Dawe, Robert S.

Haridas, Amrutha

McGuire, Victoria A.

English

University of Dundee Online Publications

                                                                    University of DundeeAnalysis of whole blood protoporphyrin and plasma porphyrin in patients on dapsoneHaridas, Amrutha; Dawe, Robert S.; McGuire, Victoria A.Published in:Photodermatology, Photoimmunology & PhotomedicineDOI:10.1111/phpp.12962Publication date:2024Licence:CC BYDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Haridas, A., Dawe, R. S., & McGuire, V. A. (2024). Analysis of whole blood protoporphyrin and plasma porphyrinin patients on dapsone. Photodermatology, Photoimmunology & Photomedicine, 40(2), Article e12962.https://doi.org/10.1111/phpp.12962General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 11. May. 2024Photodermatol Photoimmunol Photomed. 2024;40:e12962.	 	 	 | 1 of 3https://doi.org/10.1111/phpp.12962wileyonlinelibrary.com/journal/phppReceived:	15	November	2023  | Revised:	27	February	2024  | Accepted:	3	March	2024DOI: 10.1111/phpp.12962  L E T T E RAnalysis of whole blood protoporphyrin and plasma porphyrin in patients on dapsoneDear Editor,Dapsone is a sulphonamide antibiotic that also has anti- inflammatory effects and is commonly used to treat of a range of dermatological conditions with different causes including dermatitis herpetiformis, pyoderma gangrenosum, Sweet's syndrome, urticarial vasculitis and leprosy.1 Dapsone is known to cause haemolytic anaemia espe-cially in patients with glucose 6- phosphate dehydrogenase (G6PD) deficiency2 and always causes some degree of haemolysis. It has also been reported to precipitate episodes of acute intermittent porphyria and variegate porphyria.3,4	For	more	than	35 years,	pho-tosensitivity has been reported as an infrequent side- effect of dap-sone	treatment	for	leprosy	and	more	recently	for	linear	IgA	bullous	dermatosis.5We aimed to find out whether or not dapsone is associated with elevated protoporphyrin in the blood. The prompt for this was an observation in one of our patients on dapsone. This patient was fifty- one when he was referred to the Scottish Photobiology Service for	 phototesting	 with	 suspected	 chronic	 actinic	 dermatitis	 (CAD).	Monochromator	 phototesting	 did	 not	 show	 features	 of	 a	 cutane-ous porphyria: abnormalities were to ultraviolet B and ultraviolet A2	(long	wavelength	ultraviolet	A)	rather	than	visible	light	and	was	most	marked	at	24 h	 (not	at	7 h	as	seen	 in	photosensitive	porphyr-ias)—which	confirmed	the	diagnosis	of	CAD.Porphyrin biochemistry was requested alongside phototest-ing to determine whether Porphyria Cutanea Tarda was underly-ing	 the	 CAD.	 Initial	 blood	 porphyrin	 biochemistry	 showed	 raised	total erythrocyte porphyrin which was predominantly metal- free protoporphyrin in the absence of a plasma porphyrin peak. Two further blood samples were analysed whilst the patient continued on dapsone that gave abnormal results, but these returned to nor-mal when retested after dapsone was stopped for more than a year (Figure 1A,B).We considered that dapsone might be the explanation for raised erythrocyte porphyrin, possibly related to increased turnover in his bone marrow to compensate for dapsone haemolysis—his reticulo-cyte count was approximately 4%–5% whilst on dapsone. We found only one reported study, investigating porphyrin levels in people with leprosy on dapsone treatment and untreated.6 This study found leprosy to be associated with increased blood protoporphyrin but did not find an increase attributable to dapsone.This was a retrospective study measuring blood protoporphyrin and plasma porphyrin levels in consenting patients on dapsone in samples stored by Scottish Health Research Register and Biobank (SHARE),	a	research	initiative	by	NHS	research	Scotland.7	SHARE	is	a database of volunteers (aged 11+) who consent to the access and use of their health records to identify them as potentially