F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.124022.1 Case Report Articles Case Report: Treatment of porphyria cutanea tarda with low dose hydroxychloroquine

[version 1; peer review: 1 approved, 2 approved with reservations]

 Awad Andrew Conceptualization Data Curation Formal Analysis Methodology Writing – Original Draft Preparation Writing – Review & Editing a 1 Nirenberg Alexander Investigation Writing – Review & Editing 2 Sinclair Rodney Conceptualization Methodology Writing – Review & Editing https://orcid.org/0000-0001-6751-1428 1 3 4 Sinclair Dermatology, East Melbourne, VIC, 3002, Australia Dorevitch Pathology, Heidelberg, VIC, 3084, Australia University of Melbourne, Parkville, VIC, 3010, Australia Epworth Healthcare, Richmond, VIC, 3121, Australia andrew.awad@sinclairdermatology.com.au

No competing interests were disclosed.

 17 8 2022 2022 11 945 11 8 2022 Copyright: © 2022 Awad A et al. 2022 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

 Porphyria cutanea tarda hemochromatosis hydroxychloroquine The author(s) declared that no grants were involved in supporting this work. 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 autosomal-dominant 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.

Appearance of the hands showing extensive erosions and intact blisters.

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.

Histopathology revealed an intact sub-epidermal blister with minimal dermal inflammation ( Figure 2). Haematological investigations demonstrated; C282Y hemochromatosis (HFE) gene mutation, mildly elevated liver function tests (LFTs) consistent with alcohol intake and elevated ferritin (756 μg/L). Hepatitis and HIV serology were negative. The porphyrin screen showed elevated urinary total porphyrin (3.4 μmol/L), uroporphyrin (3.2 μmol/L), faecal total porphyrin (330 μmol/L), Isocoprophyrin (125 μmol/L), plasma porphyrin (207 nmol/L) and red cell porphyrin (1.8 μmol/L rbc). The patient was referred for venesection but had a major syncopal episode and declined further venesection. Treatment was then commenced with oral hydroxychloroquine 5 mg daily (compounded extemporaneously) and up-titrated over six months to 200 mg daily. Within 12 months the PCT was in complete remission with normal LFTs and ferritin (462 μg/L) and hydroxychloroquine was ceased. The porphyrin screen showed normal levels of urinary total porphyrin (0.17 μmol/L), red cell porphyrin (0.41 μmol/L red cells) and plasma total porphyrin (13 nmol/L).

Punch biopsy of right hand demonstrating a sub-epidermal blister with festooning of dermal papilla and with adjacent epidermal hyperplasia with hypergranulosis.

In the superficial dermis there are some thick-walled blood vessels, which stain for Periodic acid–Schiff (PAS). In the upper dermis there is a sparse lymphocytic infiltrate.

 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.

 References Ryan Caballes F Sendi H Bonkovsky HL : Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 2012;32(6):880–893. 22510500 10.1111/j.1478-3231.2012.02794.x Jalil S Grady JJ Lee C : Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin. Gastroenterol. Hepatol. 2010;8(3):297–302.e1. 19948245 10.1016/j.cgh.2009.11.017 Horner ME Alikhan A Tintle S : Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int. J. Dermatol. 2013;52(12):1464–1480. 24261722 10.1111/ijd.12305 Doss MO Kühnel A Gross U : Alcohol and porphyrin metabolism. Alcohol Alcohol. 2000;35(2):109–125. 10.1093/alcalc/35.2.109 Singal AK Kormos-Hallberg C Lee C : Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin. Gastroenterol. Hepatol. 2012;10(12):1402–1409. 10.1016/j.cgh.2012.08.038 Stölzel U Köstler E Schuppan D : Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda. Arch. Dermatol. 2003;139(3):309–313. 12622622 10.5256/f1000research.136191.r172322 Reviewer response for version 1 Ricci Andrea 1 Referee https://orcid.org/0000-0002-4812-3750 Department of Medical and Surgical Science for Children and Adults, Universita degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy

Competing interests: No competing interests were disclosed.

