ABSTRACT
Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.
Subject(s)
Liver , Porphyrias , Animals , Chimera , Disease Models, Animal , Hepatocytes/pathology , Hepatocytes/transplantation , Humans , Liver/pathology , Mice , Porphyrias/pathologyABSTRACT
Porphyria refers to a group of fascinating diseases from a metabolic and nutritional standpoint as it provides an example of how metabolic manipulation can be used for therapeutic purposes. It is characterized by defects in heme synthesis, particularly in the erythrocytes and liver. Specific enzymes involved in heme biosynthesis directly depend on adequate levels of vitamins and minerals in the tissues. Moreover, micronutrients that are required for producing succinyl CoA and other intermediates in the Krebs (TCA) cycle are indirectly necessary for heme metabolism. This review summarizes articles that describe the nutritional status, supplements intake, and dietary practices of patients affected by porphyria, paying special attention to the therapeutic use of nutrients that may help or hinder this group of diseases.
Subject(s)
Nutrients/metabolism , Nutritional Status/genetics , Porphyrias/metabolism , Dietary Supplements , Humans , Micronutrients/metabolism , Micronutrients/therapeutic use , Minerals/metabolism , Minerals/therapeutic use , Porphyrias/diet therapy , Porphyrias/genetics , Porphyrias/pathology , Vitamins/metabolism , Vitamins/therapeutic useSubject(s)
Heme/biosynthesis , Porphyrias , Biosynthetic Pathways , Humans , Porphyrias/diagnosis , Porphyrias/pathology , Porphyrias/therapyABSTRACT
Syndromic disorders with skin fragility belong to different groups of genodermatoses: epidermolysis bullosa (EB), Ehlers-Danlos syndrome and porphyria. The genetic defects mainly concern structural proteins which assure the mechanical stability of the skin and other tissues. Depending on the expression pattern of the affected protein in the skin, cutaneous fragility may manifest as superficial erosions, blisters, wounds, wound healing defects or scars. Extracutaneous manifestations are manifold and involve the heart, skeletal muscles, intestine, kidneys, blood vessels or the skeleton. Syndromic types of EB include in addition to skin blistering: (i) cardiomyopathy in case of desmoplakin, plakoglobin, or kelch-like protein mutations; (ii) muscular dystrophy in case of plektin mutations; (iii) pyloric atresia in case of integrin α6ß4 or plectin mutations; (iv) nephrotic syndrome in case of CD151 or integrin α3 mutations. Lysyl hydroxylase 3 mutations affect posttranslational modifications of collagens and lead to a dystrophic epidermolysis bullosa-like multisystemic disorder. Ehlers-Danlos syndromes are due to defects of dermal collagens or their processing and affect the skin, joints and blood vessels. Finally porphyrias are complex metabolic disorders with photosensitivity and sometimes skin fragility, liver or neurologic problems. Their pathogenesis relies on the accumulation of precursors in the tissues. Although these syndromes are rare in clinical practice, knowledge of the syndromic constellation contributes to early diagnosis and detection of complications.
Subject(s)
Ehlers-Danlos Syndrome/pathology , Epidermolysis Bullosa/pathology , Porphyrias/pathology , Skin Diseases, Vesiculobullous/pathology , Ehlers-Danlos Syndrome/genetics , Epidermolysis Bullosa/genetics , Humans , Mutation , Porphyrias/genetics , Skin Diseases, Vesiculobullous/genetics , SyndromeABSTRACT
Congenital erythropoietic porphyria, also called Gunther's disease, is a very rare genetic autosomal recessive diseaseaffecting less than 1 per 1,000,000 children. Pathogenesis involves genetic mutation encoding uroporphyrinogen-III cosynthase which leads to accumulation of porphyrin in many tissues, leading to extreme skin photosensitivity, red cell lysis, splenomegaly and reduced life expectancy. Herein, we report a 12-year mentally challenged girl with multiple blisters and scars on sun exposed sites since birth. She had hepatomegaly, erythrodontia, severe anaemia with haemolytic blood picture and mildly elevated liver enzymes. Skin biopsy showed deposition of amorphous eosinophilic porphyrins in the dermis, thus confirming a diagnosis of congenital erythropoietic porphyria.
