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The cutaneous porphyrias
The Cutaneous Porphyrias Joel L. Cohen, MD, and Henry W. Lim, MD This review focuses on the following porphyrias with cutaneous manifestations: congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), hereditary coproporphyria (HCP), variegate porphyria (VP), and erythropoietic protoporphyria (EPP). Each is discussed in the order of the defective enzymes as they appear in the heine biosynthetic pathway (Table). For all cutaneous porphyria s, the pathophysiologic aspects of photosensitivity involve the generation of reactive oxygen species as well as participation of inflammatory mediators (complement system, eicosanoids) and inflammatory cells (mast cells, neutrophils).
Congenital Erythropoietic Porphyria CEP is caused by heteroallelic, or less commonly, homoallelic mutations in uroporphyrinogen III synthase (URO-S) gene. Affected persons usually have less than 10% of the normal activity of this enzyme in erythrocytes. CEP patients present with severe photosensitivity which results in profound skin fragility manifested by blisters, erosions, and scarring in sun-exposed areas. Eventual consequences of these lesions include deformities and mutilations--particularly of the face, hands, and scalp--as well as secondary infections. Facial hypertrichosis of lanugo hair, pigment alterations, ocular scarring, and red-stained teeth (erythrodontia) are also frequently seen. Extracutaneous manifestations include splenomegaly, profound hemolytic anemia, porphyrin-induced cholelithiasis, contracture of digits caused by severe cutaneous scarring, and osteolytic mutilations secondary to bone marrow hypertrophy resulting in susceptibility to fractures.1 Treatment modalities include avoiding exposure to the sun, oral administration of charcoal and cholestyramine (as porphyrin absorbents), splenectomy (to minimize hemolytic anemia), hypertransfusion, and chemically induced bone marrow suppression with hydroxyurea (to inhibit erythropoiesis). Because the enzymatic defect in CEP is expressed
Curr Probl Dermatol, January/February 2000
mainly in erythrocytes, bone marrow transplantation (BMT) has been attempted in a few cases. In 1991, the first allogenic BMT was done on a 10-year-old girl. After the procedure, erythrocyte URO-S levels became normal and her cutaneous symptoms improved. However, she died 11 months later of a cytomegalovirus infection. In 1996, a 2-year-old girl with severe CEP underwent 2 BMTs with her HLAidentical heterozygous sister as donor. The second attempt resulted in complete chimeric enzyme correction. One year later, she tolerated sunlight exposure and had a complete clinical recovery. However, HLAidentical donors are only available in 30% of CEP cases. In 1991, the URO-S gene was mapped to chromosome 10q25.3 --~ q26.3. More than 20 mutations in the gene have been described. 2 C73R (Cys--+Arg at 73), the most common mutation, is associated with <2% normal URO-S activity, and hence is correlated with the most severe phenotype. The presence of other mutations with higher residual enzyme activity accounts for the phenotypic heterogeneity of CEP. Prenatal diagnosis is now available. 3 The focus of future treatment is on gene therapy. Animal models of CEP exist in cattle, swine, squirrels, and cats. Using a murine system, researchers have done in vitro studies of gene therapy for CEP in which they used recombinant retroviral vectors on myeloid stem cells or pluripotent stem cells. The studies have shown promising results. 4
Porphyria Cutanea Tarda As the most common cutaneous porphyria, PCT has a worldwide distribution. In North America, it is estimated to affect 1 in 25,000 people. The disease usually occurs in middle-aged persons. Characteristic photodistributed cutaneous manifestations include skin fragility, blisters, erosions, scarring, milia, hypertrichosis, scarring alopecia, pigmentary or sclerodermoid changes, dystrophic calcifications, scleromalacia, and photoonycholysis. Three types of PCT have been elucidated. All are
35
TABLE Cutaneous porphyrias
Porphyria
Congenital erythropoietic porphyria Porphyria cutanea tarda, hepatoerythropoietic porphyria Hereditary coproporphyria Variegate porphyria Erythropoietic protoporphyria
Defective enzyme
Uroporphyrinogen Ill synthase
Number of mutations
10q25.3-26.3
> 20 C73R most common and most severe > 10 G281E found in both HEP and PCT 10 > 10 > 30
Uroporphyrinogen decarboxylase l p 3 4 Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferroc helatase
