Clinic and treatment of porphyria cutanea tarda (author's transl)]

Symptomatology and pathogenesis of porphyria cutanea tarda (PCT) are shortly reviewed. The different possibilities in the treatment of PCT are discussed with special reference to the phlebotomy according to Ippen and to the chloroquine administration according to the regimen described by Kordac and Semradova in 1974. 75 PCT patients were treated with chloroquine (Resochin, Nivaquine). After 9.3 +/- 3.4 months (means +/- SE) all patients excreted normal amounts of porphyrins, and the clinical symptoms disappeared. 14 of these patients relapsed after a mean period of 21 months after the withdrawal of chloroquine.     

Management of porphyria cutanea tarda in the setting of chronic renal failure: a case report and review

The treatment of porphyria cutanea tarda (PCT) in patients with chronic renal failure poses a therapeutic challenge. In the absence of renal failure, phlebotomy and oral antimalarials have been the standard of care for PCT. However, in the presence of renal failure, associated chronic anemia often precludes the use of phlebotomy, and oral antimalarials are usually ineffective. We describe a patient with severe symptomatic PCT and chronic renal failure whose disease was successfully managed with a combination of high-dose erythropoietin and small volume phlebotomy. We also review several previously reported approaches to management of PCT in the setting of renal failure, which include small repeated phlebotomy, erythropoietin, deferoxamine, chloroquine, plasma exchange, high-efficiency/high-flux hemodialysis, cholestyramine, charcoal hemoperfusion, and kidney transplantation. An algorithm for the management of these patients is proposed.     

Iron metabolism and chloroquine phosphate therapy in porphyria cutanea tarda

The knowledge about the influence of chloroquine phosphate (CQ) on the iron metabolism in porphyria cutanea tarda (PCT) is still insufficient. In a study on 138 PCT patients treated with CQ, we observed decreasing serum iron concentration, transferrin saturation, and hepatic siderosis, as well as an increasing level of transferrin. After a one-year therapy with CQ, the patients showed normal porphyrinuria. Since there were no statistical correlations between the degree of hepatic siderosis and porphyrinuria, and since we repeatedly found remission of the PCT in spite of the continued existence of hepatic siderosis, the removal of iron cannot be regarded as the only principle of action in CQ therapy. In comparison with chloroquine, phlebotomy obviously has--even with regard to the iron deposits--no decisive advantages.     

Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda

OBJECTIVE: To examine the role of hemochromatosis (HFE) gene mutations, which are associated with porphyria cutanea tarda (PCT), in the therapeutic response to chloroquine. DESIGN: We retrospectively analyzed a database (Excel version 2001 [Microsoft Excel, Redmond, Wash]; date range of search, 1985-1999) of chloroquine-treated patients with PCT on whether HFE mutations (C282Y and H63D) might have influenced the clinical response, urinary porphyrin excretion, liver enzyme activities, and serum iron markers. Serum samples and corresponding complete sets of data before and after therapy were available in 62 of 207 patients with PCT who were treated exclusively with chloroquine. SETTINGS: Academic teaching hospital. INTERVENTION: For treatment, low-dose chloroquine diphosphate, 125 to 250 mg twice weekly, was used during a median time of 16 months (range, 12-26 months). RESULTS: Of the 62 German patients with PCT, 37 (60%) carries HFE mutations. Chloroquine therapy was accompanied by clinical remission and reduced urinary porphyrin excretion (P<.001) in the 24 patients (39%) with HFE wild type as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum iron markers following chloroquine therapy were limited to patients with PCT and HFE wild type. All patients homozygous for the C282Y mutation (3 [5%] of 62) had high serum iron, ferritin, and transferrin saturation and failed to respond to chloroquine treatment. CONCLUSIONS: The therapeutic response to chloroquine was not compromised by C282Y heterozygosity and compound heterozygosity of HFE mutations. Because HFE C282Y homozygotes (+/+) did not respond to chloroquine and a decrease in serum iron concentration was limited to patients with PCT and HFE wild type, phlebotomy should be first-line therapy in patients with PCT and HFE mutations.     

