposed areas of his skin for several months. With further examination, he admitted to moderate photosensitivity and exhibited skin fragility, erosions, crusts, vesicles, and bullae in sun-exposed sites including the hands, ears, posterior neck, and distal posterior forearms for several weeks (see Patient with PCT pretreatment). No mucosal lesions were present, and his medical history included consuming 12 to 15 beers per day and smoking one pack of cigarettes per day for 40 years. His family history was unremarkable.

Four 4 mm punch biopsies were performed, ruling out pseudoporphyria, porphyria cutanea tarda (PCT), and epidermolysis bullosa acquisita (EBA); the biopsies were then sent for direct immunofluorescence (DIF) and histology. DIF results supported the diagnosis of PCT demonstrating vascular staining with immunoglobulin G (IgG) in the superficial dermis and prominent fibrin staining along the dermal-epidermal junction. Festooning of the dermal papillae within the vesicle was observed along with caterpillar bodies in the roof of the vesicle. Subsequent serum and urine porphyria values confirmed the diagnosis (see Plasma porphyrin profile and Urine porphyrin profile).

Other pertinent lab indices included an elevated aspartate aminotransferase (AST) of 87 units/L (U/L), an alanine aminotransferase (ALT) of 61 U/L, hemoglobin (Hgb) of 15.6 g/dL, red blood cell count of 4.49 x 106/mcL, mean corpuscular volume of 98.9, glomerular filtration rate greater than 60 mL/min/1.73 m2, creatinine 0.7 mg/dL, blood urea nitrogen 9 mg/dL, iron 53 mcg/dL, and an unremarkable hepatitis panel.

Fecal samples were deferred because of the patient's elevated porphyrins in the plasma and urine along with clinical findings. I.M. triamcinolone with topical corticosteroid ointment was initiated to ameliorate symptoms for temporary relief (see Patient with PCT posttreatment). Instructions to use sun protection clothing and sunscreen were heeded. Phlebotomy every 4 weeks was initiated to monitor Hgb levels and serum iron. The patient agreed to actively engage in alcohol cessation.

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Etiopathogenesis

Occurring in all races and both genders, the porphyria disorders are rare, with a prevalence of 1 in 10,000 to 1 in 100,000 individuals. PCT is the most common porphyria disorder out of a group of nine disorders, resulting in a defect of the fifth enzyme in heme biosynthesis.1 First named by Dr. Jan G. Waldenström in 1937, classification can be divided into erythropoietic and hepatic forms; however, from the perspective of a dermatology clinician, porphyria disorders can be categorized into cutaneous and noncutaneous forms (see Classification of porphyria disorders into cutaneous and noncutaneous forms).2

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A variety of triggers have been elucidated to precipitate PCT, some of which include alcohol use (87%), smoking (81%), estrogens (66% in females), iron overload secondary to hemochromatosis (53%), viral infections such as hepatitis C (69%), and HIV (13%)1. Halogenated chemicals and medications have also been implicated in the etiology of PCT. Presently, no single element can explain the photosensitivity elicited by porphyrins in the presence of UV radiation.1 Interactions between reactive oxygen species, components of the complement system and matrix metalloproteinases are thought to contribute to cutaneous lesions.2

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Alcohol use increases iron stores even with moderate consumption and is known to decrease hepcidin levels, thereby elevating iron absorption from the intestine and increasing oxidative stress in hepatocytes.1,3 Body iron stores impact liver function indices such as gamma-glutamyl transferase, AST, and ALT.3 Iron also promotes uroporphyrin overproduction in multiple ways by increasing the oxidation rate of uroporphyrinogen and heptacarboxylporphyrinogen into their respective porphyrins; it increases the inhibitor of uroporphyrinogen decarboxylase (UROD), thus indirectly decreasing the activity of UROD; lastly, it increases aminolevulinic acid (ALA) levels, therefore increasing uroporphyrin synthesis.4

