Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. Keywords: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPaseNational Institutes of Health (U.S.) (Grant F32 DK095726)National Institutes of Health (U.S.) (Grant R01 GM049224

Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients

Reversible Decrease of Portal Venous Flow in Cirrhotic Patients: A Positive Side Effect of Sorafenib

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients

Imagerie vasculaire quantitative anatomique et fonctionnelle

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Regression of Hypervascular Nodules in a Patient with Wilson's Disease Awaiting Liver Transplantation

This paper describes the regressive course over one year of hypervascular nodules in a patient with Wilson's disease. CT revealed multiple, enhancing nodules (up to 3 cm in diameter) detected in the liver in the early arterial phase after the administration of intravenous contrast material. Most of these nodules became isodense in the portal venous phase. After one year of efficient therapy combining d-penicillamine and zinc acetate, most of the nodules had disappeared, while the liver contours had become more regular. To our knowledge, the regression of large hypervascular nodules has not previously been reported in patients with Wilson's disease

Porphyria and kidney diseases

International audienceThe kidneys, after the bone marrow and liver, are third in terms of the amounts of haem synthesized daily. Haem is incorporated into haemoproteins that are critical to renal physiology. In turn, disturbances in haem metabolism interfere with renal physiology and are tightly interrelated with kidney diseases. Acute intermittent porphyria causes kidney injury, whereas medical situations associated with end-stage renal disease, such as porphyrin accumulation, iron overload and hepatitis C, participate in the inhibition of uroporphyrinogen decarboxylase and predispose the individual to porphyria cutanea tarda. Even if some of these interactions have been known for a long time, the clinical situations associated with these interrelations have strikingly evolved over time with the advent of new therapeutic strategies for dialysis therapy and a better understanding of the pathophysiological mechanisms of porphyria-associated kidney disease. Physicians should be aware of these interactions. The aim of this review is to summarize the complex interactions between kidney physiology and pathology in the settings of porphyria and to emphasize their often-underestimated importance

Emergency therapy for liver metastases from advanced VIPoma: surgery or transarterial chemoembolization?

VIPoma is a rare neuroendocrine tumor (NET) with a high potential to develop hepatic metastases and poor prognosis. The primitive tumor is nonsymptomatic and usually localized within the pancreas. Liver metastasis drives the prognosis and induces profuse watery diarrhea or renal failure. We herein present severe renal failure or diarrhea in two patients hospitalized in intensive care justifying emergency treatment of liver metastasis. The two patients experienced severe diarrhea due to a hypersecretion of vasoactive intestinal peptide (VIP) from liver metastasis released into the blood circulation. Therapeutic management was discussed and liver transarterial chemoembolization (TACE) was performed with chemotherapy-loaded embospheres, which cause necrosis of tumor lesions. TACE controlled the hormonal syndrome and made patients eligible for curative surgery. Tumor necrosis occurred and VIP levels collapsed. Surgery was performed in one of the two cases after TACE and the patient was considered in remission. Both patients were still alive after 3 years of follow up. Thus, TACE is feasible and appears to be an effective emergency treatment in patients with a VIP-hormonal syndrome due to liver metastases. Despite the biological disorder due to the hormonal secretion, an aggressive approach is warranted in VIP liver metastasis

Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay

Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of ALAS2 mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria

Hepatocellular carcinoma in acute hepatic porphyrias: A Damocles Sword

International audiencePorphyrias are inherited diseases with low penetrance affecting the heme biosynthesis pathway. Acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP) together constitute the acute hepatic porphyrias (AHP). These diseases have been identified as risk factors for primary liver cancers (PLC), mainly hepatocellular carcinoma (HCC: range 87-100%) but also cholangiocarcinoma, alone or combination with HCC. In AHP, HCC annual incidence rates range from 0.16 to 0.35% according to the populations studied. Annual incidence rates are higher in Swedish and Norwegian patients, due to a founder effect. It increases above age 50. The pathophysiology could include both direct toxic effects of heme precursors, particularly δ-aminolevulinic acid (ALA), compound heterozygosity for genes implied in heme biosynthesis pathway or the loss of oxidative stress homeostasis due to a relative lack of heme. The high HCC incidence justifies radiological surveillance in AHP patients above age 50. Efforts are made to find new biological non-invasive markers. In this respect, we describe here the first report of PIVKA-II clinical utility in the follow-up of an AIP patient that develop an HCC. In this manuscript we reviewed the epidemiology, the physiopathology, and the screening strategy of HCC in AHP