Human immunodeficiency virus and risk of porphyria cutanea tarda: a possible association examined in a large hospital.

BACKGROUND: Human immunodeficiency virus (HIV) infection has been reported to be a risk factor for porphyria cutanea tarda (PCT). PURPOSE: To assess the strength of the association between HIV infection and PCT in a large hospital setting. METHODS: All patients (N = 210) diagnosed of PCT between 1990 and 2014 were retrospectively investigated for HIV infection and co-precipitating factors. High-performance liquid chromatography was used to assess the appearance of pre-PCT urinary porphyrin abnormalities among a group (N = 22) of HIV-infected patients without PCT using the urine of patients co-infected with hepatitis C virus (HCV) without PCT for comparison. RESULTS: Twenty-six HIV-infected patients (19 males and seven females) were diagnosed of PCT. During the same interval of time, ~8000 different patients infected with HIV were attended in the hospital of infectious diseases department. Examination of risk factors showed that 25 out of 26 of the PCT patients with HIV were co-infected with HCV. No chromatographic abnormalities were found in the urine of non-PCT-HIV-infected patients, whereas 39% co-infected patients showed urinary porphyrin abnormalities. CONCLUSIONS: In our large hospital series, the appearance of PCT among HIV-infected patients is low (<1%) and most present co-infection with HCV. Therefore, in most HIV-infected patients with PCT, hepatitis C and not HIV may induce uroporphyrinogen decarboxylase deficiency.

Deferasirox for porphyria cutanea tarda: a pilot study.

OBJECTIVE: To determine the efficacy and safety of deferasirox (an oral iron-chelating agent approved to reduce iron stores in patients with chronic iron overload due to blood transfusions) in a pilot trial for the treatment of patients with porphyria cutanea tarda (PCT), the most common of the porphyrias and often difficult to treat. DESIGN: Prospective, open-label, noncomparative study. SETTING: University-affiliated tertiary health care center in Dallas, Texas. PATIENTS: Ten patients with PCT were enrolled in this 6-month study. The diagnosis was established by documenting the presence of elevated porphyrin level in the urine and a history of developing 3 or more blisters per month for at least 3 months prior to enrollment. Patients were treated with 250 mg/d of deferasirox, with an increase to 500 mg/d after 2 months if new blisters continued to develop. MAIN OUTCOME MEASURE: The improvement in number of blisters at the end of the 6-month treatment period was assessed. RESULTS: Of 10 patients, 8 completed the study. Seven had resolution of blistering, 6 had a reduction in urinary porphyrin levels, and 7 had a reduction in ferritin levels. The treatment was well tolerated. CONCLUSIONS: In this small pilot study, deferasirox induced improvement in cutaneous findings of PCT in 8 patients who completed 6 months of treatment. Most patients also had a substantial reduction in urinary porphyrin and ferritin levels. Future larger controlled studies are needed to confirm these findings. Deferasirox may be a useful alternative to existing treatment modalities for PCT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00599326.

Mast cells and transforming growth factor-beta expression: a possible relationship in the development of porphyria cutanea tarda skin lesions.

BACKGROUND: Porphyria cutanea tarda (PCT) is a metabolic disease characterized by vesicles and blisters in sun-exposed areas and scleroderma-like lesions in sun-exposed and non-sun-exposed areas. Mast cells participate in the pathogenesis of bullous diseases and diseases that show sclerosis, including PCT. Moreover, transforming growth factor-beta (TGF-beta) is the main cytokine in the development of tissue sclerosis. The correlation of mast cells and TGF-beta with the lesions of PCT has not been examined, however. The possible role of mast cells and TGF-beta (and the relationship between them) in the development of PCT lesions is discussed. METHODS: To quantify mast cells and cells expressing TGF-beta in skin samples from patients with PCT and controls, immunohistochemical studies were performed in tissue sections allied to morphometric analyses. RESULTS: The numbers of mast cells and cells expressing TGF-beta per square millimeter were increased in the PCT group relative to controls, and there was a direct and significant correlation between the mast cell number and cells expressing TGF-beta in PCT. CONCLUSIONS: The results suggest that the increased number of mast cells and of cells expressing TGF-beta, as well as their direct correlation, may contribute to the pathogenesis of the skin lesions in PCT.

Porphyria cutanea tarda: effects and risk factors for hepatotoxicity from high-dose chloroquine treatment.