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Hgb contains about 70% of the body's iron and is the oxygen-carrying protein of the blood.5 PCT involves the defect in one of the enzymes of heme biosynthesis. The heme molecule is composed of porphyrin and an iron atom. The mutation of the enzyme causes heme biosynthesis to be incomplete. As a result, low heme levels perpetuate, thereby causing precursor molecules to build up in an attempt to correct the heme deficit.6 The excess porphyrins in plasma and urine in PCT are mainly uroporphyrin and heptacarboxyl porphyrin, which accumulate as a result of impaired UROD activity and increased oxidative stress.4,6 Typically, the urine in PCT exhibits elevated uroporphyrin isomers I>III and 7-carboxyl porphyrin isomers III>I. Fecal examination shows elevated porphyrins and isocoproporphyrins but is not mandatory for PCT.7

Clinical manifestations usually are not caused by a mutation in the UROD gene alone. An additional inactivation of UROD activity initiated by a few triggers, such as mentioned previously, influences susceptibility.7 In fact, PCT is the only porphyria that can emerge in the absence of an inherited mutation of an affected enzyme.1

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Clinical presentation

The words porphyrin and porphyria come from the Greek word porphyrus, meaning purple. A dark brown or reddish color caused by the presence of excess porphyrins can be found in the urine of affected patients. The color of their urine may further deepen after light exposure. PCT causes chronic blistering cutaneous phototoxicity, crusts, milia, purplish heliotrope discoloration in the periorbital areas, onycholysis, sclerodermoid skin changes, scars, and hypertrichosis, but it has no neurologic manifestations. Although PCT is a hepatic porphyria, the lack of neurologic involvement distinguishes it from acute hepatic porphyrias.

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Evidence of liver impairment is frequent, and the incidence of hepatocellular carcinoma is increased in patients with PCT. Iron levels may be increased, which contribute to a greater susceptibility to liver damage.1 Clinical characteristics rarely occur unless there is 75% or more decrease in hepatic UROD activity.4

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Histology

The deposition of periodic acid-Schiff-positive glycoproteins in and around the vessel walls in the upper dermis most likely causes the classic festooning found in PCT.2 A distinctive feature found in the roofs of bullae in PCT have been coined as “caterpillar bodies.” These bodies are characteristically found in PCT along with pseudoporphyria and erythropoietic protoporphyria.8 DIF microscopy supported the diagnosis of PCT by demonstrating IgG vascular staining in the superficial dermis and fibrin staining along the dermal-epidermal junction. Festooning of the dermal papillae within the vesicle were observed along with caterpillar bodies in the roof of the vesicle (see Subepidermal bulla).9

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Diagnosis

Diagnosis of PCT is made using a combination of clinical history and quantitative analysis of porphyrins and their precursors. Photosensitivity, especially in conjunction with vesiculobullous lesions on sun-exposed areas, should prompt a dermatologic evaluation. The most common profile for the individual with PCT is a middle-aged man who drinks alcohol excessively, and has evidence of hepatic disease or injury with elevated serum aminotransferases. Other patient profiles having a relatively high predisposition of PCT are those with diabetes mellitus, younger women who take oral contraceptives, men diagnosed with prostate cancer who take estrogens, and patients on chronic hemodialysis. Patients on chronic hemodialysis often have iron overload from undergoing numerous blood transfusions.10

Differential diagnoses such as pseudoporphyria and EBA must be considered. Pseudoporphyria, often caused by medications such as furosemide, nonsteroidal anti-inflammatory drugs, and tetracycline, clinically and histologically resembles PCT; however, porphyrin studies are normal.11 EBA has a wide spectrum of clinical presentations and can mimic PCT clinically but not histologically. Additionally, patients with EBA have a higher frequency of mucosal involvement.12

Prognosis is favorable for patients with PCT who avoid alcohol. Overall severity of liver disease determines the general prognosis and long-term outcome.10

