Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.

[Porphyria cutanea tarda. Case report]. / Porfiria cutánea tarda. Caso clínico.

Porphyria cutanea tarda (PCT) is the most common type of porphyria: it is characterized by blistering lesions, erosions and crusts on the back of the hands, associated with photosensitivity and facial hypertrichosis. It is produced by acquired or hereditary deficiency of the enzyme UROD, fifth enzyme in the chain of production of the Heme group. This causes accumulation of porphyrins in the liver, which are subsequently mobilized to the skin, where lesions are generated by photosensitivity. This deficiency can be exacerbated by multiple causes. We report a 51-year-old female presenting with the characteristic dermal lesions described above, which disappeared when she discontinued her hormone replacement therapy with estradiol and dydrogesterone. Urinary and blood uroporphyrin and hexacarboxyl porphyrins were elevated and plasma ferritin was 479 ng/ml. Hormone replacement therapy was discontinued and phlebotomies were attempted but not tolerated by the patient. The dermic lesions have not relapsed.

Porphyria cutanea tarda in a child following multi-agent chemotherapy.

Porphyria cutanea tarda (PCT) is a blistering skin disorder that occurs most commonly in middle-aged individuals. It is caused by decreased uroporphyrinogen decarboxylase (UROD) activity, which results in elevated levels of uroporphyrinogen. Occurrence remains very rare in children with some sources quoting as few as 50 reports of childhood cases.1 The literature reports occasional cases of PCT onset with various drugs, including barbiturates, estrogens, griseofulvin, rifampicin, sulfonamides, imatinib, methotrexate, tamoxifen, and cyclophosphamide, however its incidence in childhood is uncommon.2-6 We present a case of new-onset PCT in an eight year-old following treatment of pre-B cell acute lymphoblastic leukemia with multi-agent chemotherapy.

Porphyria cutanea tarda induced by tamoxifen.

Porphyria cutanea tarda (PCT) results from a decrease in the activity of uroporphyrinogen decarboxylase. In the sporadic form, the decrease in the activity is restricted to the liver and is generally related to alcohol, estrogens, iron overload, hepatitis C infection, and halogenated aromatic hydrocarbons. We describe the development of porphyria cutanea tarda in a 53-year-old woman one year after breast cancer surgery and the initiation of treatment with tamoxifen. No additional drugs were prescribed. After tamoxifen was discontinued, a gradual clinical and laboratorial improvement was noticed suggesting a causative role of the drug. There are many reports discussing tamoxifen side-effects, but there are only three case reports in the literature that describe tamoxifen as a probable trigger of porphyria cutanea tarda. In this report, the potential porphyrinogenicity of tamoxifen and clinical implications are the targets of our discussion.

An unusual bullous eruption: olanzapine induced pseudoporphyria.

A 27-year-old man with a background of schizophrenia presented during the summer months with a 2-day history of a blistering eruption predominantly affecting his hands, forearms and face. He had not knowingly been exposed to any chemicals or toxins and was otherwise well. Clinical examination revealed multiple, large, tense blisters affecting the sun-exposed sites. Histology subsequently demonstrated subepidermal blisters with minimal inflammation and negative immunofluorescence. Porphyrin biochemistry including faecal, urinary and serum samples were unremarkable and thus a diagnosis of pseudoporphyria was reached. There were no obvious triggers, however, olanzapine (an atypical antipsychotic) had been commenced 2 months previously and was deemed to be the most likely cause. This is the first report of pseudoporphyria being associated with an atypical antipsychotic and highlights the importance of eliciting an accurate drug history by specifically enquiring about any recent medication changes that could account for the clinical presentation.

Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C.

There is a strong association between porphyria cutanea tarda (PCT) and chronic viral hepatitis C. Therapy for chronic viral hepatitis C may improve PCT. However, there are only a few reports of the de novo development of PCT during therapy for chronic viral hepatitis C. We describe the development of PCT in a 56-year-old patient with chronic viral hepatitis C after 12 wk of peginterferon/ribavirin therapy. In addition, the patient was homozygous for the H63D hereditary hemochromatosis gene (HFE) mutation. The association of PCT with chronic viral hepatitis C and the possible role of hepatic iron overload and ribavirin-induced hemolytic anemia in the development of PCT during therapy for chronic viral hepatitis C are discussed.

Furosemide-induced pseudoporphyria in a patient with chronic kidney disease: case report.

