Porphyria cutanea tarda (PCT) is the most common form of porphyria across the world. Unlike other forms of porphyria, which are inborn errors of metabolism, PCT is usually an acquired liver disease caused by exogenous factors, chief among which are excess alcohol intake, iron overload, chronic hepatitis C, estrogen therapy, and cigarette smoking. The pathogenesis of PCT is complex and varied, but hereditary or acquired factors that lead to hepatic iron loading and increased oxidative stress are of central importance.
Iron loading is usually only mild or moderate in degree (less than that associated with full-blown hemochromatosis) and is usually acquired and/or due to mutations in HFE. Among acquired factors are excessive alcohol intake and chronic hepatitis C infection, which, like mutations in HFE, decrease hepcidin production by hepatocytes. The decrease in hepcidin leads to increased iron absorption from the gut. In the liver, iron-loading and increased oxidative stress leads to the formation of non-porphyrin inhibitor(s) of uroporphyrinogen decarboxylase and to oxidation of porphyrinogens to porphyrins. The treatment of choice of active PCT is iron reduction by phlebotomy and maintenance of a mildly iron-reduced state without anemia. Low-dose anti-malarials (cinchona alkaloids) are also useful as additional therapy or as alternative therapy for active PCT in those without hemochromatosis or chronic hepatitis C.
In this review, we provide an update of PCT with special emphasis upon the important role often played by the hepatitis C virus. Overview of Porphyria Cutanea Tarda (PCT) Porphyria cutanea tarda (PCT) is the most common type of porphyria worldwide with an estimated prevalence in various countries ranging from 1:5,000 to 1:70,000 (-). PCT is known by many other names, including symptomatic porphyria, idiosyncratic porphyria, chemical porphyria, or acquired hepatic porphyria. PCT typically presents as a chronic, gradually progressive cutaneous disorder, with vesicles, milia, and bullae on the backs of the hands and forearms. Clinical features rarely develop unless there is at least 75% decrease in activity of hepatic uroporphyrinogen decarboxylase (UROD) (-).
UROD is the fifth enzyme in the heme biosynthetic pathway. UROD deficiency is usually acquired (75-80% of cases), but 20-25% of subjects with familial PCT have a genetic predisposition with partial (50%) deficiency in UROD activity. Those with genetic predisposition need fewer other factors to decrease the activity further down to the threshold of 75% in order for symptomatic disease to occur. Nature of Metabolic Defect and Pathogenesis of PCT PCT is a heterogeneous disease and has been classified into three subtypes. Type I, accounting for 75-80%, is acquired PCT, in which deficiency of UROD is limited to hepatocytes.
Type II, accounting for 20-25%, is hereditary, in which there is partial deficiency 50% of UROD in all tissues. Type III is a very rare form in which there exists an apparently genetic predisposition that leads to decreased UROD activity limited to hepatocytes (-). It is thought that the genetic abnormality in type III PCT is in a still unidentified gene other than UROD.
There is only one UROD gene in humans; it is located on chromosome 1P34, is around 10 kb in length, and consists of 10 exons. Classification of Porphyria Cutanea Tarda Several lines of evidence support the concept that, in PCT, there occurs in the liver the formation of an inhibitor of UROD, which is derived from uroporphyrinogen or hydroxymethylbilane, the tetrapyrrole precursor of uroporphyrinogen. Formation of the inhibitor, which more likely than not is an oxidation product, is increased by iron, a well-known oxidant, by activity of cytochrome P-4501A2, by alcohol excess, and by estrogen therapy. Based on mass spectroscopic evidence obtained from studies in a murine model of PCT, it has been claimed that uroporphomethene is the inhibitor. However, others have cast doubt upon the interpretation of the mass spectroscopic evidence.
Thus, the precise structure and nature of the UROD inhibitor remains unresolved. Pathogenesis of Porphyria Cutanea Tarda UROD catalyzes the step-wise decarboxylation of uroporphyrinogen to the corresponding coproporphyrinogen. Uroporphyrins which contain 8-carboxylate groups and heptacarboxylated porphyrins accumulate in various organs as a consequence of impaired UROD activity and increased oxidative stress.
