Porphyria cutanea tarda precipitated by intravenous iron in a haemodialysis patient

William McKane1,, Christina A. Green2 and Ken Farrington1

Departments of 1Renal Medicine and 2 Dermatology, Lister Hospital, Coreys Mill Lane, Stevenage, Hertfordshire, UK

Keywords: porphyria; haemodialysis; intravenous iron; bullous dermatosis



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Bullous dermatosis of haemodialysis (HD) was first documented by Gilchrest in 1975 [1], in a report describing five patients with cutaneous disease indistinguishable from porphyria cutanea tarda (PCT), but with no detectable abnormalities of porphyrin metabolism. It has since become clear that dialysis patients do have modestly elevated plasma porphyrin levels, with a pattern of accumulation that is similar, but not identical to that which occurs in PCT [2]. The term ‘pseudoporphyria’ has been used to describe dialysis patients with this PCT-like syndrome. This terminology is misleading, as pseudoporphyria is generally used to describe drug eruptions that mimic PCT, in patients with completely normal porphyrin metabolism. PCT is the commonest of the porphyrias, therefore it is not surprising that cases of true PCT have now been described in dialysis patients [3].

The relationship between iron overload and PCT has long been recognized [4] and venesection remains the cornerstone of treatment. Paradoxically, contemporary HD patients tend to have functional iron deficiency requiring aggressive iron supplementation, often in the form of intravenous iron. This report describes a patient who developed a PCT-like syndrome following a course of intravenous iron.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 52-year-old Caucasian lady with adult polycystic kidney disease (on renal replacement therapy since 1991) presented to the dermatology clinic in October 1999 with a 2-month history of a blistering, pruritic rash on the dorsum of the hands and forearms. On examination, she had numerous unilocular bullae on the dorsum of both hands with hyperpigmented atrophic macules and widespread atrophic scarring from previous bullae, but no milia. There was no evidence of pseudoscleroderma or facial hypertrichosis. The clinical diagnosis was judged to be either bullous dermatosis of dialysis or pemphigoid. A biopsy was taken and the patient was commenced on prednisone 20 mg daily. Two weeks later there had been no improvement and the prednisone was discontinued. The biopsy demonstrated a subepidermal bulla, with preservation of the dermal papillae and no acantholysis or inflammation. Direct immunofluorescence for IgA, IgG, IgM and C3 was negative. The results of the porphyrin analysis of blood, stool and urine are given in Table 1Go (porphyrin analysis was performed as previously described [3]). The pattern and degree of abnormal porphyrin metabolism indicated a defect in the haem biosynthetic pathway at the level of uroporphyrinogen decarboxylase (URO-D). On the basis of the biochemical findings a diagnosis of PCT was made and a search for risk factors was instituted.


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Table 1. Porphyrin analysis of plasma, erythrocytes, urine and stool, at presentation

 
At the time of presentation with the dermatosis, she was receiving thrice-weekly on-line haemodiafiltration using a high-flux, polysulfone membrane and ultra-pure water (2 pool Kt/V 1.3). Her residual renal function was negligible, although she did pass approximately 30 ml of urine daily. Relevant medications included epoietin (120 iu/kg/week) and ethinyloestradiol (commenced 1991 as hormone replacement therapy). No new drugs had been prescribed in the preceding 3 months. For 15 months prior to presentation, weekly 50 mg doses of intravenous ferrous saccharate (Venofer®, Syner-Med, Croydon, UK) had been administered in accordance with a standardized unit protocol. Over this period the serum ferritin had risen from 272 ng/ml to 668 ng/ml, although the percentage of hypochromic red cells remained modestly elevated at 7.1% (0–5). Her haemoglobin was 11.3 g/dl, white cell count 4.4x109/l, platelet count 126x109/l and C reactive protein 7 mg/l. She was hepatitis B surface antigen negative and hepatitis C antibody and RNA negative. HFE genotype by polymerase chain-reaction was normal.

One month after presentation, the intravenous iron was discontinued and over the following 2 months the rash resolved completely, with no other change in treatment or dialysis prescription. Repeat analysis of plasma taken 8 months later demonstrated a similar degree of disturbance of porphyrin metabolism, consistent with a diagnosis of true PCT. The patient remains in remission to date and the ferritin has fallen to 258 ng/ml.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
The biochemical abnormalities in this patient are diagnostic of a true PCT, despite the difficulties associated with the interpretation of urinary porphyrins in patients who are almost anuric [3]. In particular, the presence of isocoporphyrins and the hepta/hexa/ penta-carboxylate porphyrins in the faeces are characteristic and are not a feature of uraemia alone [2,3]. A ratio of uroporphyrin to heptacarboxylate porphyrin in the plasma of >8 in dialysis patients is said to exclude true PCT [5]. The urinary ratio (which reflects the plasma ratio) in this case was 2, suggesting a diagnosis of PCT.