Subject(s)
Anemia, Hemolytic/diagnosis , Intellectual Disability , Photosensitivity Disorders/diagnosis , Porphyria, Erythropoietic/diagnosis , Porphyrias/congenital , Biopsy , Child , Female , Hepatomegaly , Humans , Photosensitivity Disorders/metabolism , Photosensitivity Disorders/pathology , Porphyria, Erythropoietic/complications , Porphyria, Erythropoietic/metabolism , Porphyrias/metabolism , Porphyrias/pathologySubject(s)
Antineoplastic Agents/adverse effects , Drug Eruptions/etiology , Imatinib Mesylate/adverse effects , Porphyrias/chemically induced , Drug Eruptions/pathology , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Middle Aged , Porphyrias/pathology , Skin/pathologySubject(s)
Porphyrias/pathology , Skin/radiation effects , Sunlight/adverse effects , Biopsy , Diagnosis, Differential , Humans , Male , Middle Aged , Skin/pathologyABSTRACT
Porphyria is a group of eight metabolic disorders characterized by defects in heme biosynthesis. The presentation of porphyria is highly variable, and the symptoms are nonspecific, which accounts in part for delays in establishing a diagnosis. In this study, we report the characteristics of 36 Chinese acute porphyria patients. Most of them were female (33/36), and the median age was 25.3 years (range 18-45 years). The most frequent presenting symptom was abdominal pain (32/36). Hyponatremia was the most common electrolyte abnormality (29/36), and the serum sodium concentration was significantly negatively correlated with convulsion (p = 0.00). Genetic testing provided a precise diagnosis of the patients. Genetic analysis of the porphobilinogen deaminase (PBGD) gene was performed for 10 subjects. Of them, 9 were found to harbor a mutation in the PBGD gene, proving a diagnosis of acute intermittent porphyria, and, in 1 case, a novel Cys209Term mutation was found.
Subject(s)
Abdominal Pain , Hydroxymethylbilane Synthase/genetics , Hyponatremia , Mutation, Missense , Porphyrias , Abdominal Pain/genetics , Abdominal Pain/pathology , Abdominal Pain/physiopathology , Acute Disease , Adolescent , Adult , Amino Acid Substitution , Female , Humans , Hyponatremia/genetics , Hyponatremia/pathology , Hyponatremia/physiopathology , Male , Middle Aged , Porphyrias/diagnosis , Porphyrias/genetics , Porphyrias/pathology , Porphyrias/physiopathology , Tertiary Care CentersABSTRACT
Pseudoporphyria describes a photodistributed bullous disorder with negative urinary, fecal, and serum porphyrin studies. Although pseudoporphyria is thought to be extremely rare (less than 100 reported cases4-5), we propose that this entity is underreported. One author (KB) has seen four cases of pseudoporphyria in the past four years. We describe a patient with nonpruritic, nonpainful bulla on the dorsum of his hands. Biopsy revealed a split at the dermal-epidermal junction; laboratory tests and urinary porphyrin evaluation were negative.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Drug Eruptions/diagnosis , Porphyrias/diagnosis , Skin Diseases, Vesiculobullous/diagnosis , Aged , Diagnosis, Differential , Drug Eruptions/etiology , Drug Eruptions/pathology , Hand , Humans , Male , Porphyrias/etiology , Porphyrias/pathology , Skin Diseases, Vesiculobullous/etiology , Skin Diseases, Vesiculobullous/pathologyABSTRACT
The Syrian hamster Harderian gland (HG) is an organ that undergoes physiological autophagy in response to oxidative stress induced by porphyrin production. Porphyrin production in the HG has marked sex differences and is closely linked to reproductive function. In the present study, we observed that the estrous cycle and associated estrogen variations may affect oxidative-stress-induced proteolytic processes. In particular, significant changes in autophagic activity were detected during the estrous cycle. Notably, increased activation of macroautophagy as well as chaperone-mediated autophagy in the estrus phase coincided with a minimal antioxidant capability and the highest protein damage levels. By contrast, autophagic machinery was found to be blocked in the diestrus phase, likely due to mammalian target of rapamycin activation, which could be corroborated by the subsequent pS6K activation. Analogous results were observed regarding proteasome activity, which also showed maximal activity in the estrus phase. Interestingly, all these mechanisms were associated with important morphological changes in the HG during the estrous cycle. We observed statistically significant increases in Type II cells, which may be related to extensive autophagy in the estrus phase. Physiologically, this would result in a significant release of porphyrins specifically when females are more receptive. These data support the role of porphyrins as pheromones, as other authors have previously suggested, thus making the HG a scent organ. In addition, these results suggest a porphyrin-based approach to the treatment of porphyria during pregnancy, a condition for which no treatment is currently known.