 8 6 2023 Copyright: © 2023 Ricci A 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

The authors report an interesting case report which reminds us that hydroxychloroquine is an effective treatment for PCT. This should be kept in mind for all those patients who cannot undergo phlebotomy (for instance, cirrhotic patients, or those affected by myelodysplastic disorders) even though the choice to use hydroxychloroquine should be always weighed against the risk of adverse events in patients who are already affected by a liver disease.

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.

Isocoproporphyrin is misspelled.

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.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Partly

Is the case presented with sufficient detail to be useful for other practitioners?

Yes

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 background of the case’s history and progression described in sufficient detail?

Yes

Reviewer Expertise:

Rare liver diseases, iron overload disorders (hemochromatosis, ferroportin disease, hemoglobinopathies), porphyrias

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

 10.5256/f1000research.136191.r172317 Reviewer response for version 1 Wahlin Staffan 1 Referee https://orcid.org/0000-0002-5985-9464 Department of Upper GI Diseases, Karolinska University, Stockholm, Sweden

Competing interests: No competing interests were disclosed.

 23 5 2023 Copyright: © 2023 Wahlin S 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

This is a short report about a fairly standard PCT patient who was successfully treated to reach clinical and biochemical remission.

I have two main concerns:

The title of the report does not really reflect the content; " low dose" is true only in comparison with other non-PCT indications. In PCT, the recommended dose of hydroxychloroquine is 100 mg twice weekly (for chloroquine, 125 mg twice weekly). The reason for keeping the dose low is mainly a significant risk of hepatotoxicity in higher doses. 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.

 Some details:

In Introduction: " Type 1 is an acquired disorder triggered by  risk factors such as iron overload..."

Porphyrins absorb mainly visible light around 405 nm (could be expressed as "longer wavelength UVA and visible light around 405 nm"). Saying UV radiation is misleading as it suggests that protection with UV blocking creams may help. They don't.

Units. Are umol/L standard in Australia? In Europe, nmol/L and, in the US, mcg/dL is standard/preferred. Check what is most appropriate for the journal.

The last sentence about the limitation is unnecessary.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Partly

Is the case presented with sufficient detail to be useful for other practitioners?

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 background of the case’s history and progression described in sufficient detail?

Yes

Reviewer Expertise:

Liver diseases. Porphyria.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

 10.5256/f1000research.136191.r156729 Reviewer response for version 1 To-Figueras Jordi 1 Referee Clinical Biochemistry Department, Hospital Clinic of Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain

Competing interests: No competing interests were disclosed.

 16 12 2022 Copyright: © 2022 To-Figueras J 2022 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve

This is an OK addition to the literature of PCT. 

The authors should however clarify the haemochromatosis status. In the case report, they should indicate if the patient is heterozygous for the C282Y mutation (hence C282Y/WT?) and add the H63D status (WT/WT?). According to reviews (i.e. Kowdley et al. (2019) 1 ), HFE status would be defined by a C282Y homozygous or C282Y/H63D compound heterozygous. Please clarify.

'Case report' section: " red cell porphyrin" should read as "red cell protoporphyrin"; " plasma porphyrin" should read as "plasma total porphyrin".

 The case the authors reported adds to the PCT literature. Even if venesection is considered a treatment of choice for PCT that has been empirically proven to reduce overproduction of porphyrins through reduction of hepatic iron depots, it is an invasive procedure. Needle phobia of the patient induced consideration of low-dose oral chloroquine as an alternative. And that simple and well-known regime induced remission even if haemochromatosis was suspected. The point is that, PCT being a benign disease, non-invasive treatments (chloroquine or oral antivirals when PCT is induced by HCV infection) should be preferred to venesection as a first choice.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Partly

Is the case presented with sufficient detail to be useful for other practitioners?

Yes

Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?

Yes

Is the background of the case’s history and progression described in sufficient detail?

Yes

Reviewer Expertise:

Porphyria

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

References : ACG Clinical Guideline: Hereditary Hemochromatosis. Am J Gastroenterol .2019;114(8) : 10.14309/ajg.0000000000000315 1202-1218 31335359 10.14309/ajg.0000000000000315