Results of treatment of porphyria cutanea tarda with bloodletting and chloroquine

In 59 patients showing clear clinical and biochemical signs of porphyria cutanea tarda (PCT), we tested 3 different modes of therapy: 20 patients received combined treatment with repeated bleeding and chloroquine, 24 patients were exclusively treated with oral chloroquine in low doses, and 15 patients underwent repeated phlebotomy only. On an average, the time necessary for remission amounted to 3.5, 10.2, and 12.5 months, respectively. So the combined therapy proved the quickest. In patients with the acquired form of PCT, the pattern of urinary porphyrin normalized; those suffering from hereditary PCT retained the typically high uro/copro ratio. The values of the plasma porphyrin count and the plasma porphyrin index (PPI), which had been greatly enhanced before, went down to normal after therapy.     

STUDIES ON LOW DOSE CHLOROQUINE THERAPY AND THE ACTION OF CHLOROQUINE IN SYMPTOMATIC PORPHYRIA

Summary.— Eight patients with symptomatic porphyria (porphyria cutanea tarda symptomatica, PCT) were treated with small doses of chloroquin sulphate over periods ranging from 2 to 16 weeks. A good clinical and biochemical response was obtained in all but one patient, who relapsed after initial improvement. Manifestations of acute untoward reaction were seen in one patient only. It is concluded that low dose chloroquine therapy is both safe and effective in PCT.
Studies in porphyric rats indicate that the mechanism of action of chloroquine in PCT is probably not related, as has been suggested, to the formation of a chloroquine-porphyrin complex which damages liver cells and thereby leads to a reduction in hepatic porphyrin stores.
Chloroquine therapy led to increased urinary iron excretion and an increase in the desferrioxamine-chelatable iron in patients with PCT. It is suggested that the prolonged beneficial effects of chloroquine treatment may be related to reduction in a specific pool of liver iron.     

High-dose hydroxychloroquine treatment of porphyria cutanea tarda.

BACKGROUND: High-dose hydroxychloroquine is rarely used in the treatment of porphyria cutanea tarda (PCT). OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of a novel high-dose hydroxychloroquine regimen in patients with PCT. METHODS: Sixty-five first episodes and 28 recurrent episodes of PCT were treated with hydroxychloroquine, 250 mg three times daily, for 3 days. In patients with a high urine porphyrin concentration a single phlebotomy of 500 ml was performed before therapy of the first episode. Modified high-dose hydroxychloroquine regimens were used in patients with markedly elevated liver transaminases with or without associated chronic liver disease. RESULTS: Long-term follow-up data showed an overall relapse rate of 33%, significantly higher among male patients (45%) than among female patients (17%) (p less than 0.05). A transient hepatotoxic reaction occurred in the majority of patients. The reaction seemed to be especially severe among phlebotomized female patients. CONCLUSION: Hydroxychloroquine, 250 mg three times daily, is a rapid, efficacious, and safe treatment in patients with PCT.     

Hydroxychloroquine versus phlebotomy in the treatment of porphyria cutanea tarda

Hydroxychloroquine and phlebotomy were compared in the treatment of porphyria cutanea tarda (PCT). Thirty patients received hydroxychloroquine (200 mg twice weekly) for 1 year and thirty-one underwent twice-monthly phlebotomies of 400 ml whole blood each, also for 1 year. Clinical signs of disease improved equally in both groups. At the end of the year, urinary porphyrin excretion had significantly improved in twenty-two out of thirty hydroxychloroquine-treated subjects, but in only eight out of the thirty-one patients who received phlebotomy. Liver histology showed significant regression of steatosis and siderosis in both groups compared with the pretrial biopsy, but the activity of liver disease, as judged by the extent of necrosis, inflammation and fibrosis, worsened in twelve hydroxychloroquine and in seven phlebotomy-treated patients. It is concluded that hydroxychloroquine is more effective than phlebotomy in decreasing porphyrin production. However, further work is needed to assess whether long-term hydroxychloroquine treatment favours the progression of the chronic liver disease associated with PCT.     