associated with defective uroporphyrinogen decarboxylase (URO-D), the fifth enzyme in the heme biosynthesis pathway. The sporadic adult-onset form (type I) accounts for 80% of cases. In this form, diminished URO-D activity is restricted to the liver, whereas other tissues have enzyme levels within the reference range. There is no detectable mutation of the URO-D gene and no family history of the disease. Familial PCT (type II) accounts for less than 15% of cases and usually appears in childhood. Although inherited in an autosomal dominant pattern, it has been documented to have only a 10% penetrance. In type II, the activity of URO-D is decreased in all tissues. Type III PCT is also familial; however, defective URO-D is confined to the liver. Type III accounts for only 5% of PCT cases. The URO-D gene is on the short arm of chromosome 1. Genetic heterogeneity exists, as 11 mutations of the gene have been described. Except for one, all patients were homoallelic or heteroallelic for missense mutations, -t preserved residual URO-D activity. 2 Knowt~ nrecipitating agents for PCT are ethanol. estrogen-containing medications, and polyhalogenated aromatic hydrocarbons. A recent study of PCT patients found that ascorbic acid deficiency may be another factor in the pathogenesis of PCT. PCT that occurs after exposure to polyhalogenated aromatic hydrocarbons (especially hexachtorobenzene) and various dioxins has been considered by some as type IV, or toxic PCT. These hydrocarbon compounds are known to inactivate hepatic URO-D in a dose-related fashion. PCT is strongly association with iron overload, particularly hemochromatosis. Recently, connections have been found between C282Y and H63D mutations in the HFE gene associated with hemochromatosis and
36
Chromosomal location
3q12 lq22-23 18q22
In vitro restoration Prenatal of enzyme diagnosis function
Yes
Yes
No
No
No No No
No No Yes
PCT. 5 Renal failure and dialysis also have well-established connections with PCT. Infections with hepatitis C virus and HIV have occurred frequently in cases of PCT. In fact, PCT can be a presenting manifestation of the hepatitis C infection, and is seen at both the early and late stages of HIV infection. 5,6 Increased incidences of autoimmune disease, abnormal glucose tolerance, and hepatic tumors have also been documented in PCT. Thus, the underlying common denominator in these associations is liver damage, leading to an alteration in hepatic porphyrin metabolism and subsequent cutaneous symptoms. Aside from avoiding precipitating agents, the treatment of PCT includes phlebotomy and hydroxychloroquine. In anemia or renal failure, standard phlebotomy protocols are contraindicated. Furthermore, with hemodialysis, antimalarial medications are ineffective because the porphyrins removed from the liver cannot be cleared by dialysis. For these patients, combination of phlebotomy, erythropoietin and high-flux hemodialysis with a highly permeable (polysulfone) membrane have been effective] In recalcitrant cases, eryti~upoietin with small repeated phlebotomies (50 mL every 2 weeks) has proved successful. Deferoxamine has been used with success in some patients. Although plasma exchange has also been effective, it is a complex procedure with significant risks associated with the numerous transfusions. In the setting of hepatitis C virus and PCT, a 1997 case report not only demonstrated a suppression in hepatitis C viremia, but also improvement in PCT symptoms with a 6-week course of interferon-13.
Hepatoerythropoietic Porphyria HEP is a rare homozygous form of familial (type II) PCT; fewer than 30 cases have been reported. It is
Curr Probl Dermatol, January/February 2000
caused by a homozygous or compound heterozygous inheritance of defective URO-Dgene. 8 Although 1 URO-D mutation (G218E, a glutamate for glycine substitution at amino acid 281) has been reported to occur in both HEP and PCT, all other URO-D mutations in HEP are different from those found in familial PCT. Because some patients are doubly heterozygous for separate URO-D mutations, it has been suggested that URO-D mutations found in PCT are probably null mutations without enzyme activity, whereas URO-D mutations in HEP have some residual activity, and hence would manifest symptoms only if present in homozygous or compound heterozygous form. 9 Levels of URO-D have been found to be decreased to less than 10% of the reference range in erythrocytes and skin fibroblasts. 2 In all tissues, URO-D activity is reduced to 10% to 25% of the reference range, with resulting porphyrin accumulations manifesting with severe childhood cutaneous symptoms. Clinically, newborns with HEP have dark urine. During later weeks, a severe photosensitivity becomes apparent. As in CER profound blistering leads to scarring, pigmentary alterations, sclerodermatous changes, and mutilation. Hypertrichosis is also a frequent finding. Many patients also suffer from a hemolytic anemia. In 1 patient, neurologic sequelae (including hemiparesis) developed. Unfortunately, avoiding the sun is the only successful treatment modality reported for HER