INTRODUCTION: Pseudoporphyria is a rare photodermatosis with characteristics similar to those of porphyria cutanea tarda, without, however, presenting abnormalities in porphyrin metabolism. Its etiology is related to chronic kidney disease, ultraviolet radiation and certain medications. The aim of the present study is to describe a case of furosemide-related pseudoporphyria in a patient with chronic kidney disease. CASE DESCRIPTION: A 76-year-old male patient with stage 4 chronic kidney disease and in continuous use of furosemide presented ulcerated lesions with peripheral erythema and central hematic crust in the legs. On a skin infection suspicion, treatment with quinolone and neomycin sulfate was initiated, without improvement. A biopsy of the lesion was performed, with histopathological examination demonstrating findings compatible with porphyria, although the patient did not present high porphyrin levels. The diagnosis of furosemide-induced pseudoporphyria was then established, with medication suspension, and there was a significant improvement of the lesions. DISCUSSION: There are few cases of pseudoporphyria described, but it is believed that this condition is underdiagnosed, especially in patients with chronic kidney disease. Both clinical and histopathological findings closely resemble porphyria, differentiating it from normal levels of porphyrin in plasma, urine, or feces. CONCLUSIONS: Although the lesions are mostly benign, they may increase the morbidity and mortality of these patients, so a proper diagnosis and early treatment are extremely important.

Remission of porphyria cutanea tarda after anastrozole treatment of breast cancer.

Porphyria cutanea tarda (PCT) is sometimes precipitated or aggravated by increased exposure to estrogen, estrogen-like compounds, or tamoxifen. We report the case of a 37-year-old white woman who developed sporadic PCT after she took oral contraceptives for 10 years. She was heterozygous for the common H63D mutation of the hemochromatosis-associated HFE gene. The PCT responded partially to the cessation of oral contraceptives and to phlebotomy therapy to maintain low iron stores, but only remitted after she received anastrozole therapy for management of adenocarcinoma of the breast at age 59 years. The pertinence of HFE mutations, anastrozole and tamoxifen treatment, and chemotherapy to the development and management of PCT in women with breast cancer is discussed.

[Is tamoxifene porphyrinogenic?]. / Je tamoxifen porfyrinogenní?

BACKGROUND: As reported in previous studies, porphyria cutanea tarda (PCT) developed in several tamoxifene-treated patients with breast cancer. We studied the group of patients with cancer having only tamoxifene therapy after the initial surgery. We evaluated their clinical and laboratory results and compared them with the results of the group of patients suffering also from breast tumor, but treated after the surgery with other systemic therapies, mostly with chemotherapy. METHODS AND RESULTS: 20 patients were complexly studied, 10 of them with only tamoxifene therapy, and 10 without it. Diagnosis of the breast tumor was histologically confirmed in all of them. With the use of laboratory methods we examined their urinary excretion of diagnostically important porphyrins (uro- and coproporphyrin), then total blood count, liver function tests (ALT and AST), blood sugar, cholesterin, serum iron and ferritin, and performed also urinanalysis and detection of possible anti-HCV antibodies. The laboratory examination was repeated in the patient subgroup after three months, urinary uro- and coproporphyrin excretion also in the the control group, for to have an opportunity to follow the dynamics of laboratory changes. All the patients were examined during their regular laboratory controls performed so as not to be bothered with repeated additional phlebotomies. We did not confirm in our patients suffering from breast tumor the results of other autors, suggesting the connection between tamoxifene-therapy and development of porphyria cutanea tarda. CONCLUSIONS: Isolated cases of PCT can be induced through the effect of various hepatotoxic factors. However, the influence of common porphyrinogenically acting noxious substances (alcohol, HCV virus or iron overload as a result of the HFE gene mutations) were not found in our patients.

[Medicine-caused itch, wounds and bullous skin in three patients with pseudoporphyria]. / Medicinudløst hudkløe, sår og blærer hos tre patienter med pseudoporfyri.

Pseudoporphyria cutanea tarda is a well described bullous skin disorder which resembles porphyria cutanea tarda. However, the levels of porphyrins in plasma, urine and faeces are normal. We present three cases of patients with classical symptoms of pseudoporphyria. Two of the patients developed pseudoporphyria after the combination of intensive sunbathing and medications well known to cause pseudoporphyria. The third case received haemodialysis and furosemide.

Chromosomal linkage analysis of porphyria in mice induced by hexachlorobenzene-iron synergism: a model of sporadic porphyria cutanea tarda.

Genetic susceptibility to toxic chemicals is of major importance but most studies concentrate on candidate genes and searches for unknown susceptibility genes are uncommon. Human sporadic porphyria cutanea tarda is usually precipitated by alcohol, oestrogens, hepatitis viruses, HIV or haemodialysis. The mechanism is not known but there is a role for iron metabolism and an underlying genetic predisposition is suspected. A similar porphyria in humans has also been caused by hexachlorobenzene. These human porphyrias can be modelled in iron-loaded mice exposed to hexachlorobenzene, in which C57BL/10ScSn is a prototype susceptible strain whereas DBA/2 mice are extremely resistant. A search for susceptibility genes was undertaken using complex trait analysis with DNA microsatellite markers of 'high' and 'low' responders from an F2 intercross. Correlation of markers with susceptibility, defined as accumulation of uroporphyrin in the liver, was assessed by chi-squared test for the proportion of C57BL/10ScSn and DBA/2 alleles present. Susceptibility loci on chromosomes 12, 14 and 17 were identified. Further analysis of markers on chromosomes 14 and 17 by MAPMAKER/EXP and MAPMAKER/QTL gave LOD scores of 7.3 and 3.6, respectively. Typing of chromosome 12 for the Ahr gene, using a restriction fragment length polymorphism distinguishing between the b-1 and d alleles, gave significant but not perfect linkage. However, no strong association between alleles or expression of Cyp1a1/2 genes, regulated by Ahr, and susceptibility for porphyria was detected. The results demonstrate that the porphyria induced by hexachlorobenzene in C57BL/10ScSn mice is a complex trait determined by at least three genes, which may be of relevance to susceptibility in the development of sporadic porphyria cutanea tarda and unknown aspects of liver damage.