Low-dose oral chloroquine in the treatment of porphyria cutanea tarda

Seven patients with porphyria cutanea tarda received a total of ten courses of low-dose oral chloroquine therapy (125 mg chloroquine phosphate twice weekly). Patients were treated for a mean 14.9 months during which time all went into clinical and biochemical remission. Relapse occurred in four patients on a total of six occasions after a mean 17 months. In four patients there was no relapse after a mean 47.3 months. There were no adverse side-effects from the treatment. Low-dose oral chloroquine therapy appears to be a safe, effective and convenient treatment for porphyria cutanea tarda, although relapses may occur requiring further therapy.     

Does chloroquine therapy of porphyria cutanea tarda influence liver pathology?

Background  Porphyria cutanea tarda (PCT) is regularly associated with changes in liver tissue. On the other hand, systematic investigations are lacking on whether there is a correlation between the severity of liver damage and chloroquine treatment.
Patients and methods  During a 20-year period, liver biopsies were obtained in 89 patients with PCT confirmed by biochemical analysis of urine and feces and low-dose chloroquine therapy. Seventeen patients with alcohol-induced liver disease were excluded. In 8 of 63 patients, only a single biopsy was available. Classification of liver damage was performed according to the Riedel score. Electron microscopy was available from 24 patients. In a second group of patients, the HFE status was investigated and Berlin blue stains of liver biopsies were performed.
Results  There was no correlation between the duration of cutaneous symptoms and liver pathology. After 12 months chloroquine treatment, 45 patients (81%) disclosed an improvement of liver pathology, nine (16%) had no change, and a worsening was observed in one patient (3%). All patients achieved a complete clinical and biochemical remission. In 13 of 16 patients with a relapse, there was again a deterioration of liver damage. Patients with HFE mutations had a significant higher risk ( P  < 0.05) for hepatic siderosis.
Conclusions  The severity of liver damage was not correlated with the disease duration. Chloroquine treatment resulted in PCT remission (clinical and biochemical) and in 81% to an improvement of liver morphology.     

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.     

Liver iron overload and desferrioxamine treatment of porphyria cutanea tarda

The aim of this paper is to evaluate invasive and non-invasive indices of iron store and compare the effectiveness of different ferrodepletive protocols in 150 patients with porphyria cutanea tarda (PCT). Iron removal was performed either by intensive phlebotomy (22 cases) or slow subcutaneous and high intravenous doses of desferrioxamine (18 and 5 cases, respectively), and several laboratory parameters were studied; among these, oligo-elements and urinary porphyrins (detected by HPLC) were taken into account before and after the treatments. Serum iron, transferrin saturation, ferritin (RIA) and nuclear magnetic resonance results were compared with invasive findings in order to detect the metal deposition in liver tissue (atomic absorption concentration, optic or electron-microscopic detection). Liver iron overload was observed in 95% of cases. Full normalization of the disease took place by all the treatments, even if it required slightly more time in the phlebotomy group. We may conclude that ferrodepletive treatments are highly effective in PCT and, considering the fact that siderosis and liver damage always accompany the disease, these treatments are proposed as first choice in such cases.     

A comparative study of the results of phlebotomy therapy and low-dose chloroquine treatment in porphyria cutanea tarda

Longer remissions after the phlebotomy therapy than after the low-dose chloroquine treatment were ascertained by means of the long-term follow-up of a large group of porphyria cutanea tarda patients. An attempt to prove the dependence of the length of laboratory and clinical remission on the values of initial porphyrinuria, on the degree of morphological liver changes, and on the total amount of blood withdrawn at phlebotomy was unsuccessful. On the contrary, a direct relationship was observed between the length of remission and the age of the subject on commencing treatment. At the same time, it was impossible to prove a causal relationship between the length of remission and initial porphyrinuria, the degree of morphological liver changes, and the total dose of drug taken, in the group of patients on the low-dose chloroquine therapy.     