Hereditary Coproporphyria HCP is also a rare cutaneous porphyria, with fewer than 150 cases reported. It is associated with a deficiency of coproporphyrinogen oxidase (COPRO-O). Levels of this enzyme are 50% of those found in subjects without the deficiency. An even rarer type of porphyria, harderoporphyria (HDP), is caused by a more extreme deficiency of COPRO-O, with levels at only 10% of the reference range. These deficiencies result in an accumulation of COPRO-III. Photosensitivity occurs in only 20% of cases of HCR Neurovisceral symptoms are prominent. These symptoms (in order of decreasing frequency) are abdominal pain, vomiting, extensive fatigue and muscle weakness (even paralysis), depression and agitation, constipation, skin lesions, fever, epilepsy, hypertension, jaundice, tachycardia, and diarrhea.i° Although
Curr Probl Dermatol, January/February 2000
usually less severe than acute intermittent porphyria (ALP), HCP has resulted in death from respiratory paralysis. One recent report describes the occurrence of hepatocellular carcinoma in a woman with HCR although this association is less common than in AIP or VR Other than avoiding exposure to the sun, there are no effective therapeutic modalities for the cutaneous manifestations. Treatment of an acute neurovisceral attack has focused on avoiding all possible precipitating factors. As with the other acute hepatic porphyrias, glucose loading (to suppress synthesis of &aminolevulinic acid) has been used with some success in treating mild attacks. More success has been seen with using heme compounds (hematin and heine arginate) to treat acute attacks. These substances were initially found to be useful in treating severe cases of AIP and VP by suppressing the &aminolevulinic acid synthase through negative feedback. Overall, heme arginate is more stable and has fewer adverse effects than hematin. In addition, less than 1% of heine arginate infusions are complicated by thrombophlebitis, and there are no detectable changes in measured clotting parameters. 11 Early treatment with heme arginate has been shown to be more successful than hypertonic glucose in preventing the progression of neurologic manifestations and life-threatening paralysis in acute porphyric attacks, In 1994, the COPRO-O gene was mapped to chromosome 3q12. Since then, 10 different mutations in the gene have been described. 12 Although most carriers of this gene defect remain asymptomatic, development of an easily available screening test to detect clinically latent carriers would be useful because these patients can then be counseled to avoid precipitating factors.
Variegate Porphyria VP is an acute hepatic porphyria inherited in an autosomal dominant form. The neurovisceral symptoms of VP are comparable to those of AIP and the cutaneous symptoms are often indistinguishable from those of PCT. The following acute symptoms are associated with VR in decreasing order of frequency: pain, vomiting, hypertension, tachycardia, constipation, neuropathy, bulbar paralysis, and seizures. 13 Although cases of VP are documented worldwide, the disease is most prevalent in South African whites. This is believed to be the result of a "founder" effect in the
37
descendants of a Dutch couple who came to South Africa in 1688. The disease is caused by an estimated 50% reduction in activity of the enzyme protoporphyrinogen oxidase (PROTO-O). The diagnosis is made from the results of a porphyrin profile. As in AIP and HCR urinary 5aminolevulinic acid and porphobilinogen levels are elevated during acute attacks, and are believed to account for the neurovisceral symptoms. Unlike in AIR however, urinary levels of these heine precursors are within the reference range when VP patients are asymptomatic (between attacks). But during these asymptomatic periods, VP patients often have elevated fecal levels of PROTO and COPRO (only mild elevation during acute attacks in AIP). In VP, the urinary COPRO level is higher than the URO level, and the fecal PROTO concentration exceeds that of COPRO. In PCT, the urinary level of URO is greater than that of COPRO, and isocoproporphyrin is the predominant fecal porphyrin. In patients with suspected PCT, porphyrin profiles should be done to exclude VR as VP may be life-threatening when patients are exposed to precipitating factors. The treatment of the cutaneous symptoms of VP centers on protecting patients from the sun. Modalities used successfully in PCT such as antimalarial medications and phlebotomy have not proved beneficial. Beta carotene is not efficacious. Treatment of the acute neurovisceral symptoms of VP is similar to that of HCR The gene encoding the human COPRO-O enzyme has been cloned and mapped to chromosome lq22-23, and 12 mutations have been characterized. 14 Gene therapy is a distinct possibility in the near future. Finally, as most gene carriers are asymptomatic but risk having acute attacks, the development of an easily available screening test would be helpful so that carriers can be counseled on the avoidance of precipitating factors.