Porphyrins with many carboxylate residues are water soluble, while those with few e.g., protoporphyrin with 2 carboxylate (-COOH) residues are insoluble in water. Thus, those with higher numbers of −COOH residues, such as uro- and heptacarboxyl-porphyrins are excreted primarily in the urine; those with intermediate numbers of −COOH groups e.g., coproporphyrins, with 4-COOH are excreted in both urine and stool; whereas, protoporphyrin is secreted only into the bile and excreted only in the stool. Within cells, different water solubilities influence where various porphyrins accumulate. Due to their hydrophilic nature, uro –and heptacarboxyl- porphyrins accumulate in the cytosol and lysosomes and are not associated with or dissolved in membranes to any appreciable extent. The ability of porphyrins to absorb light of 400-410 nm (the Soret band) (, -) is the key factor in producing the photocutaneous lesions observed on sun-exposed areas in affected individuals.
The delocalized Pi-electrons of aromatic porphyrins readily absorb energy of violet light and enter a higher energy state. This excited state then transfers its excess energy to molecular oxygen which in turn raises electrons of oxygen to a higher energy state “singlet oxygen”. Roberto fonseca zamazu rar. The reactive oxygen species give rise to the phototoxic damage characteristic of PCT , as well as further catalyzing the oxidation of porphyrinogens to porphyrins. Major Clinical, Laboratory, Histopathological Features, and Risk Factors of PCT PCT clinically presents with blisters, vesicles, and/or milia days to weeks after sun exposure (, ) in areas likely to be exposed to the sun and to minor trauma, such as the dorsa of the hands and forearms. These lesions typically first arise and are worse in the summer and often take weeks or months to resolve. Chronic skin damage may result in scarring, changes in cutaneous pigmentation at the sites of blisters and milia. Other skin manifestations may include a purplish heliotrope suffusion of periorbital areas , hypertrichosis, usually involving the lateral aspects of the face, chloracne, sclerodermatous changes, dystrophic calcification with ulceration, alopecia, and onycholysis.
Typical Cutaneous Manifestations of PCT Due to marked excretions of porphyrins in the urine, patients with PCT may have urine that appears pink, red, or brown, especially after exposure of the urine to air and light (, ). Because the free porphyrins do not contain iron, urine tests for heme, hemoglobin, or myoglobin are all negative.
Thus, despite the pink-red color of urine, routine urinalysis and blood counts are normal in most patients. Persons with active PCT are usually found to have mildly elevated serum aminotransferases and gamma-glutamyl transpeptidase. The nonspecific findings of routine laboratory tests make it clear that special studies are needed to diagnose PCT. A useful initial test is direct fluorometric assay of plasma. In patients with symptomatic PCT, plasma porphyrins are elevated with maximal excitation and emission wavelengths at 400 nm and 620 nm, respectively.
When this fluorometric pattern is observed, tests for levels of porphyrins and porphyrin precursors in urine, and porphyrins in feces are used to confirm the diagnosis. If PCT is present, elevated levels of uro- and heptacarboxyl-porphyrins are found in the urine along with elevated fecal isocoproporphyrin, and plasma 8- and 7- carboxylporphyrins, with little or no elevation of erythrocyte porphyrin levels. Urinary levels of delta-aminolevulinic acid (ALA) are normal or slightly increased less than 2 times the upper limit of normal, and levels of urinary porphobilinogen (PBG) are normal. The latter help to distinguish PCT from the acute or inducible hepatic porphyrias hereditary coproporphyria, variegate porphyria, which may be present with cutaneous features indistinguishable from those of PCT. In addition, in variegate porphyria, the peak emission wavelength of plasma fluorescence is 626-628 nm, finding of considerable diagnostic value.
In active PCT, vesiculo-bullous lesions “festoon” the dermal papillae whereby these dermal projections rise irregularly into the cavities of subepidermal fluid collections. There is also deposition of periodic acid-Schiff positive, diastase-resistant glycoproteins, various immunoglobulins and complement around both the dermo-epithelial junction and blood vessels. These lesions are not unique to PCT and are found in other porphyrias of the bullous type.