The majority of cases of PCT are sporadic rather than familial, and a variety of co-factors are associated with phenotypic expression of the disease. An almost universal co-factor is hepatic iron overload, present in greater than 80% of patients with sporadic PCT [4]. A molecular basis for this is now emerging with the discovery that there is an over representation of the Cys282Tyr allelic variant of the haemochromatosis gene (HFE) in patients with PCT [6]. Furthermore, evidence from animal models indicates that excess iron contributes to the inhibition of hepatic URO-D [7]. Environmental sources of liver injury, particularly chronic hepatitis C and alcohol, may contribute to this phenomenon.

This patient did not have an abnormal HFE genotype, had not been exposed to hepatitis C and consumed no alcohol. However, during the 15 months prior to presentation she had received 3.25 g of intravenous elemental iron, prescribed according to a standardized protocol. Her ferritin was high, but within the range recommended in published guidelines for HD patients [8]. We decided, in the first instance, to withdraw the intravenous iron and her skin rapidly improved. We did not stop her oestrogen therapy, which was the other obvious potential precipitant of PCT. Since stopping the iron her skin has remained disease free through a further summer. The fact that her porphyrin profile did not improve illustrates the poor correlation between phenotypic expression and the degree of metabolic disturbance observed for all of the porphyrias.

How important is this rare association in the context of the ever-increasing use of intravenous iron by dialysis practitioners? Our patient had sporadic PCT, but all dialysis patients have modest elevations of plasma porphyrins [2,3] and it has been suggested that up to 16% of HD patients suffer from bullous skin disorders [9]. Moreover, HFE mutations are common, with 11% of healthy controls having at least one copy of the Cys282Tyr mutation [6].

Why do uroporphyrins accumulate in dialysis patients? Reduced urinary clearance is the principal mechanism, combined with the inefficiency of dialysis at removing protein-bound ‘middle molecules’. There is also evidence that erythrocyte URO-D and {delta}-aminolaevulinic acid dehydratase are inhibited in HD patients [5]. There are no specific data on hepatic URO-D in uraemia, but this case raises the possibility that the activity of the hepatic enzyme may be influenced by the aggressive iron supplementation. Given that many dialysis patients have fragile skin that is prone to bullous disease and modestly elevated plasma porphyrins, such an effect should temper nephrological enthusiasm for liberal use of intravenous iron.

This report cannot establish a definite link between intravenous iron supplementation and abnormal haem metabolism in dialysis patients, but it is likely that iron therapy contributed to the phenotypic expression of PCT in this case. Various approaches for the treatment of bullous dermatosis in HD patients have been proposed, including high-flux HD, haemofiltration, plasma exchange, transplantation as well as small volume venesection with epoietin therapy [3]. Our case illustrates that the modest improvement in porphyrin clearance achieved by on-line haemodialfiltration is insufficient to prevent disease. Given what is already known about porphyrin metabolism and iron load, we propose that in patients on iron therapy discontinuation of intravenous supplementation is a reasonable first approach. In the future, specific data on the relationship between intravenous iron and haem metabolism may add to recent concerns regarding excessive use of intravenous iron in dialysis patients.



   Acknowledgments
 
The authors wish to acknowledge the assistance of Dr Allan Deacon, SAS Porphyria Service, Department of Clinical Biochemistry, King's College Hospital, London, for advice on interpretation of the porphyrin analyses performed by his laboratory.



   Notes
 
Correspondence and offprint requests to: Dr William McKane, Department of Renal Medicine, Lister Hopital, Coreys Mill Lane, Stevenage, Herfordshire SG1 4AB, UK. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Gilchrest B, Rowe JW, Mihm MC Jr. Bullous dermatosis of hemodialysis. Ann Intern Med1975; 83: 480–483[ISI][Medline]
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  6. Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet1997; 349: 321–323[ISI][Medline]
  7. Kushner JP, Steinmuller DP, Lee GR. The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase. J Clin Invest1975; 56: 661–667[ISI][Medline]
  8. NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis1997; 30: S192–S240[ISI][Medline]
  9. Thivolet J. Pseudoporphyria cutanea tarda in hemodialysis patients. Hautarzt1979; 30: 154–157[ISI][Medline]
Received for publication: 27.11.00
Revision received 24. 4.01.



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