OR WAIT null SECS
In most HIV-infected persons, one or more dermatological conditions develop at some point during their lifetime.1 Among the spectrum of dermatological diseases, those associated with pruritus are among the most common.
In most HIV-infected persons, one or more dermatological conditions develop at some point during their lifetime.1 Among the spectrum of dermatological diseases, those associated with pruritus are among the most common.2
Common causes of pruritus are eosinophilic dermatitis, prurigo nodularis, pruritic pustular eruption, eczema, xerosis, fungal folliculitis, scabies, tinea corporis and tinea pedis, contact dermatitis, and hypersensitivity drug reactions. However, even with specialist evaluation, pruritus remains undiagnosed in a substantial number of persons who have the primary symptom of the condition. For example, a recent study from an urban HIV dermatology clinic reported that 6% of all referrals were for cryptogenic pruritus.2
Here we report a case of a patient who presented with severe pruritus as an unusual presentation of porphyria cutanea tarda, a common condition among HIV-infected persons coinfected with hepatitis C virus (HCV).
In June 2006, 2 weeks after completing a 48-week treatment regimen of pegylated interferon and ribavirin for hepatitis C and achieving an HCV RNA level below the limit of detection, a 48-year-old HIV-infected African American woman developed severe pruritus on her forearms and the anterior aspect of her hands. Two weeks after the pruritus developed, she presented to her regular HIV care provider for an acute clinical evaluation for this problem.
The patient's medical history included paranoid schizophrenia and obesity. Her surgical history was notable for a total abdominal hysterectomy 10 years ago. Her nadir CD4+ cell count was 76/µL; however, after 2 years of suppressive antiretroviral therapy, her CD4+ cell count had risen to 366/µL. Previously, pruritus and a rash developed while the patient was taking trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis, and severe neutropenia had developed while she was taking zidovudine. Her antiretroviral regimen at presentation was ritonavir-boosted lopinavir coformulation plus a fixed-dose combination of tenofovir/emtricitabine. She was also taking risperidone.
The patient smoked approximately half-a-pack of cigarettes a day but did not drink alcohol. She had a history of injection drug use, but this problem was in remission. She was unemployed and was on disability because of her HIV infection; however, she frequently supervised her daughter's and sister's young children. None of the children had rashes at the time the patient's symptoms developed. She denied exposure to new soaps, new cleaning products, pets, environmental changes, or new medications.
On examination, the patient appeared agitated and had deep excoriations on her hands and forearms. A dermatologist examined her during this visit and diagnosed eczema; triamcinolone ointment and topical emollients were prescribed. She had mild relief of symptoms with this regimen. However, several weeks later she returned with pruritus severe enough to interfere with sleep and normal activities during the day. At this time, she indicated that her pruritus had spread from her arms to include her chest, back, and legs. She also described "bumps" on her hands and ears, arising in areas of intense pruritus. During this second examination, deep excoriations and hyperpigmentation with hypopigmented macules, hypopigmented papules (measuring 1 mm), and several fluid-filled vesicles were noted on her hands (Figure 1) and forearms. Tests for urinary and serum porphyrins, measurement of ferritin level, and a complete blood count were performed (Table).
Figure 1.Before treatment. Left hand of a 48-year-old African American woman with porphyria cutanea tarda who was coinfected with HIV and hepatitis C virus.
Porphyria cutanea tarda was diagnosed based on the clinical pre-sentation of bullous lesions in sun-exposed areas, hyperpigmentation, milia, and a porphyrin profile of markedly elevated levels of urinary uroporphyrins and heptaporphyrins; phlebotomy therapy was started. Within days of the patient's first phlebotomy session, she noted significant improvement in symptoms. After her third phlebotomy session, her pruritus resolved, no new vesicles developed in sun-exposed areas, and her skin changes began to normalize (Figure 2). At her 6-month follow-up, her HCV RNA level was undetectable (ie, sustained virological response), her HIV infection remained fully suppressed, and she was without pruritus.
Figure 2.After treatment. Left hand of a 48-year-old African American woman with porphyria cutanea tarda who was coinfected with HIV and hepatitis C virus.
Porphyria cutanea tarda is 1 of 7 porphyrias, a group of diseases that arise as a result of defects in heme biosynthesis and lead to the accumulation of heme precursors.3 Common findings of porphyria cutanea tarda are hyperpigmentation, milia, and skin fragility.4 A combination of hypertrichosis and alopecia is also a common finding in porphyria cutanea tarda. In addition, porphyrin pigment may be visible in urine and may fluoresce pink with UV radiation. Fluid-filled vesicles are the most useful diagnostic sign, but they may be transient, may not be seen during a clinic visit, and may not be noted by a patient. Vesicles observed in sun-exposed areas should always lead to consideration of porphyria cutanea tarda, especially in a person with hepatitis C, HIV infection, or liver disease. Although porphyria cutanea tarda can present primarily as pruritus, this presentation is unusual. As a result, porphyria cutanea tarda is not usually considered as part of the differential diagnoses of pruritic dermatoses.