Erythropoietic Protoporphyria EPP is the second most common type of porphyria. Although usually inherited as an incompletely penetrant autosomal dominant trait, the disease has also been reported as autosomal recessive. Symptomatic EPP patients usually have less than 50% of normal ferrochelatase activity. When penetrance is incomplete, these enzyme levels are often at approximately 30% of the reference range; this is believed to result from the synergistic coinheritance of a low-output "normal"
38
ferrochetalase allele in conjunction with the mutant allele. 15 Patients with this disease typically present in early childhood with an immediate and painful photosensitivity. There have been 3 reported cases of adult EPR In 2, the patients were between 70 and 80 years old. Other cutaneous features include urticarial lesions, painful petechiae, linear scarring, and waxy thickening of the skin. Anemia, cholelithiasis, and hepatic disease are potential systemic complications. There appears to be a wide spectrum of severity in EPP-associated hepatic disease, with hepatic failure occurring in 10% of patients. 16 When it occurs, hepatic failure is rapidly progressive and plasma concentrations of protoporphyrin rise significantly. Increased levels of urinary coproporphyrin I and decreased levels of fecal protoporphyrin are also apparent, as well as accelerated photosensitivity, enlargement of the spleen, severe upper abdominal pain (caused by worsening cholestasis and splenic capsular stretch), and hemolysis. The results of a study of 1 family suggest that EPP with hepatic failure may even be a genetically distinct syndrome. Treatment of the photosensitivity in EPP includes avoidance of light exposure and the administration of beta carotene, psoralen plus ultraviolet A, and ultraviolet B. 17 Cysteine has been used with success in a limited number of patients; however, one study showed that N-acetyl cysteine failed to reduce the photosensitivity. Pyridoxine has been used with some success in treating EPP photosensitivity, probably by increasing the amount of endogenous nicotinamide. Antihistamines may have some benefit; terfenadine inhibits the immediate flare reaction induced by phototesting, and also reduces the frequency of exacerbation. Finally, there have been some reported cases in which women with EPP describe a diminution in photosensitivity during pregnancy. A recent study correlated these claims with significantly lower erythrocyte porphyrin levels during gestation. The pathophysiologic basis of this reduction is still unclear. Multiple therapeutic regimens have been tried in an effort to manage the progressive liver disease seen in some of these patients. Unfortunately, none has proved consistently effective. These treatment options in hepatic disease include liver transplantation and the administration of oral cholestyramine and chenodeoxycholic acid (to facilitate porphyrin
Curr Probl Dermatol, January/February 2000
excretion by interrupting the enterohepatic circulation) or oral iron (to augment the conversion of PROTO to heine), t7 Although liver transplantation corrects the hepatic ferrochelatase defect and removes the contribution of hepatic protoporphyrin overproduction, it does not correct the bone marrow enzyme deficiency. Though lifesaving for some, transplantation is also associated with a return of photocutaneous symptoms and recurrent hepatic damage caused by extrahepatic protoporphyrin production. For this reason, it has been suggested that combined bone marrow and hepatic transplantation should be considered to avoid hepatic allograft injury by extrahepatic protoporphyrin. The ferrochelatase gene was cloned in 1990. Within the next 2 years, the gene was localized to the long arm of chromosome 18. Thirty-eight mutations have been characterized so far.18 These include missense mutations, splicing abnormalities, intragenic deletions, and nonsense mutations. Two animal models exist for EPP: bovine and inherited mouse. Bovine EPP is an autosomal recessive disorder caused by a point mutation in the ferrochelatase gene and characterized by marked photosensitivity. Inherited mouse EPP, manifesting both the photosensitivity and hepatic complications of the human disease, has been shown in a chemical mutagenesis experiment with ethylnitrosourea. 4 Studies with these animal models provide hope for further understanding the pathophysi01ogy in the human EPP disease. The greatest hope for treating EPP lies gene therapy, which corrected the ferrochelatase deficiency in fibroblasts (in vitro) from an EPP patient. 19
Summary During the 20th century, significant progress has been made in understanding porphyrias. Clinical presentations, histologic and immunofluorescence findings, cutaneous and systemic manifestations (pathophysiologic aspects), porphyrin profiles (as diagnostic aids), and effective therapeutic modalities have all played a part. In the past 15 years, there has been a virtual explosion in our knowledge of the defective enzymes as well as the cloning and chromosomal mapping of the affected genes. Functional correction of defective genes has been successfully done in vitro, and prenatal diagnosis is now possible for AIP and CER The above have laid an excellent foundation for further advances in the use of gene therapy in affected
Curr Probl Dermato/, January/February 2000
patients, screening of gene carriers for counseling, and ensuring a wider availability of prenatal diagnosis.
