Fundamentos: A porfiria cutânea tardia é a forma mais comum das porfirias e caracteriza-se pela diminuição da atividade da enzima uroporfirinogênio descarboxilase. Há vários relatos da associação das mutações do gene HFE da hemocromatose hereditária com porfiria cutânea tardia no mundo, mas até hoje apenas um estudo foi realizado no Brasil. Objetivo: Estudar a associação da porfiria cutânea tardia com as mutações C282Y e H63D do gene HFE da hemocromatose hereditária. Identificar a associação com etilismo, hepatite C, hepatite B e infecção pelo HIV e relacioná-los com a presença ou não das mutações do gene HFE e estudar retrospectivamente a resposta terapêutica à cloroquina. Métodos: Estudo ambispectivo para detectar as mutações C282Y e H63D em 60 pacientes com porfiria cutânea tardia no período de 2003 até 2012. O histórico familiar, etilismo, hepatite C, hepatite B e anti-HIV foram investigados. O estudo das mutações HFE foi realizado com PCR em tempo real. A resposta terapêutica foi avaliada utilizando a dosagem das porfirinas urinárias (urina de 24 horas), o perfil de ferro (ferro sérico, ferritina e saturação de transferrina) e as enzimas hepáticas antes e após a remissão bioquímica. Resultados: A frequência dos alelos das mutações foi significativamente mais elevada nos pacientes com PCT para C282Y (8,3% versus 1,77%, odds ratio 5,02, IC [95%] = [4,1%; 14,8%], p=0,0001) e H63D (27,5% versus 14,05, odds ratio 2,32, IC [95%] = [19,7%; 36,4%], p=0,0004) em relação à população grupo controle. A hepatite C estava presente em 41,7% dos pacientes e estava associada à ingestão de álcool em 71,7% dos casos. Conclusões: As mutações HFE e a expressão clínica da hemocromatose hereditária podem contribuir isoladamente para o desencadeamento da PCT, independente-mente da presença de outros fatores precipitantes; o que torna a pesquisa das mutações HFE um exame necessário nos pacientes com PCT. Nos pacientes homozigotos para C282Y e heterozigotos compostos (C282Y/H63D) a flebotomia é o tratamento de primeira escolha. A porfiria cutânea tardia pode ser um marcador cutâneo para a hemocromatose e o dermatologista pode auxiliar no seu diagnóstico e tratamento precoce. / Background: Porphyria cutanea tarda (PCT) is the most common form of porphyria and is characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with PCT worldwide, although up to date only one study has been conducted in Brazil. Objective: Study the association between porphyria cutanea tarda and C282Y and H63D mutations in the HFE gene of hereditary hemochromatosis. Identify the association with alcoholism, hepatitis C, hepatitis B and HIV infection and relate them with the presence or absence of the HFE gene mutations and study retrospectively the therapeutic response to chloroquine. Methods: Ambispective study in the period from 2003 to 2012 to detect the C282Y and H63D mutations in 60 patients with porphyria cutanea tarda. The family history, alcoholism, hepatitis C, hepatitis B and HIV were investigated. HFE mutations were held with real-time PCR. The therapeutic response was assessed using the urinary porphyrins (24h urine), the iron profile (serum iron, ferritin and transferrin saturation) and the liver enzymes, before and after biochemical remission. Results: The frequency of alleles of the mutations were significantly higher in patients with PCT for C282Y (8.3% vs. 1.77%, odds ratio 5.02, CI [95%] = [4.1%; 14.8%], p = 0.0001) and H63D (27.5% vs. 14.05, odds ratio 2.32, CI [95%] = [19.7% and 36.4%], p = 0.0004) in relation to group control population. Hepatitis C was found in 41.7% of the patients and was associated with the ingestion of alcohol in 71.7% of cases. Conclusions: The HFE mutations and clinical expression of hereditary hemochromatosis can contribute in an isolated manner to the outbreak of PCT, independently of the existence of other precipitating factors. This makes the search for HFE mutations necessary in patients with PCT. In patients who are homozygous for C282Y and compound heterozygotes (C282Y/H63D) phlebotomy is the treatment of first choice. Porphyria cutanea tarda can be a cutaneous marker for hemochromatosis and the dermatologist can help in its diagnosis and early treatment.

ABSTRACT The porphyrias are a diverse group of metabolic disorders arising from diminished activity of enzymes in the heme biosynthetic pathway. They can present with acute neurovisceral symptoms, cutaneous symptoms, or both. The complexity of these disorders is demonstrated by the fact that some acute porphyria patients with the underlying genetic defect(s) are latent and asymptomatic while others present with severe symptoms. This indicates that there is at least one other risk factor required in addition to the genetic defect for symptom manifestation. A systematic review of the heme biosynthetic pathway highlighted the involvement of a number of micronutrient cofactors. An exhaustive review of the medical literature uncovered numerous reports of micronutrient deficiencies in the porphyrias as well as successful case reports of treatments with micronutrients. Many micronutrient deficiencies present with symptoms similar to those in porphyria, in particular vitamin B6. It is hypothesized that a vitamin B6 deficiency and related micronutrient deficiencies may play a major role in the pathogenesis of the acute porphyrias. In order to further investigate the porphyrias, a computational model of the heme biosynthetic pathway was developed based on kinetic parameters derived from a careful analysis of the literature. This model demonstrated aspects of normal heme biosynthesis and illustrated some of the disordered biochemistry of acute intermittent porphyria (AIP). The testing of this model highlighted the modifications necessary to develop a more comprehensive model with the potential to investigated hypotheses of the disordered biochemistry of the porphyrias as well as the discovery of new methods of treatment and symptom control. It is concluded that vitamin B6 deficiency might be the risk factor necessary in conjunction with the genetic defect to trigger porphyria symptoms.