Similarly, liver histopathology is mostly non-specific and includes red fluorescence of unfixed hepatic tissue (which is seen in various types of porphyria), necrosis, inflammation, varying siderosis and steatosis (, ). Hemosiderosis is usually mild to moderate but may be severe when accompanied by mutations that underlie hemochromatosis. Indeed, PCT shows a clear dose-response relationship in individuals carrying either C282Y or H63D gene mutations. In a meta-analysis done by Ellervik and colleagues, C282Y homozygotes were demonstrated to have the highest risk for PCT while H63D heterozygozity with wild type conferred the lowest risk.
Other features include needle-shaped hydrophilic cytoplasmic inclusions thought to be mainly composed of uro-and/or heptacarboxyl porphyrin crystals. These crystals have been localized to the areas of cytoplasm that contain ferritin granules further suggesting the role of iron in oxidation of porphyrinogens and subsequent crystallization of porphyrins. Hepatic Histopathology in PCT Iron enhances uroporphyrin overproduction in several ways. First, iron increases reactive oxygen species (ROS), which increase the rate at which uroporphyrinogen and heptacarboxylporphyrinogen are oxidized into their respective porphyrins. Second, it decreases the activity of UROD by increasing formation of an inhibitor, probably derived from hydroxymethylbilane and/or uroporphyrinogen. Third, iron increases intracellular ALA levels providing more substrate for uroporphyrinogen and subsequent uroporphyrin synthesis.
Despite the importance of hepatic siderosis in PCT, iron by itself is insufficient to cause uroporphyrin overproduction in the absence of other predisposing factors (, -). Other known risk factors for PCT include UROD mutations , alcohol, smoking (, ), hepatotoxic aromatic hydrocarbons (e.g., hexachlorobenzene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and others), certain genetic variations in the genes for cytochrome P4501A2, and glutathione-S-transferase GSTM1 , hepatic tumors (benign, malignant, or metastatic) , dialysis, sarcoidosis, estrogens, and chronic infection with the hepatitis C or human immunodeficiency virus.
Overview of the Hepatitis C Virus (HCV) and Chronic Hepatitis C (CHC) HCV is a hepatotropic member of the flaviviridae family and is known to infect an estimated 170-200 million people worldwide (, ). HCV has six known major genotypes (-) which may be further divided into 50 subtypes (1a, 1b, etc.). Certain genotypes are more prevalent at different parts of the globe. Genotype 1 is predominant in the USA, accounting for 70% of infections. Furthermore, 55% of these are subtype 1a while 40% are 1b; the remaining small proportion is due to subtype 1a/1b co-infection. Most of the remaining 30% of infected individuals in the USA are due to HCV of genotypes 2 or 3, while genotypes 4-6 account for a small proportion.
In contrast, 80% of HCV infections in Europe are due to subtype 1b. Other global variations include the predominance of genotype 2a in Japan, Taiwan, and China; genotype 3 in Scotland and other parts of the UK ; genotype 4 in the Middle East and Northern and Central Africa; genotype 5 in South Africa; and genotype 6 in South East Asia. The virus is transmitted mainly by the parenteral route and to a lesser extent by vertical and sexual transmission. Acute HCV infection may begin insidiously or present abruptly. It has a limited course that usually lasts one or two months. Acute infection is rarely detected because the majority of patients are asymptomatic.
Indeed, only 10-20% of patients develop jaundice, with a greater proportion presenting with non-specific symptoms (e.g., anorexia, fatigue, nausea, tiredness). Of those acutely infected by HCV, 60-85% develop chronic infection and approximately 70% of these develop chronic liver disease, 10-20% of which progress to cirrhosis. Indeed, CHC has become the single most common indication for orthotopic liver transplantation in the western world. Thus, cirrhosis due to CHC accounts for 40-50% of patients listed for transplant.
While the majority of patients with CHC have elevated serum aminotransferases, about a third of those infected have persistently normal levels despite a high viral load and continued hepatic injury. Patients with chronic infection frequently complain of fatigue. Other non-specific symptoms such as myalgias, arthralgias, paresthesias, pruritus, and sicca syndrome are also frequent complaints. Epidemiology/Association of PCT with HCV In most studies, there is a strong association between HCV infection and PCT (, -). Furthermore, it has been observed that HCV-infected individuals develop PCT at an earlier age than do uninfected persons with PCT (, ).