Evaluation of reproductive outcomes in women inadvertently exposed to hexachlorobenzene in southeastern Turkey in the 1950s.

In southeastern Turkey during the period of 1955-57, women were accidentally exposed to the fungicide hexachlorobenzene (HCB) after eating contaminated seed grain and developed porphyria cutanea tarda (PCT). While HCB has been shown to be a potent oocyte toxicant in primates and has been identified as an ovarian follicular fluid contaminant in women, its effect on human reproduction is poorly understood. This study was undertaken to evaluate the effects of HCB on women with a known high dose exposure. A retrospective controlled cohort comparison study of three groups was conducted. Group 1, those with confirmed PCT; Group 2, controls for the region and Group 3, controls for the country of Turkey, were followed-up after approximately 40 years (n=42/group). Blood samples were taken for analysis of serum HCB, estradiol, follicle-stimulating hormone (FSH) and inhibin. Frequency of HCB detection was greatest in Group 3, while number of cases with HCB values exceeding 1 ng/mL was significantly greater in Groups 1 and 2. There were no differences in the other biochemical measures. Interviews were completed for each patient regarding reproductive history (number of pregnancies, live births, spontaneous abortions, still births and sex of live babies). Multiple comparisons of the three groups, based on Fisher's test found the groups were inhomogeneous. When serum HCB was analyzed using correlated response logistic regression, there was a strong relationship between serum HCB levels and risk for spontaneous abortion but not sex ratio of children. The following findings were made. HCB is detectable and ubiquitous in serum samples from women in the country of Turkey with identified and unidentified exposure events. Spontaneous abortion risk is not restricted to women with identifiable exposure to HCB but to a surrogate marker of exposure (serum HCB sample). The risk of spontaneous abortion with HCB exposure requires further investigation.

PIP: During 1955-57, women in southeastern Turkey were accidentally exposed to the fungicide hexachlorobenzene (HCB) after eating contaminated seed grain and an estimated 4000 developed porphyria cutanea tarda (PCT). In a follow-up study of 225 of the original PCT patients 25-30 years after exposure, 25% still had elevated levels of urinary porphyrin excretion. These patients reported 15 spontaneous abortions in 188 pregnancies and 31 child deaths. 40 years after exposure, a retrospective controlled cohort comparative study was conducted to assess the effect of HCB on reproductive outcomes. 42 women were enrolled in each of three groups: 1) women from the initial study with confirmed PCT, 2) age-matched controls from the same region, and 3) age-matched controls from Ankara. The frequency of HCB detection in serum was highest in group 3, while the number of cases with HCB levels exceeding 1 ng/ml was significantly greater in groups 1 and 2. Analysis was compromised by the fact that the three groups were inhomogeneous. It appeared, however, that factors such as number of pregnancies, births, and abortions may contribute to determining the body burden of lipophilic chemicals such as HCB. Correlated response logistic regression revealed a significant association between serum HCB levels and risk for spontaneous abortion but not for sex ratio. Since chronic low-level HCB exposure appears ubiquitous in Turkey, the mechanism of HCB induction of spontaneous abortion merits further investigation.

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.

Tamoxifen-related porphyria cutanea tarda.

We report a case of porphyria cutanea tarda (PCT) in a patient with breast cancer following adjuvant tamoxifen. Cessation of tamoxifen resulted in a prompt decline in urinary porphyrins suggestive of a causative role. Tamoxifen is known to be hepatotoxic; however, its association with PCT is unclear. In this report, we discuss the porphyrinogenicity of tamoxifen and potential mechanisms.

Cytoplasmic liver cell inclusions--a typical feature of porphyria cutanea tarda--are absent in porphyria-related hepatic neoplasias.

Crystalline cytoplasmic needle-shaped inclusions in hepatocytes are considered to represent a specific morphological feature of porphyria cutanea tarda (PCT) and experimental PCT-like porphyrias. The cytoplasmic inclusions, however, are absent in hyperplastic hepatic nodules and hepatocellular carcinomas arising in the course of these conditions. It is assumed that porphyrins and related substances accumulated in hyperplastic and neoplastic hepatic lesions differ from those found in non-neoplastic liver tissue: the highly carboxylated porphyrins are stored in both sites, the crystal-forming substance only in non-proliferating liver tissue.