High-dose chloroquine therapy for porphyria cutanea tarda is rarely used now because of its hepatic side-effects. The mechanisms of the effects and side-effects are poorly understood. We describe here effects, side-effects and long-term follow-up in 57 patients with a first-time diagnosis of porphyria cutanea tarda treated with 1-3 phlebotomies followed by 250 mg chloroquine phosphate daily for 7 days. A hepatotoxic reaction with high serum aminotransferases occurred in almost all patients. Within 3 months, clinical remission was obtained in all patients, and biochemical remission in almost all patients. Relapse occurred in 27 patients after 0.5-12 years. Subjective side-effects occurred more frequently in women, who also had higher maximum ALAT, ferritin and uroporphyrin values during treatment. Both subjective side-effects and ALAT during treatment correlated with pre-treatment uroporphyrin excretion and maximum uroporphyrin during treatment, but not with markers of hereditary haemochromatosis.

Effects of vitamin E administration on the hemorheological status and redox homeostasis of patients with porphyria cutanea tarda treated with phlebotomy.

BACKGROUND: Conflicting results were reported about the efficacy of vitamin E (E) treatment in porphyria cutanea tarda (PCT). We conducted a study in PCT patients to investigate whether E treatment has any additional beneficial effects compared with phlebotomy (P) treatment alone on rheological and oxidative stress parameters. METHODS: Twenty three patients with sporadic PCT in clinical remission and 10 healthy control patients were studied. All patients were treated with P prior to the study until clinical remission was achieved. Baseline routine laboratory [blood glucose, serum lipids, C-reactive protein (CRP), iron metabolism indices, liver function tests], oxidative stress [serum thiobarbituric acid reactive substances (TBARS), plasma H-donor activity, plasma free SH-groups, erythrocyte glutathion peroxidase activity] and rheological parameters (whole blood and plasma viscosity, cell transit time, clogging rate) were measured in both groups. Then all PCT patients received E (tocopherol acetate) 200 mg/day for 8 weeks and at the end of treatment measurements identical to those performed at baseline were repeated. RESULTS: Increased urine uroporphyrin, serum CRP, TBARS concentrations, whole blood and plasma viscosity and decreased plasma H-donor activity, free SH-group level, erythrocyte glutathione peroxidase activity were detected in PCT patients treated with P alone compared with control group consistent with residual oxidative stress in PCT patients. E treatment decreased urine uroporphyrin and serum TBARS concentrations; increased plasma H-donor activity and did not influence whole blood and plasma viscosity compared with P treatment alone. CONCLUSIONS: E treatment reduced the residual oxidative stress and did not influence increased plasma and whole blood viscosity present in PCT patients receiving P treatment prior to clinical remission.

Porphyria cutanea tarda in a Swedish population: risk factors and complications.

There are varying reports on the prevalence of risk factors in porphyria cutanea tarda (PCT). We reviewed 84 patients with PCT in a restricted uptake area in Gothenburg, Sweden and evaluated different potential risk factors for the disease and complications. Besides a thorough medical history, the patients were investigated with urinary porphyrin analyses, transferrin saturation, ferritin and liver tests. Subsamples of patients were tested for antibodies to hepatitis C virus (n = 68), haemochromatosis gene mutations (n = 58) and with the oral glucose tolerance test (n = 31). We found a prevalence of about 1 patient with PCT in 10 000 inhabitants. Nineteen (23%) patients reported heredity for PCT. Identified risk factors were alcohol abuse (38% of male patients), oestrogen treatment (55% of female patients), anti-hepatitis C virus positivity (29% of male patients), diabetes (17%) or impaired glucose tolerance (45% of tested patients) and haemochromatosis gene mutations (57% of tested patients). All patients positive for anti-hepatitis C virus belonged to the non-hereditary group. During follow-up we observed a high incidence of stroke, no case of hepatocellular carcinoma and a normal life expectancy.

Variegate porphyria.

Variegate porphyria is a rare, hereditary form of hepatic porphyria characterized by acute systemic symptoms as in acute intermittent porphyria in addition to cutaneous symptoms simulating porphyria cutanea tarda. We describe a 22-year-old female from India who first presented to the emergency department with acute symptoms and was later confirmed to have variegate porphyria.

Long-standing changes in the urinary profile of porphyrin isomers after clinical remission of porphyria cutanea tarda.

Patients with overt porphyria cutanea tarda (PCT) show a distinctive and abnormal urinary profile of porphyrin excretion. It is not known, however, whether clinical remission of the disease produces complete normalization of this profile. We selected 46 patients, previously diagnosed with PCT, who after treatment presented normal levels of total porphyrins in urine (< 35 nmol/mmol creatinine). We analyzed their urine specimens by hplc to identify and quantify the various porphyrins and we compared the urinary porphyrin profiles to those of 40 healthy volunteers. While healthy volunteers gave a pattern dominated by excretion of coproporphyrin III, 80% of the PCT patients in clinical remission showed the characteristic profile of PCT, with decreased coproporphyrin-to-uroporphyrin ratio and/or inversion of the normal coproporphyrin III-to-coproporphyrin I ratio. Detection of uroporphyrin III and heptacarboxyl III intermediates was significantly more common among the patients than the controls (p < 0.05). This study shows that PCT patients demonstrate persistent changes in urinary porphyrin profiles during clinical remission, even when total urinary porphyrin excretion has fallen to the normal range.