REFERENCES 1. Fritsch C, Bolsen K, Ruzicka T, et al. Congenital erythropoietic porphyria. J Am Acad Dermatol 1997;36:594-610. 2. Elder GH. Update on enzyme and molecular defects in porphyria. Photodermatol Photoimmunol Photomed 1998;14: 66-9. 3. Ged C, Morean-Gandry F, Taine L, et al. Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis. Prenat Diagn I996; 16:83-6. 4. de Verneuil H, Ged C, Boulechfar S, et al. Porphyrias: animal models and prospects for cellular and gene therapy. J Bioenerg Biomembr 1995;27:239-48. 5. Bonkovsky IlL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998;27:1661-9. 6. Lim HW, Pereira A, Sassa S, et al. Early-stage HIV infection and hepatitis C virus infection are associated with elevated serum porphyrin levels. J Am Acad Dermatol 1998;39:9569. 7. Peces R, de Salamanca E, Fontanellas A, et al. Successful treatment of haemodialysis-related porphyria cutanea tarda with erythropoietin. Nephrol Dial Transplant 1994;9:4335. 8. Roberts AG, Eider GH, de Salamanca RE, et al. A mutation (G218E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. J Invest Dermatol 1995;104: 500-2. 9. Meguro K, Fujita H, Ishida N, et al. Molecular defects of uroporphyrinogen decarboxylase in a patient with hepatoerythopoietic porphyria. J Invest Dermatol 1994;102:6815. 10. Martesak P. Hereditary coproporphyria. Semin Liver Dis 1998;18:25-32. 11. Tenhunen R, Mustajok P. Acute porphyria: treatment with heme. Semin Liver Dis 1998;18:53-5. 12. Schreiber W, Zhang X, Senz J0 et al. Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene. Hum Mutat 1997;10:196-200. 13. Kirsch RE, Meissner PN, Hilt RJ. Variegate porphyria. Semin Liver Dis 1998;18:33-41. 14. Frank J, McGrath J, Lam H, et al. Homozygous variegate porphyria: identification of mutations of both alleles of the protoporphyrinogen oxidase gene in severely affected proband. J Invest Dermatol 1998;110:452-5. 15. Gouya L, Deybach J, Lamoril J, et al. Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele. Am J Hum Genet 1996;58:292-9. 16. Gross, U, Frank M, Doss MO. Hepatic complications of ery-
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thropoietic protoporphyria. Photodermatol Photoimmunol Photomed 1998;14:52-7. 17. Mascaro JM. Management of the erythropoietic porphyrias. Photodermatol Photoimmunol Photomed 1998;14:44-5. 18. Rufenacht UB, Gouya L, Schneider-Yin X, et al. Systemic analysis of molecular defects in the ferrochelatase gene from
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patients with erythropoietic protoporphyria. Am J Hum Genet 1998;62:1341-52. 19. Mathews-Roth MM, Michel JL, Wise RJ. Amelioration of the metabolic defect in erythropoietic protoporphyria by expression of human ferrochelatase in culture cells. J Invest Dermatol 1995;104:497-9.
Curr Probl Dermatol, January/February 2000
Congenital Erythropoietic Porphyria CEP is caused by heteroallelic, or less commonly, homoallelic mutations in uroporphyrinogen III synthase (URO-S) gene. Affected persons usually have less than 10% of the normal activity of this enzyme in erythrocytes. CEP patients present with severe photosensitivity which results in profound skin fragility manifested by blisters, erosions, and scarring in sun-exposed areas. Eventual consequences of these lesions include deformities and mutilations--particularly of the face, hands, and scalp--as well as secondary infections. Facial hypertrichosis of lanugo hair, pigment alterations, ocular scarring, and red-stained teeth (erythrodontia) are also frequently seen. Extracutaneous manifestations include splenomegaly, profound hemolytic anemia, porphyrin-induced cholelithiasis, contracture of digits caused by severe cutaneous scarring, and osteolytic mutilations secondary to bone marrow hypertrophy resulting in susceptibility to fractures.1 Treatment modalities include avoiding exposure to the sun, oral administration of charcoal and cholestyramine (as porphyrin absorbents), splenectomy (to minimize hemolytic anemia), hypertransfusion, and chemically induced bone marrow suppression with hydroxyurea (to inhibit erythropoiesis). Because the enzymatic defect in CEP is expressed
Curr Probl Dermatol, January/February 2000
mainly in erythrocytes, bone marrow transplantation (BMT) has been attempted in a few cases. In 1991, the first allogenic BMT was done on a 10-year-old girl. After the procedure, erythrocyte URO-S levels became normal and her cutaneous symptoms improved. However, she died 11 months later of a cytomegalovirus infection. In 1996, a 2-year-old girl with severe CEP underwent 2 BMTs with her HLAidentical heterozygous sister as donor. The second attempt resulted in complete chimeric enzyme correction. One year later, she tolerated sunlight exposure and had a complete clinical recovery. However, HLAidentical donors are only available in 30% of CEP cases. In 1991, the URO-S gene was mapped to chromosome 10q25.3 --~ q26.3. More than 20 mutations in the gene have been described. 2 C73R (Cys--+Arg at 73), the most common mutation, is associated with <2% normal URO-S activity, and hence is correlated with the most severe phenotype. The presence of other mutations with higher residual enzyme activity accounts for the phenotypic heterogeneity of CEP. Prenatal diagnosis is now available. 3 The focus of future treatment is on gene therapy. Animal models of CEP exist in cattle, swine, squirrels, and cats. Using a murine system, researchers have done in vitro studies of gene therapy for CEP in which they used recombinant retroviral vectors on myeloid stem cells or pluripotent stem cells. The studies have shown promising results. 4