Most heme is synthesized in the bone marrow for hemoglobin and in the liver for cytochromes. Smaller amounts of heme are required for myoglobin, catalase, guanylate cyclase, and nitric oxide synthase.5 With porphyrias related to abnormal heme synthesis in the liver (ie, hepatic porphyrias), abnormal concentrations of heme precursors lead to a spectrum of visceral, neuropsychiatric, hepatic, and cutaneous manifestations.6 Chronic cutaneous manifestations are most prominent with 3 of the hepatic porphyrias: variegate porphyria, hereditary coproporphyria, and porphyria cutanea tarda. In patients with porphyria cutanea tarda, symptoms are generally limited to the skin, whereas patients with variegate porphyria and hereditary coproporphyria classically present with neurological symptoms, muscle weakness, and abdominal pain.3 However, when variegate porphyria and hereditary coproporphyria are identified early, dermatological findings may be the only sign of disease.7,8
The defect in the heme biosynthetic pathway that leads to porphyria cutanea tarda is impaired function or expression of hepatic uroporphyrinogen decarboxylase (UROD).6 UROD is 1 of 8 enzymes involved in heme biosynthesis; it functions in the cell cytoplasm to catalyze the sequential removal of 4 carboxyl groups from the acetate side chains of uroporphyrinogen III to form coprophyrinogen III. When UROD activity is decreased below a certain threshold (around 50%), the 7 and 8 carboxyl group porphyrin heme precursors accumulate.9 Porphyrins with the 7 and 8 carboxyl group numbers are water-soluble, are excreted primarily in the urine, and are referred to as uroporphyrins and heptacarboxyporphyrins.9
UROD can become diminished either through genetic mutations in familial porphyria cutanea tarda (types II and III) or as a result of impaired activity of normally expressed UROD in sporadic (acquired) porphyria cutanea tarda (type I). Of the 3 forms, the sporadic form is by far the most common, accounting for 80% to 90% of cases. In sporadic porphyria cutanea tarda, it is believed that an inhibitor of hepatic UROD becomes activated, which decreases UROD activity.
Multiple disease states are associated with sporadic porphyria cutanea tarda, all presumably through inhibition of UROD activity. These diseases include hemochromatosis, alcoholism, chronic hepatitis C, HIV infection, myeloproliferative disorders, and hepatocellular carcinoma.3 In addition, chronic hemolysis and estrogen therapy have been associated with porphyria cutanea tarda. The proportion of porphyria cutanea tarda cases associated with each of these conditions varies by population. However, results of studies from Sweden, France, and Spain suggest that in many populations, hepatitis C is among the most common underlying diseases and is present in 20% to 80% of patients with sporadic porphyria cutanea tarda.10-12
In sporadic porphyria cutanea tarda, disordered iron homeostasis and hepatic iron overload appear to play a central role, possibly leading to activation of an inhibitor of UROD via an oxidation pathway. The importance of hepatic iron in porphyria cutanea tarda pathogenesis is suggested by mouse model studies and liver histopathology. In a mouse model of sporadic porphyria cutanea tarda, iron overload leads to increased buildup of uroporphyrins. Reduction of iron through either chelation or an iron-deficient diet leads to markedly lower accumulation of uroporphyrins in mice.13 Histopathological examination of liver biopsy specimens from humans with porphyria cutanea tarda typically shows hepatic siderosis.5 Further evidence of the role of iron overload in porphyria cutanea tarda comes from the success of treatment with phlebotomy and the associated reduction in total body iron stores.14
Dermal injury, the usual clinical manifestation of porphyria cutanea tarda, occurs through oxidative pathways. Uroporphyrins and heptacarboxyporphyrins are photoactive molecules that absorb visible violet light energy in sun-exposed dermis leading to an electron excitation state.4 When the porphyrins transition from the electron excitation state back to the resting state, surrounding molecules become oxidized, which leads to cellular injury, particularly in cell membranes. Disruption of cell membranes leads to increased mechanical fragility, dermal erosions, and cutaneous vesicles. Healing of these lesions leads to indolent sores that heal with milia, hypopigmentation, and scarring.3
In addition to dermal injury, porphyria cutanea tarda has been associated with hepatic malignant tumors; however, causation has not been established between porphyria cutanea tarda and malignant tumors.15,16 Whether porphyria cutanea tarda independently increases the risk of hepatocellular carcinoma among persons with chronic hepatitis C and iron hepatic siderosis is unclear. However, the development of porphyria cutanea tarda in a patient with chronic hepatitis C or with HIV infection may be a marker of worsening liver disease or of a malignant tumor. Thus, screening for liver cancer by serum marker (a fetoprotein) and hepatic imaging (ultrasonography) is appropriate whenever the diagnosis of porphyria cutanea tarda is made.