Porphyria cutanea tarda and neoplasms. Apropos of 2 cases

Porphyria cutanea tarda (PCT) may be associated with various neoplasma. Two additional cases are reported here. In the first case, a 58-year old alcoholic man had been presenting for two years with clinical signs of PCT. The diagnosis was confirmed by porphyrin assays in the urine. He also had cirrhosis of the liver. During a routine fibroscopy in search of oesophageal varices, a gastric adenocarcinoma was discovered by chance. Following partial gastrectomy the skin lesions of PCT improved dramatically within a few weeks, leaving only moderate cutaneous fragility. Urinary porphyrin assays performed 18 and 40 months after gastrectomy gave normal results, although no specific treatment had been prescribed. The second case concerns a 67-year old man, also alcoholic, with clinical and biochemical PCT. For the previous 12 months he had received chemotherapy (Adriamycin, then BCNU combined with melphalan, vincristine and prednisone) for multiple IgA K myeloma. The myeloma was active when PCT was diagnosed with, in particular, chronic anaemia. Treatment with chloroquine improved the cutaneous signs of PCT but had no effect on urinary porphyrins after 5 months. Comments PCT has been reported to be associated with cancers. The best known of these cancers is primary carcinoma of the liver (4, 27, 32), but its frequency is diversely evaluated depending on the diagnostic methods (e. g. patient autopsied or not) and on the selection of patients (age, duration of the disease).(ABSTRACT TRUNCATED AT 250 WORDS)     

Porphyria cutanea tarda

Porphyria cutanea tara (PCT) has a prevelance of about 40 new diagnoses per 1 million people per year and is the most frequently occurring type of porphyria worldwide. Inhibition of the uroporphyrinogen decarboxylase (UROD) is the main cause of the disease, which can be the result of a heterozygous or homozygous mutation of the UROD gene; however, xenobiotics or other diseases may play an important role for the precipitation of the disease. Risk factors include alcohol, estrogen, iron overload, and hemochromatosis, hepatitis C or poisoning, e.g., with polyhalogenated aromatic compounds such as hexachlorobenzene. Signs and symptoms are blisters, skin fragility, erosions hyperpigmentation, sclerodermoid plaques. Therapy includes sun protection, prevention of risk factors, phlebotomy, and chloroquine.     

Two cases of infantile porphyria cutanea tarda: successful treatment with oral S-adenosyl-L-methionine and low-dose oral chloroquine

In a 7-year-old girl and a 12-year-old boy, with photosensitivity and hypertrichosis, the diagnosis of familial porphyria cutanea tarda was confirmed by the characteristic pattern of urinary porphyrin excretion, diminished erythrocyte uroporphyrinogen decarboxylase and elevated plasma porphyrin index with emission maxima at 617-618 nm. The patients were treated with a combination of low-dose oral chloroquine and oral S-adenosyl-L-methionine (SAM); in one case alkalinization of urine was also applied. Complete clinical and biochemical recovery was achieved within 3 months. No adverse ophthalmological or other side-effects were observed. We propose that the treatment of choice should be oral SAM (12 mg/kg/day) for 3 weeks and oral chloroquine (2 X 100 mg weekly) for about 120-150 days or until improvement of clinical and biochemical abnormalities is attained. So far no relapses have occurred. This combined therapy appears to be safe, simple, effective and very convenient for both patients and physicians.     

The management of porphyria cutanea tarda

Porphyria cutanea tarda (PCT), the commonest of all porphyrias, is usually characterized by blisters and fragility of skin in light-exposed areas. It can be clinically indistinguishable from other disorders including variegate porphyria and the diagnosis can only be made by rigorous biochemical analysis. PCT does not cause acute attacks of porphyria. It is usually an acquired condition caused by inhibition of the uroporphyrinogen decarboxylase enzyme in the liver. Hereditary haemochromatosis, hepatitis C virus infection, alcohol, oestrogens and a family history of PCT are the major risk factors for the condition and should be searched for specifically in all patients. Liver disease, including hepatocellular carcinoma, is common in patients with PCT, and should be investigated for at presentation by means of a liver biopsy where possible. Patients with severe hepatic pathology or longstanding untreated PCT need to be monitored for the development of hepatocellular carcinoma in the long term. Low dose twice weekly chloroquine is the mainstay of treatment, but venesection should be used in patients with severe iron overload or hepatitis C-related liver disease. Subsequently, long-term follow-up is needed in all patients to monitor for relapse.     