Although the presence of any single risk factor is likely not sufficient to cause PCT, HCV is thought to be a strong trigger for the development of deranged porphyrin metabolism in those with other known predisposition (, ). O’Reilly et al. Reported only minimal elevations of urinary porphyrins in 59 subjects infected with HCV but with few or no concomitant susceptibilities. Subjects found to have mildly elevated porphyrins were on a variety of medications that may have influenced porphyrin metabolism, and none had overt PCT. Nomura et al. Confirmed these results and also found HCV and HIV co-infection to be significantly associated with elevated serum porphyrins.
In addition, Jalil et al. Analyzed records of 143 patients with well documented PCT. They found that most subjects with clinically manifest PCT had three or more known susceptibility factors.
Factors that Underlie the Association of HCV and PCT Although CHC is among factors known to increase risk of PCT, it is not clear if the virus, per se, plays a role in the development and pathogenesis of PCT, or whether this association is mainly due to iron overload and/or increased oxidative stress, which often occur in the context of CHC. It has been known for many years that 1) most patients with PCT have some degree of iron overload; 2) iron removal ameliorates porphyrin overproduction and clinical features; and 3) administration of iron produces relapse of PCT.
Serum iron indices and iron content of the liver are often elevated in patients with CHC (, ). The precise molecular mechanisms by which iron may influence HCV-induced liver disease are not fully understood. Among several proposed mechanisms are iron-induced immunologic modifications and iron effects on signal transduction and HCV proliferation. Elevated hepatic iron and increased serum iron indices also have been associated with PCT , and iron is known to exert several actions that increase oxidation of porphyrinogens and lead to inhibition of UROD.
Therefore, iron can be considered as a common factor for the development and progression of both CHC- and PCT- induced liver diseases. Based on these facts, it can be anticipated that patients with iron overload like those with hereditary hemochromatosis (HH) have a higher risk for the development and progression of both CHC- and PCT- induced liver diseases. Indeed, significantly increased frequencies of both C282Y and H63D mutations of HFE in PCT patients have been reported from studies in Northern Europe and the USA (, ).
The preponderance of the evidence suggests that patients with CHC who are heterozygous for H63D or C282Y mutations are at a higher risk of severe hepatocellular injury and fibrosis. Therefore, even in patients harboring HFE mutations that cause milder defects in iron homeostasis, it is possible that the presence of HFE mutations leads to the inactivation of UROD through interaction with other factors like HCV infection, which change iron homeostasis in the liver.
Transgenic mice expressing an HCV polyprotein and fed a high-iron diet were found to have not only higher degrees of hepatic steatosis, lipid peroxidation, and mitochondrial injury, but also a higher risk of development of hepatocellular carcinoma (HCC), compared to mice fed a normal diet. Using human hepatoma cells, expressing an HCV subgenomic replicon, Fillebeen et al. showed that HCV replication altered the expression of several genes related to iron metabolism. Alteration of these genes, in turn, can contribute to development of PCT in the context of HCV infection. Recently, Nishina et al. Have shown that HCV increases reactive oxygen species (ROS), which leads to increase hepatic expression of CCAAT/enhancer binding protein homologous protein (CHOP) via an increase in histone deacetylase (HDAC) activity.
CHOP is a nuclear protein that inhibits C/EBPα via the binding of their carboxy terminal domains. Thus, the CHOP-C/EBPα heterodimer renders the C/EBPα monomer unavailable to bind its DNA enhancer elements that lead to hepcidin production. Hepcidin, a 25-amino acid cysteine-rich peptide, is the key regulator of iron absorption and metabolism in humans, which induces internalization and degradation of ferroportin, and this in turn leads to the reduction of iron exported from cells. Therefore, over-expression of hepcidin in mice and humans leads to iron deficiency, whereas its deficiency leads to iron overload. In HCV-infected individuals (as with FL-N/35 transgenic mice with the full length HCV polyprotein ), compared to controls, hepcidin expression levels are low relative to the iron content of hepatocytes (, ). Interestingly, in a recent study, Ajioka et al.