The standard therapies for porphyria cutanea tarda are phlebotomy (1 unit per week until the serum ferritin level normalizes) and low-dose chloroquine (125 to 250 mg twice weekly).14 Phlebotomy reduces iron overload and hepatic siderosis, which leads to decreased porphyrin production and may lead to rapid resolution of symptoms. Biochemical abnormalities persist longer, often for several months after initiating phlebotomy.14 Chloroquine can effectively control symptoms of porphyria cutanea tarda by forming water-soluble complexes with porphyrins; these complexes are more efficiently eliminated via the kidneys than are porphyrins. Treatment of an underlying cause of porphyria cutanea tarda, when identified, has the greatest chance of achieving a durable response and preventing a relapse of this porphyria. Indeed, treatment of hepatitis C is considered the primary treatment modality for HCV-associated porphyria cutanea tarda because this porphyria generally occurs only with active HCV disease.4
Remarkably, in the patient in this case, symptomatic porphyria cutanea tarda developed after complete suppression of HCV viremia. This is highly unusual because of the presumed relationship between active HCV disease and porphyria cutanea tarda. The presentation of porphyria cutanea tarda after the completion of therapy for hepatitis C was unexpected, and we are unaware of previously published cases reporting this timing in presentation.
The other unusual and noteworthy aspect of this case is the prominence of pruritus in this patient. While pruritus may accompany porphyria cutanea tarda, it is usually not severe.17 This case serves as a reminder that porphyria cutanea tarda should be part of a differential diagnosis of pruritus in persons with HIV infection or hepatitis C, even when the timing and presentation are atypical.
No potential conflict of interest relevant to this article was reported by the authors.
References1. Coldiron BM, Bergstresser PR. Prevalence and clinical spectrum of skin disease in patients infected with human immunodeficiency virus. Arch Dermatol. 1989;125:357-361.
2. Zancanaro PC, McGirt LY, Mamelak AJ, et al. Cutaneous manifestations of HIV in the era of highly active antiretroviral therapy: an institutional urban clinic experience. J Am Acad Dermatol. 2006;54:581-588.
3. Kauppinen R. Porphyrias. Lancet. 2005;365:241-252.
4. Murphy GM. The cutaneous porphyrias: a review. The British Photodermatology Group. Br J Dermatol. 1999;140:573-581.
5. Lambrecht RW, Thapar M, Bonkovsky HL. Genetic aspects of porphyria cutanea tarda. Semin Liver Dis. 2007;27:99-108.
6. Dombeck TA, Satonik RC. The porphyrias. Emerg Med Clin North Am. 2005;23:885-899, x.
7. Brodie MJ, Thompson GG, Moore MR, et al. Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood. Q J Med. 1977;46:229-241.
8. Kirsch RE, Meissner PN, Hift RJ. Variegate porphyria. Semin Liver Dis. 1998;18:33-41.
9. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. 2006;135:281-292.
10. Murphy A, Dooley S, Hillary IB, Murphy GM. HCV infection in porphyria cutanea tarda. Lancet. 1993;341:1534-1535.
11. Linde Y, Harper P, Floderus Y, Ros AM. The prevalence of hepatitis C in patients with porphyria cutanea tarda in Stockholm, Sweden. Acta Derm Venereol. 2005;85:164-166.
12. Gisbert JP, GarcÃa-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol. 2003;39:620-627.
13. Gorman N, Zaharia A, Trask HS, et al. Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda. Hepatology. 2007;46:1927-1934.
14. KÃ¶stler E, Wollina U. Therapy of porphyria cutanea tarda. Expert Opin Pharmacother. 2005;6:377-383.
15. Palmieri C, Vigushin DM, Peters TJ. Managing malignant disease in patients with porphyria. QJM. 2004;97:115-126.
16. Gisbert JP, GarcÃa-Buey L, Alonso A, et al. Hepatocellular carcinoma risk in patients with porphyria cuÂtanea tarda. Eur J Gastroenterol Heptol. 2004;16:689-692.
17. Sommer S, Wilkinson SM. Porphyria cutanea tarda masquerading as chronic hand eczema. Acta Derm Venereol. 2004;84:170-171.