Porphyria Cutanea Tarda As the most common cutaneous porphyria, PCT has a worldwide distribution. In North America, it is estimated to affect 1 in 25,000 people. The disease usually occurs in middle-aged persons. Characteristic photodistributed cutaneous manifestations include skin fragility, blisters, erosions, scarring, milia, hypertrichosis, scarring alopecia, pigmentary or sclerodermoid changes, dystrophic calcifications, scleromalacia, and photoonycholysis. Three types of PCT have been elucidated. All are
35
TABLE Cutaneous porphyrias
Porphyria
Congenital erythropoietic porphyria Porphyria cutanea tarda, hepatoerythropoietic porphyria Hereditary coproporphyria Variegate porphyria Erythropoietic protoporphyria
Defective enzyme
Uroporphyrinogen Ill synthase
Number of mutations
10q25.3-26.3
> 20 C73R most common and most severe > 10 G281E found in both HEP and PCT 10 > 10 > 30
Uroporphyrinogen decarboxylase l p 3 4 Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferroc helatase
associated with defective uroporphyrinogen decarboxylase (URO-D), the fifth enzyme in the heme biosynthesis pathway. The sporadic adult-onset form (type I) accounts for 80% of cases. In this form, diminished URO-D activity is restricted to the liver, whereas other tissues have enzyme levels within the reference range. There is no detectable mutation of the URO-D gene and no family history of the disease. Familial PCT (type II) accounts for less than 15% of cases and usually appears in childhood. Although inherited in an autosomal dominant pattern, it has been documented to have only a 10% penetrance. In type II, the activity of URO-D is decreased in all tissues. Type III PCT is also familial; however, defective URO-D is confined to the liver. Type III accounts for only 5% of PCT cases. The URO-D gene is on the short arm of chromosome 1. Genetic heterogeneity exists, as 11 mutations of the gene have been described. Except for one, all patients were homoallelic or heteroallelic for missense mutations, -t preserved residual URO-D activity. 2 Knowt~ nrecipitating agents for PCT are ethanol. estrogen-containing medications, and polyhalogenated aromatic hydrocarbons. A recent study of PCT patients found that ascorbic acid deficiency may be another factor in the pathogenesis of PCT. PCT that occurs after exposure to polyhalogenated aromatic hydrocarbons (especially hexachtorobenzene) and various dioxins has been considered by some as type IV, or toxic PCT. These hydrocarbon compounds are known to inactivate hepatic URO-D in a dose-related fashion. PCT is strongly association with iron overload, particularly hemochromatosis. Recently, connections have been found between C282Y and H63D mutations in the HFE gene associated with hemochromatosis and
36
Chromosomal location
3q12 lq22-23 18q22
In vitro restoration Prenatal of enzyme diagnosis function
Yes
Yes
No
No
No No No
No No Yes
PCT. 5 Renal failure and dialysis also have well-established connections with PCT. Infections with hepatitis C virus and HIV have occurred frequently in cases of PCT. In fact, PCT can be a presenting manifestation of the hepatitis C infection, and is seen at both the early and late stages of HIV infection. 5,6 Increased incidences of autoimmune disease, abnormal glucose tolerance, and hepatic tumors have also been documented in PCT. Thus, the underlying common denominator in these associations is liver damage, leading to an alteration in hepatic porphyrin metabolism and subsequent cutaneous symptoms. Aside from avoiding precipitating agents, the treatment of PCT includes phlebotomy and hydroxychloroquine. In anemia or renal failure, standard phlebotomy protocols are contraindicated. Furthermore, with hemodialysis, antimalarial medications are ineffective because the porphyrins removed from the liver cannot be cleared by dialysis. For these patients, combination of phlebotomy, erythropoietin and high-flux hemodialysis with a highly permeable (polysulfone) membrane have been effective] In recalcitrant cases, eryti~upoietin with small repeated phlebotomies (50 mL every 2 weeks) has proved successful. Deferoxamine has been used with success in some patients. Although plasma exchange has also been effective, it is a complex procedure with significant risks associated with the numerous transfusions. In the setting of hepatitis C virus and PCT, a 1997 case report not only demonstrated a suppression in hepatitis C viremia, but also improvement in PCT symptoms with a 6-week course of interferon-13.
