Novedades en las porfirias eritropoyéticas / New Developments in Erythropoietic Porphyrias

En los últimos años se han producido importantes avances en la genética de las porfirias y, concretamente, en las porfirias eritropoyéticas -protoporfiria eritropoyética (PPE) y porfiria eritropoyética congénita (PEC)-, que han dado lugar a una nueva concepción de las mismas como enfermedades no monogénicas. Se han identificado mutaciones en nuevos genes como responsables o modificadores de la gravedad de la porfiria, permitiendo esclarecer las discrepancias geno-fenotípicas observadas entre pacientes portadores de las mismas mutaciones, así como identificar el defecto genético responsable de algunos casos de porfiria en los que los estudios moleculares del gen uroporfirinógeno sintetasa (UROS) en la PEC o del gen ferroquelatasa (FECH) en la PPE no identificaban ninguna mutación. La mejor caracterización y conocimiento de la genética de estas enfermedades permitirá establecer cuadros geno-fenotípicos concretos y realizar una clasificación molecular con implicaciones prácticas y pronósticas (AU)

In recent years, important advances have been made in our understanding of the genetics of porphyrias, particularly with respect to erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP), 2 forms of erythropoietic porphyria no longer considered to be monogenic. The identification of mutations in genes not previously associated with these disorders as causative factors or modulators of severity has helped to explain the presence of genotypic and phenotypic differences between patients carrying the same mutations. These advances have also led to the identification of causative genetic defects in patients who, based on molecular studies, had no mutations in the uroporphyrinogen III synthase gene UROS (in CEP) or in the ferrochelatase gene FECH (in EPP). Better understanding and characterization of the genetics of porphyrias will allow us to determine genotypic and phenotypic correlations and improve the molecular classification of these diseases, which will have both practical and prognostic implications (AU)

New developments in erythropoietic porphyrias.

In recent years, important advances have been made in our understanding of the genetics of porphyrias, particularly with respect to erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP), 2 forms of erythropoietic porphyria no longer considered to be monogenic. The identification of mutations in genes not previously associated with these disorders as causative factors or modulators of severity has helped to explain the presence of genotypic and phenotypic differences between patients carrying the same mutations. These advances have also led to the identification of causative genetic defects in patients who, based on molecular studies, had no mutations in the uroporphyrinogen III synthase gene UROS (in CEP) or in the ferrochelatase gene FECH (in EPP). Better understanding and characterization of the genetics of porphyrias will allow us to determine genotypic and phenotypic correlations and improve the molecular classification of these diseases, which will have both practical and prognostic implications.

Increased serum hepcidin levels in patients with porphyria cutanea tarda.

BACKGROUND: Increased iron stores- are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down-regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. OBJECTIVE: To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. METHODS: Hepcidin levels were measured by a competitive enzyme-linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). RESULTS: The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin-6 (IL-6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. CONCLUSION: Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse.

The association between porphyria cutanea tarda and diabetes mellitus: analysis of a long-term follow-up cohort.

BACKGROUND: An association between porphyria cutanea tarda (PCT) and diabetes mellitus (DM) is widely reported, but the pathogenetic link remains unknown. OBJECTIVES: To investigate the natural history of DM in the setting of PCT and to determine which PCT features and risk factors may be associated with the development of DM. METHODS: This retrospective longitudinal study included 81 Spanish patients with PCT with at least 10 years of strict follow-up. Patients attended our Porphyria Unit for follow-up visits and the data were collected in the period 2004-2008. We classified patients into two groups: patients with glucose metabolism alterations (GMA: DM or impaired fasting glucose), and patients without. PCT features and PCT and DM risk factors were retrieved from clinical charts and compared between groups. RESULTS: We identified 33 patients (41%) with GMA, of whom 27 (82%) developed GMA a long time after the diagnosis of PCT (mean 12·7 years). In bivariate analysis, these patients had significantly higher mean serum ferritin at diagnosis (651 vs. 405 ng mL(-1); P = 0·005), a higher prevalence of persistently elevated serum ferritin (52% vs. 15%; P < 0·001 for trend) and a higher prevalence of family history of DM (48% vs. 19%; P = 0·004). In multivariate analysis, persistently elevated serum ferritin [odds ratio (OR) 10·66, 95% confidence interval (CI) 1·95-58·19; P = 0·006] and family history of DM (OR 4·82, 95% CI 1·34-17·33; P = 0·016) remained significantly associated with the presence of GMA. CONCLUSIONS: GMA are highly prevalent in patients with PCT and mostly develop a long time after the diagnosis of PCT. Persistent hyperferritinaemia seems to be a risk biomarker of GMA in patients with PCT, probably in the setting of chronic iron overload and hepatic inflammation. Strict long-term monitoring of glucose metabolism and serum ferritin may be advisable in the routine follow-up of patients with PCT.

Urinary uronate and sulfated glycosaminoglycan levels: markers for interstitial cystitis severity.

PURPOSE: Urologists frequently rely on symptom and problem indexes to monitor patients with interstitial cystitis (IC). Uronic acid is a component of most glycosaminoglycans (GAGs), which is a protective bladder urothelium coating. We evaluated whether urinary uronate and sulfated GAG levels correlate with IC severity and we characterized urinary GAG species. MATERIALS AND METHODS: Urine samples, and a completed O'Leary-Sant IC symptom and problem index questionnaire were obtained from 37 patients with IC and 14 normal individuals. Patients with IC were in group 1-1 or 2 indexes less than 50% the maximum score or group 2-each index 50% or greater the maximum score. All patients fulfilled National Institute of Diabetes and Digestive and Kidney Diseases criteria except glomerulations. Urinary uronate was fractionated using cetyltrimethylammonium bromide (CETAB). Uronate and sulfated GAG levels in urine, CETAB precipitates and CETAB supernatants were measured by the Bitter and Muir, and Farndale assays, respectively, and normalized to creatinine in microg/mg creatinine. GAG species were analyzed by agarose gel electrophoresis. RESULTS: Mean urinary uronate levels were increased in group 2 compared with normal and group 1 values regardless of glomerulations and treatment (1,614 +/- 904.6 vs 612.4 +/- 327.2 and 593.8 +/- 422.1 microg/mg creatinine, respectively, p <0.001). A small portion of urinary uronate was CETAB precipitable, representing macromolecular GAGs. Uronate levels in CETAB precipitates and CETAB supernatants were approximately 2.8-fold increased in group 2 (8.0 +/- 5.07 and 1,393 +/- 671.9 microg/mg creatinine, respectively) compared with normal and group 1 values (p <0.001), and they contained fast and slow moving GAG species. Uronate and sulfated GAG had 80% and 88% sensitivity, and 92.3% and 69.2% specificity, respectively, to detect IC severity. CONCLUSIONS: The majority of urinary GAGs likely exist as small oligosaccharides. Urinary uronate and sulfated GAG levels are increased in patients with IC who have severe disease. They may become useful markers for monitoring IC.