Case Report: Treatment of porphyria cutanea tarda with low dose hydroxychloroquine

Background: Porphyria cutanea tarda (PCT) is a complex metabolic disease resulting from altered activity of the enzyme uroporphyrinogen decarboxylase (UROD) in the liver resulting in accumulation of uroporphyrin. PCT presents as a blistering photodermatitis with skin fragility, vesicles, scarring and milia. Case: We report a case of PCT in a 67-year-old man with hemochromatosis (HFE) gene mutation who, following a major syncopal episode in response to venesection was commenced on low dose hydroxychloroquine. Conclusions: Low dose hydroxychloroquine provided a safe and effective alternative to venesection in this patient who was needle phobic.


Introduction
Porphyria cutanea tarda (PCT) is the most common type of porphyria and results from a decline of uroporphyrinogen decarboxylase (UROD), an enzyme involved in heme synthesis and resulting in accumulation of uroporphyrin. 1 There are two types of PCT. Type 1 is an acquired disorder triggered by iron overload or viral infection. Type II is an autosomaldominant genodermatosis. 2 The cutaneous manifestations arise when cutaneous porphyrins absorb ultraviolet radiation (UV) and generate reactive oxygen species (ROS) that induce skin photosensitivity, sub-epidermal blistering, erosions, milia and scar formation. 3 We present a case of a patient diagnosed with type 1 PCT and hemochromatosis, successfully treated with low dose hydroxychloroquine.
Case report A 67-year-old Caucasian male, who worked as a plumber, presented with a two-month history of skin fragility and pruritic blisters on dorsal hands, spreading up the arms. He noted that broken blisters healed with firm little "white spots" and described lethargy and darkening of urine. For many years he had regularly consumed three cans of beer daily. Examination revealed intact blisters alongside numerous erosions over the hands and elbows and milia on inspection of the left hand ( Figure 1). There was no forehead hypertrichosis.
The clinical differential diagnosis included hepatocutaneous porphyria and epidermolysis bullosa acquisita (EBA). Skin biopsy, blood, urinary and faecal porphyrins were performed and he was advised to reduce alcohol consumption and sun exposure.

Discussion
The most common triggers for type 1 PCT are alcohol, environmental chemicals, hemochromatosis and viruses. 2 Our patient possessed two of the above triggering factors (alcohol and hemochromatosis). Alcohol may trigger PCT by increasing iron absorption through dissociating iron from its binding proteins as well as directly inhibiting UROD. 4 Hemochromatosis causes iron excess and can trigger PCT by catalysing ROS formation and increasing uroporphyrin concentration through direct oxidation of uroporphyrinogen and inhibition of UROD. 1 Hydroxychloroquine increases porphyrin excretion in PCT and is as effective as phlebotomy with remission in 6-9 months. 5 The HFE mutation type appears to be important in hydroxychloroquine therapeutic response, with homozygosity for the C282Y mutation resulting in treatment failure, but heterozygosity, as demonstrated in our case, did not. 6 The use of compounded low-dose hydroxychloroquine minimised risk of acute toxicity and provided a safe and effective alternative to venesection in our patient. The dose was up-titrated until clinical remission was achieved. A limitation of this case report was the small sample size of only one patient.

Conclusions
Oral hydroxychloroquine provided a safe and effective alternative to venesection in this patient who was needle phobic.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.

Consent
Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Open Peer Review
I find this report clearly written and informative. However, a few points should be corrected/clarified: This patient carried a heterozygous C282Y variant in the human homeostatic iron regulator protein (HFE) gene, which should be mentioned as such (not "hemochromatosis" gene, as there are several other genes -HJV, TFR2, etc. -which cause hemochromatosis). A C282Y heterozygous mutation is by no means sufficient to cause HFE-related hemochromatosis, which is mainly associated with a C282Y homozygous genotype. A compound heterozygous C282Y/H63D genotype may be regarded as a "risk genotype" for liver iron overload, but is not sufficient in itself to define "classic" HFE-related hemochromatosis. In sum, the authors should consider that the iron overload phenotype of their patient cannot be explained by his HFE genotype (I assume that the patient did not carry further pathogenic variants in this gene). Furthermore, they should report the patient's serum iron, transferrin, and transferrin saturation levels at baseline (both serum iron and transferrin saturation should be above the range of normality in a typical hemochromatosis patient, whereas serum transferrin should be normal/below range).
○ Did the patient change his habits as to daily ethanol consumption? As the authors hint, this could be the main reason for his iron overload phenotype.

○
The patient did not undergo a liver biopsy, which is reasonable enough a choice, provided ○ the hepatopathy he was affected by is reasonably diagnosed as alcohol-related. This should be specified somewhere in the text. If the authors think that alcohol use alone does not fully explain this patient's liver disease, they should clarify why other causes of hepatopathy (i.e. NAFLD, autoimmune, etc.) have not been investigated.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Toxic retinopathy is also an issue. This case was treated with 5 mg daily uptrited to 200 mg daily. In a PCT context, that should be regarded as "high dose". The patient did ok with normal LFTs during the treatment period.
Please don't say that the patient had hemochromatosis. He had a HFE gene variant on one allele, he was heterozygous. The moderately elevated serum ferritin was more likely a result of alcohol overconsumption (>20 beer cans per week). His main risk factor was alcohol. The HFE mutation may have made him more vulnerable.

2.
Some details: The last sentence about the limitation is unnecessary.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No Is the case presented with sufficient detail to be useful for other practitioners? Partly

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