Subject(s)
Autophagy , Estrous Cycle/metabolism , Harderian Gland/metabolism , Porphyrins/metabolism , Proteolysis , Animals , Estrogens/metabolism , Female , Humans , Mesocricetus , Porphyrias/metabolism , Porphyrias/pathology , Pregnancy , Pregnancy Complications/metabolism , Pregnancy Complications/pathologyABSTRACT
The lecture presents data concerning biosynthesis of haem and mechanisms of its regulation in bone marrow and liver. The basic pathogenic mechanisms of porphyrias development and their classification are exposed. The optimal list of laboratory tests to diagnose porphyrias is presented. The role and significance of various laboratory analysis techniques to diagnose porphyrias are demonstrated. The technology of laboratory analysis in case of porphyria suspicion is described.
Subject(s)
Heme/biosynthesis , Porphyrias , Porphyrins , Aminolevulinic Acid/urine , Humans , Porphyrias/blood , Porphyrias/classification , Porphyrias/diagnosis , Porphyrias/pathology , Porphyrias/urine , Porphyrins/blood , Porphyrins/metabolism , Porphyrins/urineSubject(s)
Blister/chemically induced , Blister/diagnosis , Finasteride/adverse effects , Porphyrias/chemically induced , Porphyrias/diagnosis , Biopsy , Blister/pathology , Coproporphyrins/blood , Finasteride/administration & dosage , Humans , Male , Middle Aged , Porphyrias/pathology , Treatment OutcomeABSTRACT
Immunofluorescence is a valuable auxiliary diagnostic tool for autoimmune bullous diseases and inflammatory disorders, since their clinical and histopathologic findings may be inconclusive. It is a feasible laboratory method that requires experienced technicians and detects in situ and circulating immune deposits that may be involved in the pathogenesis of such skin diseases.
Subject(s)
Basement Membrane/chemistry , Fluorescent Antibody Technique, Direct , Fluorescent Antibody Technique, Indirect , Skin Diseases/diagnosis , Biopsy , Complement C3/analysis , Humans , Immunoglobulins/analysis , Lichen Planus/diagnosis , Lichen Planus/pathology , Lupus Erythematosus, Cutaneous/diagnosis , Lupus Erythematosus, Cutaneous/pathology , Pemphigus/diagnosis , Pemphigus/pathology , Porphyrias/diagnosis , Porphyrias/pathology , Skin Diseases/pathology , Vasculitis/diagnosis , Vasculitis/pathologyABSTRACT
A imunofluorescência é um valioso instrumento auxiliar no diagnóstico das dermatoses bolhosas autoimunes e desordens inflamatórias, uma vez que seus achados clínicos e histopatológicos podem não ser determinantes. Consiste em um método laboratorial factível, que requer profissionais técnicos experientes, e detecta imunocomplexos in situ e/ou circulantes, que podem estar envolvidos na patogênese de tais enfermidades cutâneas.
Immunofluorescence is a valuable auxiliary diagnostic tool for autoimmune bullous diseases and inflammatory disorders, since their clinical and histopathologic findings may be inconclusive. It is a feasible laboratory method that requires experienced technicians and detects in situ and circulating immune deposits that may be involved in the pathogenesis of such skin diseases.
Subject(s)
Humans , Basement Membrane/chemistry , Fluorescent Antibody Technique, Direct , Fluorescent Antibody Technique, Indirect , Skin Diseases/diagnosis , Biopsy , /analysis , Immunoglobulins/analysis , Lichen Planus/diagnosis , Lichen Planus/pathology , Lupus Erythematosus, Cutaneous/diagnosis , Lupus Erythematosus, Cutaneous/pathology , Pemphigus/diagnosis , Pemphigus/pathology , Porphyrias/diagnosis , Porphyrias/pathology , Skin Diseases/pathology , Vasculitis/diagnosis , Vasculitis/pathologyABSTRACT
The porphyrias are clinically and genetically heterogeneous metabolic disorders resulting from a predominantly hereditary dysfunction of specific enzymes involved in heme biosynthesis. Today, the clinical, biochemical, and genetic characteristics of this fascinating group of diseases are well established. Recently, different in vitro and animal models have facilitated the investigation of etiopathologic mechanisms in the different types of porphyria and the development of causal treatment strategies such as pathway interference, enzyme replacement, and gene therapy. The continuous progress in basic science has made an invaluable contribution to the rapid translation of discoveries made in the laboratory into new diagnostics and therapeutics in the near future.