Hepatoerythropoietic Porphyria HEP is a rare homozygous form of familial (type II) PCT; fewer than 30 cases have been reported. It is
Curr Probl Dermatol, January/February 2000
caused by a homozygous or compound heterozygous inheritance of defective URO-Dgene. 8 Although 1 URO-D mutation (G218E, a glutamate for glycine substitution at amino acid 281) has been reported to occur in both HEP and PCT, all other URO-D mutations in HEP are different from those found in familial PCT. Because some patients are doubly heterozygous for separate URO-D mutations, it has been suggested that URO-D mutations found in PCT are probably null mutations without enzyme activity, whereas URO-D mutations in HEP have some residual activity, and hence would manifest symptoms only if present in homozygous or compound heterozygous form. 9 Levels of URO-D have been found to be decreased to less than 10% of the reference range in erythrocytes and skin fibroblasts. 2 In all tissues, URO-D activity is reduced to 10% to 25% of the reference range, with resulting porphyrin accumulations manifesting with severe childhood cutaneous symptoms. Clinically, newborns with HEP have dark urine. During later weeks, a severe photosensitivity becomes apparent. As in CER profound blistering leads to scarring, pigmentary alterations, sclerodermatous changes, and mutilation. Hypertrichosis is also a frequent finding. Many patients also suffer from a hemolytic anemia. In 1 patient, neurologic sequelae (including hemiparesis) developed. Unfortunately, avoiding the sun is the only successful treatment modality reported for HER
Hereditary Coproporphyria HCP is also a rare cutaneous porphyria, with fewer than 150 cases reported. It is associated with a deficiency of coproporphyrinogen oxidase (COPRO-O). Levels of this enzyme are 50% of those found in subjects without the deficiency. An even rarer type of porphyria, harderoporphyria (HDP), is caused by a more extreme deficiency of COPRO-O, with levels at only 10% of the reference range. These deficiencies result in an accumulation of COPRO-III. Photosensitivity occurs in only 20% of cases of HCR Neurovisceral symptoms are prominent. These symptoms (in order of decreasing frequency) are abdominal pain, vomiting, extensive fatigue and muscle weakness (even paralysis), depression and agitation, constipation, skin lesions, fever, epilepsy, hypertension, jaundice, tachycardia, and diarrhea.i° Although
Curr Probl Dermatol, January/February 2000
usually less severe than acute intermittent porphyria (ALP), HCP has resulted in death from respiratory paralysis. One recent report describes the occurrence of hepatocellular carcinoma in a woman with HCR although this association is less common than in AIP or VR Other than avoiding exposure to the sun, there are no effective therapeutic modalities for the cutaneous manifestations. Treatment of an acute neurovisceral attack has focused on avoiding all possible precipitating factors. As with the other acute hepatic porphyrias, glucose loading (to suppress synthesis of &aminolevulinic acid) has been used with some success in treating mild attacks. More success has been seen with using heme compounds (hematin and heine arginate) to treat acute attacks. These substances were initially found to be useful in treating severe cases of AIP and VP by suppressing the &aminolevulinic acid synthase through negative feedback. Overall, heme arginate is more stable and has fewer adverse effects than hematin. In addition, less than 1% of heine arginate infusions are complicated by thrombophlebitis, and there are no detectable changes in measured clotting parameters. 11 Early treatment with heme arginate has been shown to be more successful than hypertonic glucose in preventing the progression of neurologic manifestations and life-threatening paralysis in acute porphyric attacks, In 1994, the COPRO-O gene was mapped to chromosome 3q12. Since then, 10 different mutations in the gene have been described. 12 Although most carriers of this gene defect remain asymptomatic, development of an easily available screening test to detect clinically latent carriers would be useful because these patients can then be counseled to avoid precipitating factors.
Variegate Porphyria VP is an acute hepatic porphyria inherited in an autosomal dominant form. The neurovisceral symptoms of VP are comparable to those of AIP and the cutaneous symptoms are often indistinguishable from those of PCT. The following acute symptoms are associated with VR in decreasing order of frequency: pain, vomiting, hypertension, tachycardia, constipation, neuropathy, bulbar paralysis, and seizures. 13 Although cases of VP are documented worldwide, the disease is most prevalent in South African whites. This is believed to be the result of a "founder" effect in the
37
descendants of a Dutch couple who came to South Africa in 1688. The disease is caused by an estimated 50% reduction in activity of the enzyme protoporphyrinogen oxidase (PROTO-O). The diagnosis is made from the results of a porphyrin profile. As in AIP and HCR urinary 5aminolevulinic acid and porphobilinogen levels are elevated during acute attacks, and are believed to account for the neurovisceral symptoms. Unlike in AIR however, urinary levels of these heine precursors are within the reference range when VP patients are asymptomatic (between attacks). But during these asymptomatic periods, VP patients often have elevated fecal levels of PROTO and COPRO (only mild elevation during acute attacks in AIP). In VP, the urinary COPRO level is higher than the URO level, and the fecal PROTO concentration exceeds that of COPRO. In PCT, the urinary level of URO is greater than that of COPRO, and isocoproporphyrin is the predominant fecal porphyrin. In patients with suspected PCT, porphyrin profiles should be done to exclude VR as VP may be life-threatening when patients are exposed to precipitating factors. The treatment of the cutaneous symptoms of VP centers on protecting patients from the sun. Modalities used successfully in PCT such as antimalarial medications and phlebotomy have not proved beneficial. Beta carotene is not efficacious. Treatment of the acute neurovisceral symptoms of VP is similar to that of HCR The gene encoding the human COPRO-O enzyme has been cloned and mapped to chromosome lq22-23, and 12 mutations have been characterized. 14 Gene therapy is a distinct possibility in the near future. Finally, as most gene carriers are asymptomatic but risk having acute attacks, the development of an easily available screening test would be helpful so that carriers can be counseled on the avoidance of precipitating factors.
