ABSTRACT
ABSTRACT Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.
Subject(s)
Porphyrias , Protoporphyria, Erythropoietic , Endopeptidase Clp , EnzymesABSTRACT
Erythropoietic protoporphyria (EPP) is an inherited disorder of the heme metabolic pathway that is characterized by accumulation of protoporphyrin in the blood, erythrocytes, and tissues, and cutaneous manifestations of photosensitivity, all resulting from abnormalities in ferrochelatase (FECH) activity due to mutations in the FECH gene. Protoporphyrin is excreted by the liver, and excess protoporphyrin leads to cholelithiasis with obstructive episodes and chronic liver disease, finally progressing to liver cirrhosis. Patients with end-stage EPP-associated liver disease require liver transplantation. We describe here a 31-year-old male patient with EPP who experienced acute-on-chronic liver failure and underwent deceased-donor liver transplantation. Surgical and postoperative care included specific shielding from exposure to ultraviolet radiation to prevent photosensitivity-associated adverse effects. The patient recovered uneventfully and was doing well 24 months after transplantation. Future prevention and treatment of liver disease are discussed in detail.
Subject(s)
Adult , Humans , Male , Acute Disease , End Stage Liver Disease/etiology , Ferrochelatase/genetics , Liver Cirrhosis/diagnosis , Liver Transplantation , Mutation , Protoporphyria, Erythropoietic/complicationsABSTRACT
Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis caused by mutations in the gene encoding the enzyme ferrochelatase. In EPP, deficient ferrochelatase activity leads to the excessive production and biliary excretion of protoporphyrin (PP). The major clinical features of EPP are photosensitivity and hepatobiliary disease that may progress to severe liver disease, that are caused by the toxicity of PP. EPP-related liver disease has been treated medically or surgically including liver transplantation. We described a 20-year-old male with severe liver disease who was diagnosed with EPP based on clinical and laboratory findings. He was treated with cholestyramine resin. Six months after the treatment, he was doing well without any abdominal pain or photosensitivity.
Subject(s)
Humans , Male , Young Adult , Bilirubin/blood , Cholestyramine Resin/therapeutic use , Edema/complications , Erythema/complications , Ferrochelatase/genetics , Liver Diseases/complications , Protoporphyria, Erythropoietic/complications , Protoporphyrins/metabolismABSTRACT
Erythropoietic protoporphyria is a genetic disorder due to a deficiency of ferrochelatase resulting in excessive accumulation and excretion of protoporphyrin. The predominant clinical feature is photosensitivity. Severe hepatic failure occurs in a small percentage of patients, and neurological symptoms are very rare. We report a case of erythropoietic protoporphyria associated with severe hepatic dysfunction and neurological symptoms. A 9-year-old girl presented with severe abdominal pain, nausea, weakness and pain of extremities, and urinary retention. Ultrasonogram and abdominal CT scanning revealed a diffuse infiltrated and enlarged liver. Liver biopsy showed deposition of dense dark brown pigment within the bile, hepatocytes and Kupffer cells. Plus, dense dark brown deposits gave a red birefringent under polarize light. Porphyrin studies demonstrated markedly elevated serum free erythrocyte protoporphyrin. This girl was diagnosed as erythropoietic protoporphyria with severe liver dysfunction and neurological symptoms.
Subject(s)
Child , Female , Humans , Abdominal Pain , Bile , Biopsy , Erythrocytes , Extremities , Ferrochelatase , Hepatocytes , Hepatomegaly , Kupffer Cells , Liver Diseases , Liver Failure , Liver , Nausea , Protoporphyria, Erythropoietic , Tomography, X-Ray Computed , Ultrasonography , Urinary RetentionABSTRACT
Erythropoietic protoporphyria (EPP), caused by decreased activity of the enzyme ferrochelatase, is characterized clinically by burning photosensitivity beginning from childhood, and chemically by excessive amounts of red blood cell protoporphyrins. 1-10% of EPP patients develop potentially fatal protoporphyric hepatic failure. The diagnosis of EPP had been missed in many cases when traditional solvent extraction qualitative screening test was used for blood porphyrins, and use of fluorescence microscopy improved this problem. We report a case of EPP screened by fluorescence microscopy of erythrocytes in a 50-year-old man complaining of photosensitivity. We recommend fluorescence microscopy could be the screening test of choice for the detection of increased red blood cell porphyrins.
Subject(s)
Humans , Middle Aged , Burns , Diagnosis , Erythrocytes , Ferrochelatase , Fluorescence , Liver Failure , Mass Screening , Microscopy, Fluorescence , Porphyrins , Protoporphyria, Erythropoietic , ProtoporphyrinsABSTRACT
Erythropoietic protoporphyria(EPP) is an inherited inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase. EPP is characterized clinically by photosensitivity to visible light commencing in childhood, and biochemically by elevated red cell free protoporphyrin levels. We report herein a case of EPP which occurred in a 44-year-old man and his family. He had suffered from immediate photosensitivity since he was 4 years old. He was presented with burning, erythema, scars and waxy thickening of the sun-exposed skin. Red cell free protoporphyrin level was elevated and urinary porphyrins were normal. Histopathologically, homogeneous eosinophilic materials that stained with PAS were deposited in perivascular area of upper dermis. He was managed with light restriction and sunscreen.
Subject(s)
Adult , Child, Preschool , Humans , Burns , Cicatrix , Dermis , Eosinophils , Erythema , Ferrochelatase , Light , Metabolism , Porphyrins , Protoporphyria, Erythropoietic , SkinABSTRACT
Erythropoietic protoporphyria, sometimes also called erythrohepitic protoporphyria or simple protoporphyria, is a heritable detect of heme synthesis in which the last enzyme of the heme synthetic pathway, ferrochelatase(or heme synthetase), is functioning subopt,imally. A 23-year-old male has experi nced erythema and edema on the fae and hands during or immediately after sun exposure, since 3 years of age. The skin lesions have been accompanied by severe itching, a buring sensation and pain. Severe episodes were followed hy head iche and vomiting. We have seen a case of erythropoietic protoporphyria presenting clinically and histo athologically, wit.h a skin lesion on the sun exposured area, and free erthrocyte protoporphyrin serologically.
Subject(s)
Humans , Male , Young Adult , Edema , Erythema , Hand , Head , Heme , Protoporphyria, Erythropoietic , Pruritus , Sensation , Skin , Solar System , VomitingABSTRACT
Erythropoietic protoporphyria (EPP) is an autosomal dominant condition due to decreased activity of ferrochelatase. The disease is characterized by a wide range of photocutaneous changes and occasionally by liver disease. The level of protoporphyin is raised in erythkocytes and it may also be increased in the feces. We report herein a case of EPP present in a family which was diagnosed by a high free erythrocyte protoporphyrin (FEP) count.
Subject(s)
Humans , Erythrocytes , Feces , Ferrochelatase , Liver Diseases , Protoporphyria, ErythropoieticABSTRACT
Erythropoietic protoporphyria (EPP) is an autosomal dominant condition due to decreased activity of ferrochelatase. The disease is characterized by a wide range of photocutaneous changes and occasionally by liver disease. The level of protoporphyin is raised in erythkocytes and it may also be increased in the feces. We report herein a case of EPP present in a family which was diagnosed by a high free erythrocyte protoporphyrin (FEP) count.