Patients with chronic kidney disease can have many dermatological manifestations. One of the very rare conditions is porphyria cutanea tarda (PCT), which manifests with hyperpigmentation of skin and photosensitivity along with painful bullae in sun-exposed areas. It is due to deficiency of uroporphyrinogen III decarboxylase enzyme which takes part in heme synthesis. The deficiency could be genetic or sporadic. Iron therapy and hepatitis C infection are known to precipitate these lesions. We report a case of PCT in a woman undergoing chronic maintenance hemodialysis, review the literature, and discuss the problems with management specific to the dialysis population.
Keywords: Bullous lesion, dermatological manifestation, dialysis, hyperpigmentation, iron therapy, porphyria cutanea tarda
|How to cite this URL:|
Anupama YJ, Parameshwara YR. Porphyria cutanea tarda: An uncommon condition in a patient on chronic hemodialysis. APIK J Int Med [Epub ahead of print] [cited 2022 Oct 6]. Available from: https://www.ajim.in/preprintarticle.asp?id=338150
| Introduction|| |
Porphyrias are rare disorders caused due to deficiency or reduced activity of enzymes in heme biosynthetic pathway. These enzymes participate in the conversion of the heme precursor compounds to heme, an essential component of the hemoglobin molecule. Porphyria cutanea tarda (PCT) is the most common of the porphyrias and is due to deficiency of enzyme that catalyzes the fifth step in the heme pathway. It is uncommonly reported among patients with chronic kidney disease and patients undergoing hemodialysis. Management of the condition is not clearly defined and poses some unusual problems in the dialysis population. Here, we report a case of PCT in a dialysis patient and review the literature.
| Case Report|| |
A 45-year-old woman who was undergoing hemodialysis twice weekly for a year complained of a gradual darkening of complexion over the past 3 months. She was hypertensive and was diagnosed to have chronic kidney disease 2 years ago and had commenced chronic hemodialysis a year later, brachiocephalic arteriovenous fistula being the vascular access. She had no other comorbidities. Her medications included nifedipine, hydralazine, calcium supplements, and sodium bicarbonate. She was receiving IV iron sucrose 200 mg/week and erythropoietin alfa 10000 units once a week. In February 2018, she had a hemoglobin level of 7.8 g/dl with transferrin saturation of 16.6% and ferritin levels of 1021 ng/ml. She was advised to reduce iron sucrose dose to 100 mg/week. She complained about the darkening complexion in May 2018 and she was advised a reduced dose of iron sucrose, 100 mg once every 2 weeks. In September 2018, she noted small blisters on fingertips and toe tips, which were excruciatingly painful. The blisters occurred singly and asymmetrically, and after a few days healed without treatment, with scarring [Figure 1],[Figure 2],[Figure 3]. She also complained of burning sensation of facial skin when she was exposed to direct sunlight. She gave no history of similar skin lesions or photosensitivity in the past. At this time, her hemoglobin, transferrin saturation, and ferritin levels were 11.4 g/dl, 32.3%, and 1728 ng/ml, respectively. Other biochemical parameters were as follows: Blood urea 74 mg%, serum creatinine 7.4 mg%, bicarbonate 18 mmol/l, serum sodium, and potassium of 135 and 4.5 mmol/l. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated 56.8 and 79 u/l, serum bilirubin was 0.4 mg/dl. She tested negative both for hepatitis B surface antigen and hepatitis C antibody. Dermatology opinion was taken. A clinical diagnosis of PCT was reached. Iron sucrose was discontinued. She was advised topical application of sunscreens and avoidance of exposure to sunlight. One unit phlebotomy was done and she was started on oral hydroxychloroquine 100 mg/day. After the phlebotomy, she noted orange discoloration of urine. There was a distinct purple hue to the urine when ultraviolet light was shone through the container, confirming the presence of porphyrins in the urine. Analysis of spot urine sample for porphyrins by high-performance liquid chromatography revealed elevated urine uroporphyrin-to-creatinine ratio; elevated penta, hexa, and hepta porphyrin levels; and elevated uroporphyrin-to-coproporphyrin ratio [Table 1]. URO-decarboxylase enzyme (UROD) activity was grossly decreased. A diagnosis of PCT was established. Small-volume phlebotomy (letting out 50 ml blood at the end of each dialysis sitting) was carried out for 4 weeks. High-flux dialysis was done. After discontinuation of iron, the rate of eruption of painful blisters slowed down and they gradually disappeared. As she developed worsening of hyperpigmentation of skin with HCQS, it was also discontinued. The skin pigmentation subsided partially over the next few months. One year later, there was a fall in hemoglobin to 9 g/dl and improvement in liver functions (AST20.8 and ALT 24.7 iu/l, respectively). Porphyrin levels and UROD levels almost remained the same. Tsat was 25.6% and ferritin had dropped to 720 ng/ml. To correct anemia, iron supplementation was required and she was treated with oral liposomal iron with the presumption that the intestinal route of iron entry to the body would allow a gradual supply of iron to the bone marrow and would not overwhelm the body with iron load as with intravenous route. However, within a month of oral iron use, she again developed a mild increase in pigmentation of skin and recurrence of painful blisters in the hands and feet. After discontinuation of iron, a gradual improvement in clinical signs was again noted. She is now being continued on erythropoietin alone.