Therapeutic and pathogenetic aspects of porphyria cutanea tarda

Seventy-three patients with porphyria cutanea tarda (PCT) were treated with chloroquine phosphate, which was administered in doses of 250 mg twice a week for more than 1 year on average. Of these patient, 49% did not have any associated ("inducing") factors. After treatment, serum transaminases and gamma-glutamyltransferase (gamma-GT) always returned to normal values. However, gamma-GT did not reach the normal range in the group without associated factors ("idiopathic group"). Of the 66 patients studied, 25 achieved an approximately physiological distribution of the pattern of urinary porphyrin fractions. Control biopsies were performed in 66 patients. Of them, 48 patients showed an improvement in liver damage. A statistically significant correlation was observed between a lasting increase in urinary prophyrin content and unchanged pathological liver morphology. A pathogenesis concept for PCT is discussed as a disease between inheritance (genetic enzyme defect) and environment ("inducing factors"). Even in the "idiopathic group" the improvement of pathological liver changes after therapeutic removal of the pathological prophyrin content in the liver cells shows that porphyrins could also cause liver damage.     

Porphyria cutanea tarda

Porphyria cutanea tarda (PCT) is a metabolic disorder of haem biosynthesis caused by decreased activity of uroporphyrinogen decarboxylase. Porphyria cutanea tarda is manifest by fragility, erosions, bullae, milia and scars on sun-exposed skin. Excess porphyrins in the skin interact with light of approximately 400 nm-wavelength radiant energy, forming reactive oxygen species. Porphyria cutanea tarda is categorized as familial, acquired or toxic. Factors that may induce clinical expression of PCT in susceptible individuals include alcohol, oestrogen, iron, polyhalogenated compounds and viral infections. Porphyria cutanea tarda is associated with an increased incidence of the haemochromatosis gene. Treatments for PCT include withdrawal of aggravating factors, phlebotomy and oral antimalarial medications.     

Ocular toxicity of antimalarials in dermatology: a survey of current practice

A questionnaire sent to 325 U.K. dermatologists regarding toxicity of antimalarials had a 70% response rate. Hydroxychloroquine (HCQ) was used by 168 respondents, chloroquine (CQ) by 66, and mepacrine by 89 (only 111 always chose one of these). HCQ was considered to be the most effective by 59%, and to have the least cutaneous side-effects by 66%; mepacrine was considered to have the lowest frequency of ocular side-effects by 50%. Thirty respondents had encountered ocular side-effects, but in most cases these were mild. Maculopathy after short-term therapy was identified as a side-effect which is rarely considered. Ocular side-effects were believed to be due to cumulative dose alone by 31%, to dose/body weight alone by 8%, to duration of treatment alone by 3%, and to combinations of these by 58%. Overall, cumulative dose was considered relevant by 85%, duration of treatment by 52%, and dose/body weight by 41%. Referral for ophthalmology screening was always performed at baseline or after an initial trial of therapy by 56%; 17% never referred patients for baseline screening; 60% routinely requested ophthalmological follow-up. In comparison, 14% of respondents routinely referred patients for baseline ophthalmological screening before PUVA therapy (only 52% of whom routinely referred patients before antimalarial therapy). The most important factor contributing to an individual's current practice was experience in training posts (52%), followed by advice of local ophthalmologists (45%), personal experience (19%), specific publications (16%), and manufacturers' recommendations (14%). Dermatologists should be more aware of the importance of dose/body weight in avoiding toxicity of HCQ, but would be helped by more flexible tablet sizes; they should also be aware that current ophthalmological advice places a greater onus on the prescriber for monitoring side-effects.