Porphyria cutanea tarda - Clinical Tree

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

The term porphyria cutanea tarda (PCT) encompasses several related inherited or acquired disorders in which deficient hepatic uroporphyrinogen decarboxylase (UROD) enzyme activity (reduced to <20% of normal) causes overproduction of polycarboxylated porphyrins. These porphyrins can mediate cutaneous photosensitivity manifested as fragility, bullae, hypertrichosis, dyspigmentation, sclerodermoid features, and scarring. PCT usually presents in adults but occasionally in children. Genetic and other diverse factors or circumstances that may cause, influence, or aggravate its expression include mutations of UROD or hemochromatosis (HFE) genes, other predisposing genetic determinants, ethanol abuse, smoking, medicinal estrogen, iron overload, hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV) infections, chronic dialysis treatment, toxic aromatic hydrocarbon exposure, and, rarely, hepatic tumors. Increased tissue iron, a common feature of alcoholism, HCV infection, hemochromatosis, and therapeutic iron supplementation, plays a central role in the pathogenesis of PCT. Iron-dependent partial oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of UROD, may be the mechanism reducing its activity sufficient to provoke manifest PCT (Phillips et al. Proc Natl Acad Sci USA 2007; 104: 5079–84). Iron-enhanced complete oxidation of porphyrinogens accumulated due to inhibited UROD activity yields photoactive porphyrins. Hepatic siderosis or porphyrin crystallization in hepatocytes may lead to fibrosis, cirrhosis, and hepatocellular carcinoma in long-term active PCT. Ferrodepletion by serial phlebotomy is the preferred first-line therapy for PCT patients with iron overload.

Management Strategy

Precise diagnosis is essential; optimal management calls for induction of remissions using strategies that are inappropriate for other porphyrias or pseudoporphyrias. Concurrent conditions that may influence management (viral infections, hemochromatosis, or other causes of iron overload, lupus erythematosus, diabetes mellitus, anemias, pregnancy, glucose-6-phosphate deficiency, renal disease) should be identified. Sun exposure and mechanical skin trauma should be minimized until full clinical remission is achieved. Eliminating contributory factors and pursuing ferrodepletion by serial phlebotomy , iron chelation , or erythropoiesis stimulation , or increasing porphyrin excretion with chloroquine or hydroxychloroquine , can reproducibly induce biochemical and clinical remissions. Phlebotomy and hydroxychloroquine protocols adjusted for pediatric parameters are available. Highly effective antiviral drugs may benefit PCT coincident with HCV or HIV infections. Other therapies are less well established (e.g., increasing porphyrin excretion by enteric sorbents or metabolic alkalinization , vitamins E and C , plasmapheresis or plasma exchange , high-flux hemodialysis , cimetidine ). Hepatoerythropoietic porphyria, caused by coinheritance of two UROD gene mutations, resists induction of remission and thus requires lifelong vigilant photoprotection. Photothermolysis using light with selected wavelengths may reduce persistent hypertrichosis.

Specific Investigations

Porphyrin concentrations and types in erythrocytes, serum or urine, feces

Hematologic and iron profiles, serum ferritin, HFE gene analysis

Liver function profile; liver imaging and elastography, liver biopsy if clinically indicated

Hepatitis A, B, C, and HIV serologies

Fasting blood glucose

Serum antinuclear antibody

Mutation analysis of the UROD gene

Porphyria cutanea tarda: recent update

Singal AK. Mol Genet Metab 2019; 128: 271–81.

Overview of PCT pathophysiology, diagnosis, and therapeutic management with an expansive bibliography.

Hepatitis C, porphyria cutanea tarda and liver iron: an update

Ryan Caballes F, Sendi H, Bonkovsky HL. Liver Int 2012; 32: 880–93.

A review emphasizing pathophysiologic roles of HCV, iron-facilitated oxidative stress, and hepcidin (a key regulator of iron absorption and metabolism that is downregulated in PCT). Treatment guidelines are offered.

Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America

Bonkovsky HL, Poh-Fitzpatrick MB, Pimstone N, et al. Hepatology 1998; 27: 1661–9.

Of 70 American patients with PCT, 53% had evidence of HCV infection, and 43% of 26 patients had HFE gene mutations.

Hepatocellular carcinoma risk in patients with porphyria cutanea tarda

Gisbert JP, Garcia-Buey L, Alonso A, et al. Eur J Gastroenterol Hepatol 2004; 16: 689–92.

Recommendations include viral hepatitis serologies and liver biopsy at initial evaluation, and monitoring PCT patients with HCV infection or advanced fibrosis/cirrhosis with semiannual ultrasonography.

The decision for liver biopsy should be made case-by-case. Patients without risk factors for hepatic siderosis or other liver pathology (e.g., women with estrogen use as the only PCT-inducing factor) may not need this invasive procedure.

First-Line Therapies

Sunlight avoidance, opaque sunscreens, physical sunlight barriers	C
Contributory factor elimination (iron supplements, alcohol intake, smoking, medicinal estrogens, hepatotoxin exposure)
Serial phlebotomies	B
Chloroquine, hydroxychloroquine	B

Efficiency of opaque photoprotective agents in the visible light range

Kaye ET, Levin JA, Blank IH, et al. Arch Dermatol 1991; 127: 351–5.

Efficacy and quality of sunscreens containing zinc oxide, titanium dioxide, and iron oxide are described.

Minimizing sunlight exposure by lifestyle changes, opaque sunscreens, protective clothing, window glass barrier filters, etc., is essential until photosensitivity remits completely.

Treatment of porphyria cutanea tarda by phlebotomy

Ippen H. Semin Hematol 1977; 14: 253–9.

Repeated venesection resulted in reduction of porphyrins and serum iron, improvement of photocutaneous lesions, and normalization of liver function in the majority of 351 patients.

Phlebotomy schedules should be adjusted to the tolerance of individual patients; typically 200–500 mL of whole blood is withdrawn at twice-weekly to fortnightly or monthly intervals. Keeping hemoglobin over 10–11 g/dL minimizes symptoms of iatrogenic anemia.

Childhood-onset familial porphyria cutanea tarda: effects of therapeutic phlebotomy

Poh-Fitzpatrick MB, Honig PJ, Kim HC, et al. J Am Acad Dermatol 1992; 27: 896–900.

Pediatric phlebotomy guidelines are described.

Plasma ferritin levels as a guide to the treatment of porphyria cutanea tarda by venesection

Ratnaike S, Blake D, Campbell D, et al. Australas J Dermatol 1988; 29: 3–8.

Phlebotomies can be terminated when iron stores, as reflected by plasma ferritin concentration, have fallen to low-normal levels.

Reduction of porphyrins in plasma (or serum or urine) and clinical improvement typically begin during therapy and continue for weeks to months after venesection stops. Clinical improvement precedes full biochemical normalization.

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