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Treatment and management

Discontinuation of contributing factors such as alcohol consumption is essential, as reintroduction of alcohol promotes recurrence. In contrast, there is a low incidence of recurrence with reintroduction of estrogens in postmenopausal women with PCT.13 Action spectrum is described as the wavelength of radiation that triggers any given reaction. The action spectrum for PCT lies in the visible range of ultraviolet radiation (UVR) at 400 to 410 nm, or the Soret band.14 Therefore, sunscreens that protect against UVB alone are inadequate for patients with PCT.10 Protection from both visible light and ultraviolet light is necessary, and many sunscreens provide inadequate protection. Both zinc oxide and titanium dioxide sunscreens, nonnanosized and opaque, are recommended for use along with photoprotective clothing.14

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Phlebotomy is the treatment of choice, typically 250 to 500 mL drawn every 2 to 4 weeks until the Hgb level drops to 10 to 11 g/dL or until serum iron drops to 50 to 60 mcg/dL.10 Dermatologists consider the Hgb level most important to follow because Hgb contains the majority of the body's iron, and clinical presentation of bullous lesions can exist despite a normal iron level, as in the case of this patient's experience. The time for clinical improvement may be 3 to 6 months depending on the severity of the condition. Phlebotomy has been shown to prompt clinical remission, decrease urinary porphyrins, and regress scleroderma-like skin changes, but has not been successful to improve liver histology. Approximately 10% to 20% of individuals with PCT relapse within 1 year, remitting again with phlebotomy.10

Therapies in the form of oral antimalarial agents have been met with success. Some may combine phlebotomy with oral agents. Chloroquine phosphate has been helpful for FDA off-label use.4,7 Chloroquine and hydroxychloroquine both bind with porphyrins, aiding their excretion. The mechanism of action for chloroquine is suppression of lymphocyte transformation in comparison to hydroxychloroquine, which inhibits eosinophilic chemotaxis, impedes neutrophil locomotion, and impairs antigen-antibody reactions. Both can cause hepatotoxicity, especially in higher doses.15

It is important to carefully monitor liver function, particularly at the initiation of therapy. Ocular toxicity is unlikely at low doses.7 Relapse rates are more prevalent after antimalarial treatment in comparison to phlebotomy.4 Serum iron and urine porphyrin levels drop slowly with improvement of symptoms. Skin fragility and bullous lesions improve first, then hypertrichosis later.7

Other FDA off-label variable treatments have also been used such as cholestyramine and iron chelators. Iron chelation therapy is sometimes implemented when iron overload is associated with anemia, such as a patient with PCT who is receiving hemodialysis. Liver failure caused by increased protoporphyrins in the bile has been treated with cholestyramine and activated charcoal.16

Key patient education points for the treatment and management of PCT include:

  • avoidance of UVR
  • wearing sun-protective clothing with nonnanosized physical blocker sunscreen is crucial
  • avoid alcohol use, estrogen supplementation, iron, and polychlorinated aromatic hydrocarbons used in pesticides, as these may trigger recurrence
  • allow 3 to 6 months to improve from phlebotomy treatment
  • resolution of PCT in patients with hepatitis C may occur after antiviral therapy
  • follow instructions as directed by the healthcare provider when taking chloroquine or hydroxychloroquine; report any seizure activity, muscle weakness, or eye problems
  • avoid hydroxychloroquine or chloroquine if pregnant or lactating.17,18
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Conclusion

This case highlights the need for investigation in individuals presenting with skin fragility and bullae in sun-exposed areas. The diagnosis can be substantiated by elevated urine uroporphyrins and coproporphyrins. Treatment can achieve complete remission, although relapse is possible. Therefore, because PCT is a multifactorial disorder, the patient should continue to be monitored clinically and biochemically. Standard treatment of affected individuals includes phlebotomy, avoidance of contributing factors to decrease susceptibility, and sun protection or avoidance.

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REFERENCES

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