|Table 1: Porphyrin and enzyme levels in the patient at diagnosis and a year after that|
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| Discussion|| |
PCT is a rare clinical problem affecting 1 in 10000 people worldwide. It occurs as a result of low levels of the enzyme responsible for the fifth step in heme production. The enzyme uroporphyrinogen III decarboxylase acts on uroporphyrinogen and converts it to coproporphyrinogen which is then converted to protoporphyrin and then incorporated into heme molecule. In the absence of the enzyme, the uroporphyrinogen accumulates and is converted to uroporphyrin. Iron, by facilitating the formation of free oxygen radicals, oxidizes uroporphyrins which get preferentially deposited in the skin, especially in parts exposed to sunlight. The oxidized porphyrins facilitate mast cell degranulation in the dermis, resulting in release of proteases locally and thereby, lysis of surrounding proteins, creating blisters. The porphyrins are a deep purple color and their deposition in the skin gives it a distinct dark color.
PCT can occur as an inherited condition in 20% of cases, while it is acquired or sporadic in 80% of cases. Type I PCT includes sporadic cases where there is a deficiency of UROD enzyme limited to hepatic cells. In addition to iron therapy, alcohol, estrogens, hepatitis C virus infection, Vitamin A deficiency, and selenium deficiency also precipitate this condition. In Type II PCT, there is usually a genetic defect and the deficiency of the enzyme is seen in all cells. Mutation involving the UROD gene which encodes for the UROD enzyme is the most common genetic abnormality and is an autosomal dominant defect. Rarely, there may be mutations of the Human haemochromatosis gene (HFE) gene, the protein product of which regulates iron absorption in the gut. Iron, alcohol, and hepatitis C infection also exacerbate the underlying genetic defect and may unmask the defect as some people with the genetic defects can live normally throughout life if not exposed to these precipitating factors.
Treatment of PCT involves correction of the precipitating factors. Avoiding exposure to sunlight, cessation of iron supplements, and stopping alcohol use are necessary. Hydroxychloroquine and chloroquine have been tried as they conjugate with the porphyrins and form water-soluble compounds which can then be easily excreted in urine. Phlebotomy is useful to reduce iron content in the body. Intravenous desferoxamine has been used to chelate iron but caries the risk of sepsis. It has also been tried as a subcutaneous infusion.
PCT is a rare condition among dialysis patients. It must be differentiated from pseudoporphyria which clinically resembles PCT, but there are no demonstrable porphyrins in blood or urine. Hepatitis C infection and regular Iron therapy are risk factors for this rare condition in the patients undergoing chronic maintenance dialysis. It is difficult to treat these patients as there is limited excretion of porphyrins through the kidneys. Uroporphyrins are not readily removed by routine dialysis and are only removed partially using high-flux dialyzers. Plasma exchange, high-volume hemofiltration, and charcoal hemadsorption are other modalities that have been tried. Phlebotomy is less well tolerated by anemic patients and hydroxychloroquine is contraindicated in patients on dialysis. Cessation of iron therapy should be done in all such patients, but they are then at risk of developing iron deficiency as a result of increased iron demand due to erythropoiesis. In some patients, the use of alternative iron compounds has been tried and ferric carboxymaltose has been used successfully in some reported cases.
Our patient has a severe reduction in UROD enzyme activity and probably has inherited PCT, as the reduced activity could be demonstrated in peripheral blood. Iron therapy precipitated the phenotypic expression. The blisters disappeared after cessation of iron therapy. We resorted to phlebotomy and multiple sittings of small-volume phlebotomy during dialysis to reduce iron stores over 1 month which helped to induce clinical remission. We also switched over to high-flux dialysis. Although clinically she does not have any phenotypic expression of PCT presently, the porphyrin levels and enzyme activity remained the same even after 1 year of stopping iron again indicating the underlying genetic defect. She has a demonstrable iron deficiency now, but reinitiating iron with a smaller oral iron dose again caused a recurrence of blisters and treatment of anemia remains a challenge.
| Conclusions|| |
PCT is a rare condition and can affect patients on dialysis. Hepatitis C and iron therapy are two important causes that may precipitate this bullous disorder. It must be differentiated from pseudoporphyria which can also cause similar bullous photosensitivity. Treating anemia in dialysis patients with PCT can be challenging.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Yedabettu Janardhana Anupama,
Department of Nephrology, Nanjappa Hospital, Shivamogga - 577 201, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]