eligible for research projects. Participants gave permission for any spare blood remaining after routine clinic tests, to be retained for anonymised research. The inclusion criteria for this study were male or female on dapsone	treatment	with	a	sample	of	≥5 mL	stored.Plasma, blood protoporphyrin (zinc/metal- free) and total eryth-rocyte protoporphyrin levels were analysed in 10 anonymised blood samples by fluorescence spectroscopy using standard, published methods8–10 by the Scottish Cutaneous Porphyria Service. Internal quality control samples were included with each assay to demon-strate acceptable performance. Biobank samples had not been light protected prior to storage, but were wrapped in foil upon retrieval from storage and protected from light throughout analysis.50% of samples from patients on dapsone showed increased metal- free protoporphyrin with metal- free protoporphyrin levels ranging from 35% to 46% (normal <30%).	All	 samples	had	normal	total erythrocyte porphyrin concentrations ranging from 0.3 to 0.7 μmol/L	rbc	(Figure 1C,D). No plasma porphyrin peak was detect-able	 in	any	of	 the	biobank	 samples.	All	 samples	were	noted	 to	be	haemolysed—it is unclear whether this is related to dapsone treat-ment and/or storage of the samples.Interestingly, we found that increased metal- free protoporphy-rin was not isolated to the original patient and was increased in half of the 10 patients on dapsone whose blood samples were obtained from	the	SHARE	biobank	and	may	help	to	explain	the	photosensitiv-ity observed in some patients on dapsone.5 The increase seen in bio-bank samples was not as dramatic as that seen in the initial patient and the total erythrocyte porphyrin levels were normal in all 10 sam-ples. This could be because none of the biobank samples had been light protected prior to storage and as protoporphyrin is light labile it is possible that this had degraded prior to analysis. Prospective studies on light protected samples may give a better understanding of these findings.The underlying cause or clinical implications of increased metal- free protoporphyrin levels in dapsone- treated patients is not This is an open access article under the terms of the Creative	Commons	Attribution	License,	which	permits	use,	distribution	and	reproduction	in	any	medium,	provided the original work is properly cited.©	2024	The	Authors.	Photodermatology, Photoimmunology & Photomedicine	published	by	John	Wiley	&	Sons	Ltd.2 of 3  |     HARIDAS et al.understood, but analysis of blood porphyrins in patients experienc-ing photosensitivity would help to inform on this. We hypothesise that dapsone could affect the enzymatic activity of ferrochelatase (which catalyses metal atom insertion into protoporphyrin) and/or perhaps the increased bone marrow activity to compensate for dap-sone	haemolysis	is	relevant.	Further	studies	would	be	needed	to	un-derstand the effects of dapsone on porphyrin levels and metabolism considering its widespread usage for different conditions.FUNDING INFORMATIONThis	study	was	funded	by	the	British	Porphyria	Association.ACKNOWLEDG EMENTSWe would like to thank the Scottish Photobiology Service, which encompasses monochromator phototesting and porphyrin bio-chemistry	through	the	Scottish	Cutaneous	Porphyria	Centre.	Access	to	 samples	 for	 this	 study	 was	 facilitated	 by	 SHARE—the	 Scottish	Health	Research	Register	and	Biobank.	SHARE	is	supported	by	NHS	Research Scotland, Universities in Scotland and the Chief Scientists Office. We also thank the volunteers who donated their leftover blood samples for analysis.CONFLIC T OF INTERE S T S TATEMENTNone to declare.DATA AVAIL ABILIT Y S TATEMENTThe data that support the findings of this study are available from the corresponding author upon reasonable request.Amrutha	HaridasRobert S. DaweVictoria	A.	McGuireScottish Photobiology Service, Photobiology Unit, Department of Dermatology, Ninewells Hospital and Medical School, NHS Tayside and University of Dundee, Dundee, UKCorrespondenceVictoria	A.	