Autoantibodies in sporadic porphyria cutanea tarda.

In an investigation of autoimmune antibodies using indirect immunofluorescence and Western blot analysis in a group of porphyria cutanea tarda patients we did not find any cytosolic antibodies potentially able to inhibit uroporphyrinogen decarboxylase. Furthermore, no known etiological factors were present in any of our patients. We therefore consider the development of the recently reported autoantibody with a molecular weight of 40 kDa a reaction to infection with the hepatitis C virus. The origin of mostly antinuclear antibodies against liver antigens (50, 45 and 56 kDa), detected in seven patients, was not identified and their etiopathogenetic implications remain unknown.

Serum organochlorines and urinary porphyrin pattern in a population highly exposed to hexachlorobenzene.

BACKGROUND: Porphyria cutanea tarda (PCT) is caused by hexachlorobenzene (HCB) in several species of laboratory mammals, but the human evidence is contradictory. In a study among adults of a population highly exposed to HCB (Flix, Catalonia, Spain), the prevalence of PCT was not increased. We aimed at analysing the association of individual urinary porphyrins with the serum concentrations of HCB and other organochlorine compounds in this highly exposed population. METHODS: A cross-sectional study on total porphyrins was carried out in 1994 on 604 inhabitants of the general population of Flix, older than 14 years. Of them, 241 subjects (comprising a random sample and the subgroup with the highest exposure) were included for the present study. The porphyrin profile was determined by high-pressure liquid chromatography. Serum concentrations of HCB, as well as common organochlorine compounds, were determined by gas chromatography coupled to electron capture detection. RESULTS: Coproporphyrin I (CPI) and coproporphyrin III (CPIII) were the major porphyrins excreted, while uroporphyrins I and III were only detected in 2% and 36% of the subjects respectively, and heptaporphyrins I and III in 1% and 6%, respectively. CPI and CPIII decreased with increasing HCB concentrations (p < 0.05). This negative association was not explained by age, alcohol, smoking, or other organochlorine compounds. No association was found between uroporphyrin I and III excretion, nor heptaporphyrin excretion, and HCB. CPIII increased with smoking (p < 0.05). CONCLUSION: HCB exposure in this highly exposed population did not increase urinary concentrations of individual porphyrins.

The decrease in uroporphyrinogen decarboxylase activity induced by ethanol predisposes rats to the development of porphyria and accelerates xenobiotic-triggered porphyria, regardless of hepatic damage.

We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.

Porphyria cutanea tarda presenting as cicatricial conjunctivitis.

PURPOSE: To report a case of porphyria cutanea tarda presenting as cicatricial conjunctivitis. DESIGN: Observational study. METHODS: A 31-year-old man presented with bilateral inferior symblepharon, superior tarsal conjunctival scarring and concretions, and recurrent conjunctival and episcleral injection. RESULTS: Four years after initial presentation, the patient developed hepatitis C, and 2 years later blisters on his scalp and hands. Direct immunofluorescence studies of biopsies taken from the palpebral conjunctiva of the right lower lid were negative for cicatricial pemphigoid. A twenty-four hour urine specimen analysis revealed elevated levels of uroporphyrins and polycarboxylated porphyrins, confirming the diagnosis of porphyria cutanea tarda. The patient was treated with repeated phlebotomies and oral hydroxychloroquine, which resulted in a significant decrease in the skin lesions, conjunctival injection, and concretions under the upper lids. CONCLUSIONS: Cicatricial conjunctivitis may be a manifestation of porphyria cutanea tarda.

High-dose vitamin E lowers urine porphyrin levels in patients affected by porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is a metabolic disorder of heme biosynthesis, characterized by reduced uroporphyrinogen decarboxylase (UROD) activity and increased urinary excretion of eight and seven carboxyl group porphyrins. Specific factors such as iron, alcohol and halogenated compounds further inhibit enzyme activity by generating reactive oxygen species. Antioxidant vitamin E has frequently been used to counteract oxidative stress in porphyria patients, but a number of studies have failed to detect any significant effect on porphyrin metabolism. Since the use of vitamin E in the treatment of porphyria is a debated question, it seemed of interest to administer high doses to five patients with PCT in order to evaluate the effects on urine porphyrin excretion. The patients had high urinary porphyrin excretion levels, but vitamin E significantly reduced the urinary excretion of eight carboxyl group porphyrins. This result is attributable to the increase in UROD activity caused by the vitamin, which is a known scavenger of the oxygen reactive species that interfere with the activity of the enzyme. In conclusion, this paper shows that vitamin E high doses significantly lowers the urine porphyrin excretion in studied patients affected by PCT.