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Showed that hepatic hepcidin expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with HH but without PCT with comparable iron overload. Therefore, they suggested that the hepatic siderosis associated with PCT likely results from dysregulated hepcidin. Taken together, it appears that HCV leads to down-regulation of hepcidin, and this can lead to iron overload, which in turn facilitates development of PCT by inhibiting UROD activity.
In addition to CHC, there are also reports that show concurrence of other viral infection like HBV, HIV, and HHV6 with PCT (, ). These associations suggest that viral infection, per se, may play a role in reducing the activity of (UROD). Additional studies investigating alteration of UROD activity in HCV infected cell lines may help to unravel the mechanism of this association. As mentioned above, besides HCV infection and HFE mutations, several environmental factors have been shown to precipitate overt clinical PCT, including alcohol abuse, tobacco use, and use of oral estrogens.
Alcohol may cause liver damage, ranging from reversible steatosis to alcoholic cirrhosis. Alcohol also exacerbates the hepatopathy of CHC. Alcohol, estrogens, iron, and CHC all produce increased oxidative stress in liver cells. Besides, it is also anticipated that there might be common molecular pathways for triggering both PCT, and its predisposing factors.
In mice, cytochrome P4501A2 (Cyp1A2) plays a major role in the development of uroporphyria. Unlike mice with normal Cyp1A2, knockout mice deficient in Cyp1A2 do not develop uroporphyria following exposure to halogenated polyaromatic hydrocarbons. As mentioned above, in a recent study, it was found that genetic variations in human CYP1A2(.1F) and GST(M1) alleles are associated with susceptibility to PCT.
GSTM1 is particularly important in the deactivation of reactive intermediates of polycyclic aromatic hydrocarbons. Management of PCT As in other types of cutaneous porphyria, avoidance of sun exposure and/or strong light of 400-410 nm wavelength (Soret band) is the most effective way to prevent the cutaneous manifestations of PCT. Avoidance of sun exposure involves the use of protective clothing (Solumbrex ®) and opaque sunscreens that contain zinc or titanium oxide. In addition, preventing or controlling various predisposing factors should be a routine part of management. Definitive therapy aimed at the pathogenic mechanism of PCT includes iron reduction, and anti-malarials that remove porphyrins from the liver and other tissues.
Among these, phlebotomy is the treatment of choice and has generally been shown to be cheap, safe, and effective. Although moderate hepatic iron overload is common in PCT, presence of hepatic siderosis in PCT is not a prerequisite for successful treatment with venesection (, ). It is recommended that a unit (450-500 mL) of blood be removed either once a week or every other week until the serum ferritin is. Treatment of CHC in the Context of PCT The principles of treatment described above can also generally be used for PCT in the setting of chronic hepatitis C (CHC). Although chloroquine effectively reduces uroporphyrin levels, it does not address the loosely-bound hepatic iron thought to be of importance in PCT pathogenesis. Due to the fact that patients with homozygous C282Y mutations of HFE (a risk factor for PCT) also failed to respond to chloroquine treatment, most investigators prefer phlebotomy in patients with both HFE gene mutations and CHC. While treatment of PCT alone with iron chelators is possible, such therapy is far more expensive and involved and phlebotomy is preferred.
Furthermore, there is paucity of data regarding use of iron-chelators in those with CHC and PCT. It has been reported that interferon alpha (IFN) therapy improved the levels of serum aminotransferases and urinary porphyrins and resolved skin lesions along with decreasing HCV RNA levels in patients with concurrent CHC and PCT (, ). On the other hand, there are also a few reports of de novo occurrence of PCT during IFN plus ribavirin therapy for CHC. In one small study reported only in abstract form, Rossini et al randomized 20 patients with both PCT and CHC into two cohorts. Group 1 received phlebotomy prior to dual therapy with pegylated interferon and ribavirin while group 2 received dual therapy without pretreatment venesection. The investigators measured levels of HCV RNA in serum before and after iron depletion in group 1 and found no significant difference, in keeping with earlier results of others (, ).