McGuire,	Scottish	Photobiology	Service,	Photobiology Unit, Department of Dermatology, Ninewells Hospital	and	Medical	School,	NHS	Tayside	and	University	of	Dundee, Dundee, UK.Email: vicky.mcguire@nhs.scotF I G U R E  1 Porphyrin	biochemistry	results.	(A,	B)	Initial	testing	in	2017	showing	elevated	metal-	free	protoporphyrin	and	total	erythrocyte	porphyrin	on	dapsone	and	returning	to	normal	after	stopping	in	September	2017.	Total	erythrocyte	porphyrin	was	measured	on	whole	blood and the blood haematocrit value used to enable results to be expressed in relation to the volume of packed erythrocytes. Dotted lines indicate blood metal- free protoporphyrin normal range <30%	(A)	and	whole	blood	TEP	normal	range	<1.7 μmol/L	rbcs	(B).	(C,	D)	SHARE	samples.	50%	of	samples	show	elevated	metal-	free	protoporphyrin	but	all	have	normal	TEP.	Dotted	lines	indicate	blood	metal-	free	protoporphyrin normal range <30% (C) and packed red blood cell TEP normal range <1.4 μmol/L	rbcs	(D).	Orange	indicates	outwith	the	normal range, green indicates within normal limits.0%10%20%30%40%50%60%70%80%90%100%0 1 2 3 4 5 6 7 8 9 10Metal-free protoporphyrin (% of total)SHARE sample number0%10%20%30%40%50%60%70%80%90%100%Metal-free protoporphyrin (% of total)00.20.40.60.811.21.40 1 2 3 4 5 6 7 8 9 10Total erythrocyte porphyrin (µmolLrbcs)SHARE sample number(A)(B)(C)(D)July 2017 July 2017 Aug 2017 Sep 2018 Jan 202200.511.522.533.54Total erythrocyte porphyrin (µmolLrbcs)July 2017 July 2017 Aug 2017 Sep 2018 Jan 2022 16000781, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/phpp.12962 by University of Dundee, Wiley Online Library on [18/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License    |  3 of 3HARIDAS et al.ORCIDAmrutha Haridas  https://orcid.org/0000-0003-3619-4217 Robert S. Dawe  https://orcid.org/0000-0002-4732-071X Victoria A. McGuire  https://orcid.org/0000-0002-7808-3278 R E FE R E N C E S	 1.	 Zhu	YI,	Stiller	MJ.	Dapsone	and	sulfones	in	dermatology:	overview	and update. J Am Acad Dermatol. 2001;45(3):420-434.	 2.	 Luzzatto	L,	Seneca	E.	G6PD	deficiency:	a	classic	example	of	phar-macogenetics with on- going clinical implications. Br J Haematol. 2014;164(4):469-480.	 3.	 Spiritos	 Z,	 Salvador	 S,	Mosquera	D,	Wilder	 J.	 Acute	 intermittent	porphyria: current perspectives and case presentation. Ther Clin Risk Manag. 2019;15:1443-1451.	 4.	 Varma	S,	Lanigan	SW.	Management	difficulties	due	to	concurrent	dermatitis herpetiformis and variegate porphyria. Br J Dermatol. 2000;143(3):654-655.	 5.	 Shigehara	 Y,	 Kato	 M.	 Dapsone-	induced	 photosensitivity:	 a	 case	report and review of literature. Photodermatol Photoimmunol Photomed.	2023;39(4):407-409.	 6.	 Pavithran	P,	Handa	F,	Sidhu	KS.	A	quantitative	assay	of	porphyrins	in	 leprosy	 patients.	 A	 spectrophotometric	 study.	 Int J Lepr Other Mycobact Dis. 1981;49(3):311-314.	 7.	 McKinstry	 B,	 Sullivan	 FM,	 Vasishta	 S,	 et	 al.	 Cohort	 profile:	 the	Scottish	research	register	SHARE.	A	register	of	people	 interested	in research participation linked to NHS data sets. BMJ Open. 2017;7:e013351.	 8.	 Poh-	Fitzpatrick	MB.	A	plasma	porphyrin	 fluorescence	marker	 for	variegate porphyria. Arch Dermatol.	1980;116(5):543-547.	 9.	 Elder	GH,	Smith	SG,	Smyth	SJ.	Laboratory	investigation	of	the	por-phyrias. Ann Clin Biochem.	1990;27(Pt	5):395-412.	10.	 Piomelli	S.	Free	erythrocyte	porphyrins	in	the	detection	of	undue	absorption	of	Pb	and	of	Fe	deficiency.	Clin Chem.	1977;23:264-269. 16000781, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/phpp.12962 by University of Dundee, Wiley Online Library on [18/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Analysis of whole blood protoporphyrin and plasma porphyrin in patients on dapsone

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Analysis of whole blood protoporphyrin and plasma porphyrin in patients on dapsone

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