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Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof‐of‐concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias. [ABSTRACT FROM AUTHOR]

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (6): 511–517 Background Iron is essential for mammalian metabolism and its cellular concentration is controlled by regulating its acquisition and storage. Haemochromatosis is a condition involving iron overload that is characterised by increased duodenal iron absorption and a progressive accumulation of iron in vital organs. Hepcidin is the main hormone that regulates iron homoestasis and it is secreted by the liver. Materials and methods We have studied how extended hepcidin administration affects the iron load status, plasma and tissue iron concentration, erythropoiesis and the expression of proteins involved on iron homeostasis in haemochromatotic ( Hfe −/− ) and wild-type mice. Results Hepcidin reverted the high plasma iron concentrations in Hfe −/− mice to normal values. The high concentration of hepatic iron was not altered in the liver of these Hfe −/− mice. Hepcidin administration did not disturb erythropoiesis in either Hfe −/− or wild-type mice and likewise, hepcidin did not modify the expression of any protein analysed in the liver, duodenum or spleen of Hfe −/− and wild-type mice. These data confirm that hepcidin administration diminishes plasma iron concentrations. Conclusion Treatment with sustained doses of hepcidin diminishes plasma iron concentrations in Hfe −/− mice. [ABSTRACT FROM AUTHOR]

Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D) and c.840C>G (p.F280L) in the HFE and transferrin receptor 2 (TFR2) genes, respectively.

Drugs metabolised by cytochrome P450 (CYP) such as analgesics may induce acute attacks in patients with hepatic porphyrias. In recent years, preclinical and clinical studies have suggested that cannabinoid pharmaceutical preparations may be potentially useful in the treatment of pain. The purpose of the study was to examine the effects of CP-55,940, a cannabinoid CB1 receptor agonist, on the hepatic heme metabolism in mice. To this end, hepatic activities of aminolevulinic acid synthase (ALAS), heme oxygenase (HO) and CYP levels were determined in mice treated with CP-55,940 (0.5 mg/kg/day; i.p.; 5 or 24 days). Results showed that treatment with CP-55,940 decreased CYP concentrations by 80% and increased HO activity by 158%. However, ALAS activity also decreased by 37%, suggesting that regulatory free heme pool was not modified. Our findings indicate that CP-55,940 and its metabolites do not behave as porphyrinogenic drugs and may potentially be safe for treating pain in patients with acute porphyrias.

Aims and Background: Carcinoembryonic antigen (CEA) belongs to a family of cell surface glycoproteins. Its level in serum has a significant value for the follow-up and treatment of patients with malignancies. The aim of this study was to correlate the concentration of tumor cytosol CEA (cCEA) with tumor size, patient age and sex, clinical stage, lymph node metastases, and overall survival rate in primary non-small cell lung carcinoma (NSCLC)., Methods and Study Design: The cCEA levels were determined in 76 NSCLC patients by luminescence assay (LIA) and radioimmunoassay (RIA)., Results: A strong correlation between LIA and RIA assay results was found (r = 0.992). No correlation was observed between serum CEA and cCEA levels. Tumors smaller than 3 cm had significantly higher cCEA levels than larger tumors, but when a logistic modeling process was applied this difference was not significant (P = 0.038). Histologically well-differentiated tumors also showed a significantly higher expression of cCEA (P <0.05). In addition, patients without lymph node involvement had higher cCEA levels than patients with tumor-positive lymph nodes (P < 0.05). Univariate statistical analysis revealed that the risk of lymph node metastases was 1.8-fold higher in patients with low cCEA levels than in patients with higher levels, taking the median value as cutoff (P = 0.04, Kruskal-Wallis test)., Conclusions: According to the results of our study, patients with overexpression of cCEA may have a better prognosis than those with low cCEA expression. cCEA might therefore be considered a good prognostic parameter as well as a prognostic factor independent of the traditional parameters for lymph node metastases.