No comparisons between the viral levels of the two groups were reported in the abstract. Mainly based on the results in their group 1, the investigators concluded that iron depletion did not seem to improve the rate of response to anti-HCV treatment in these patients. In addition to providing little data on group 2 (especially in comparison to group 1), the study was small in size and thus, lacks statistical power. Furthermore, while group 1 subjects were all infected with HCV of genotype 1b, there were two patients with genotype 2a in group 2.
It is well-known that genotype 2 HCV is more responsive to interferon-based therapy. Thus the two rather small groups were not comparable, rendering interpretation of results problematical. Treatment of PCT by iron reduction is successful even in patients with CHC. Because iron overload is found in most cases of PCT (, ), and iron is a recognized factor that influence severity and course of chronic viral hepatitis (, ), reduction of iron stores by venesection can lead to improvement of both conditions. Furthermore, the fact that patients with CHC and PCT respond poorly to interferon (IFN) and that phlebotomy enhances sustained virological response (SVR) of patients who received IFN monotherapy , suggest that venesection preceding combination anti-viral therapy may be ideal.
Therefore, it is usually wise to treat the PCT with therapeutic phlebotomies first and then deal with the treatment for CHC with peg-IFN and ribavirin or, now, with triple therapy peg-IFN+ribavirin+HCV protease inhibitor, either boceprevir or telaprevir. Iron reduction prior to combination anti-viral therapy not only helps to reduce possible deleterious effects of iron on UROD, and hence improves symptoms of PCT, but also facilitates decreasing of HCV RNA levels, and impedes the synergistic effect of iron and HCV in the progression of liver disease. It is not yet known whether the newer triple or, in future quadruple –drug regimens for CHC will prove effective also as therapy for PCT with CHC. These issues will require future study. Venesection prior to ribavirin (RBV)-based therapy may prove challenging because of the frequent development of hemolytic anemia associated with RBV therapy. Thus optimal timing of when to stop phlebotomy prior to initiating RBV-based regimen is unknown.
Due to paucity of data, some authors suggest that the hemoglobin levels be between 12-14 g/dL prior to starting RBV-based therapy after appropriate phlebotomy. Treatment of HCV-Infected Patients without PCT with Phlebotomy Iron reduction may improve the severity of CHC and increase the likelihood of response of CHC to antiviral therapy. Prior to the advent of combination therapy with pegylated IFN and ribavirin, multiple clinical trials demonstrated improved clinical response in CHC patients treated with phlebotomy and IFN monotherapy compared to IFN monotherapy alone. conducted a meta-analysis of these randomized controlled trials and reported highly significant improvements in virological response rates (P1,100 μg/g dry liver or 1+ stainable iron , and if siderosis is primarily mesenchymal. However, additional larger prospective clinical trials are needed in order to better assess whether there is a role for iron reduction in management of some patients with chronic hepatitis C.
Furthermore, with the several new stat-C small molecule drugs with potent activity against the HCV virus now under development, perhaps, in the not-too-distant future, rates of cure and tolerability of therapy will both improve further, and the numbers of subjects for whom iron reduction may be considered will decrease. Nevertheless, especially in less developed countries or in those without the means to afford expensive new multiple drug regimens, the inexpensive and safe measures of iron reduction and low iron diets may retain a useful place in the therapeutic armamentarium. Summary and Conclusions An important etiological association between CHC and PCT is well-established. Both CHC and PCT are also associated with hepatic iron overload and with increased oxidative stress. Other factors associated with PCT, such as excess alcohol and estrogen therapy, also increase oxidative stress in hepatocytes.
The importance of iron is further emphasized by the fact that iron reduction regularly and reliably leads to amelioration of PCT, whether associated with CHC or not. In addition, studies, especially from the Far East, indicate that iron reduction that is sustained for several years leads to improvement of the histopathological severity of CHC, to reduced risk of histopathological progression, and to reduced risk of development of hepatocellular carcinoma.
Thus, we recommend iron reduction as initial therapy of PCT and of CHC with PCT. In addition, iron reduction and maintenance of an iron-reduced state are reasonable therapeutic alternatives for those who do not respond to, who do not tolerate, or cannot afford, dual or triple anti-viral therapy of CHC.
Supported by a grant (DK R01 38825) and contracts (U01 DK065201, U01 DK065176) from NIH (NIDDK) and by funds provided by the American Porphyria Foundation and the Carolinas HealthCare Foundation. We thank Melanie McDermid and Kay Snider for assistance with typing and preparation of the manuscript. Statement of Conflicts of Interest: During the past three years, Dr. Bonkovsky has served as an advisor to and has received research support from Clinuvel, Inc and Novartis, Inc. He has been an adviser to Boehringer-Ingelheim, Gmbh, and Lundbeck A/S. He has received research support from Vertex, Inc. Bonkovsky is a member of the Scientific Advisory Board of the American Porphyria Foundation and is Chair of the Scientific Advisory Board of the Iron Disorders Institute.
He is a member of the Board of Directors of the Iron Disorders Institute. Bonkovsky is site PI at Carolinas Medical Center for the US Porphyria Consortium, a part of the Rare Diseases Clinical Research Network, supported by the NIH office of Rare Diseases and the NIDDK.
In recent decades,the forming area advanced both in terms of material used as well as in flexibilityand process cost reduction. New processes are been studied, including theIncremental Sheet Forming – ISF.
The ISF is a process characterized by theproduction of small batches of parts, rapid prototyping, and manufacturingflexibility with reduced operational cost. This study aims to compare thecomputer simulation with real experiments from ISF. The results of strain pathsof the three main strains simulated were consistent with the experimentalmanufacture of a symmetrical sample.
Abstract: According to the characteristic which is more and difficult to determine about the automotive panel forming factors, based on the dynamic explicit method, taking the typical automobile front fender for example, do the simulation analysis by using of DYNAFORM. On the premise of taking springback factors into account, analog the best stamping process parameters has been optimized from the analysis results after simulation such as sheet metal forming limited drawing(FLD)and sheet metal thinning drawing.
Abstract: Asymmetric Incremental Sheet Forming (AISF) is a process for the flexible production of sheet metal parts. In AISF, a part is obtained as the sum of localized plastic deformations produced by a simple forming tool that, in most configurations, moves under CNC control.
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Flexible processes with low tooling effort like AISF are suitable for sectors with small lot sizes but premium products, e.g. For the aviation and the automotive sector.
Four main process limits restrict the range of application of AISF and its take-up in industry. These are: (i) material thinning, (ii) limited geometrical accuracy, (iii) the process duration and (iv) the calculation time and accuracy of process modelling. Moreover, the material spectrum of AISF for structural parts is mostly restricted to cold workable materials like steel and aluminum. This paper presents some new investigations of incremental sheet forming combined with laser heating or stretch forming as possible hybrid approaches to overcome the above mentioned limitations of AISF. These hybrid incremental sheet forming processes can increase the technological and economical potentials of AISF. A possible application is the fabrication of lightweight sheet metal parts as individual parts or small batches, e.g.
For the aerospace industry. The present study provides a short overview of the state of the art of AISF, introduces the new hybrid process variations of AISF and compares the capabilities of the hybrid processes and the standard AISF process. Finally, two examples for applications are presented: (i) the production of a part used in an airplane for which the manufacturing steps consist of die manufacture, sheet metal forming by means of stretch forming combined with AISF and a final trimming operation using a single hybrid machine set-up; (ii) laser-assisted AISF for magnesium alloys. Abstract: Development of new technologies and processes for small batch and prototype production of sheet metal components has a very important role in the recent years. The reason is the quick and efficient response to the market demands. For this reasons new manufacturing concepts have to be developed in order to enable a fast and reliable production of complex components and parts without investing in special forming machines.
The need for flexible forming processes has been accelerated during the last 15 years, and by these developments the technology reaches new extensions. Incremental sheet metal forming (ISMF) may be regarded as one of the promising developments for these purposes. A comprehensive research work is in progress at the University of Miskolc (Hungary) to study the effect of important process parameters with particular emphasis on the shape and dimensional accuracy of the products and particularly on the formability limitations of the process. In this paper, some results concerning the determination of forming limit diagrams for single point incremental sheet metal forming will be described.
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