Erythropoietic Protoporphyria EPP is the second most common type of porphyria. Although usually inherited as an incompletely penetrant autosomal dominant trait, the disease has also been reported as autosomal recessive. Symptomatic EPP patients usually have less than 50% of normal ferrochelatase activity. When penetrance is incomplete, these enzyme levels are often at approximately 30% of the reference range; this is believed to result from the synergistic coinheritance of a low-output "normal"
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ferrochetalase allele in conjunction with the mutant allele. 15 Patients with this disease typically present in early childhood with an immediate and painful photosensitivity. There have been 3 reported cases of adult EPR In 2, the patients were between 70 and 80 years old. Other cutaneous features include urticarial lesions, painful petechiae, linear scarring, and waxy thickening of the skin. Anemia, cholelithiasis, and hepatic disease are potential systemic complications. There appears to be a wide spectrum of severity in EPP-associated hepatic disease, with hepatic failure occurring in 10% of patients. 16 When it occurs, hepatic failure is rapidly progressive and plasma concentrations of protoporphyrin rise significantly. Increased levels of urinary coproporphyrin I and decreased levels of fecal protoporphyrin are also apparent, as well as accelerated photosensitivity, enlargement of the spleen, severe upper abdominal pain (caused by worsening cholestasis and splenic capsular stretch), and hemolysis. The results of a study of 1 family suggest that EPP with hepatic failure may even be a genetically distinct syndrome. Treatment of the photosensitivity in EPP includes avoidance of light exposure and the administration of beta carotene, psoralen plus ultraviolet A, and ultraviolet B. 17 Cysteine has been used with success in a limited number of patients; however, one study showed that N-acetyl cysteine failed to reduce the photosensitivity. Pyridoxine has been used with some success in treating EPP photosensitivity, probably by increasing the amount of endogenous nicotinamide. Antihistamines may have some benefit; terfenadine inhibits the immediate flare reaction induced by phototesting, and also reduces the frequency of exacerbation. Finally, there have been some reported cases in which women with EPP describe a diminution in photosensitivity during pregnancy. A recent study correlated these claims with significantly lower erythrocyte porphyrin levels during gestation. The pathophysiologic basis of this reduction is still unclear. Multiple therapeutic regimens have been tried in an effort to manage the progressive liver disease seen in some of these patients. Unfortunately, none has proved consistently effective. These treatment options in hepatic disease include liver transplantation and the administration of oral cholestyramine and chenodeoxycholic acid (to facilitate porphyrin
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excretion by interrupting the enterohepatic circulation) or oral iron (to augment the conversion of PROTO to heine), t7 Although liver transplantation corrects the hepatic ferrochelatase defect and removes the contribution of hepatic protoporphyrin overproduction, it does not correct the bone marrow enzyme deficiency. Though lifesaving for some, transplantation is also associated with a return of photocutaneous symptoms and recurrent hepatic damage caused by extrahepatic protoporphyrin production. For this reason, it has been suggested that combined bone marrow and hepatic transplantation should be considered to avoid hepatic allograft injury by extrahepatic protoporphyrin. The ferrochelatase gene was cloned in 1990. Within the next 2 years, the gene was localized to the long arm of chromosome 18. Thirty-eight mutations have been characterized so far.18 These include missense mutations, splicing abnormalities, intragenic deletions, and nonsense mutations. Two animal models exist for EPP: bovine and inherited mouse. Bovine EPP is an autosomal recessive disorder caused by a point mutation in the ferrochelatase gene and characterized by marked photosensitivity. Inherited mouse EPP, manifesting both the photosensitivity and hepatic complications of the human disease, has been shown in a chemical mutagenesis experiment with ethylnitrosourea. 4 Studies with these animal models provide hope for further understanding the pathophysi01ogy in the human EPP disease. The greatest hope for treating EPP lies gene therapy, which corrected the ferrochelatase deficiency in fibroblasts (in vitro) from an EPP patient. 19
Summary During the 20th century, significant progress has been made in understanding porphyrias. Clinical presentations, histologic and immunofluorescence findings, cutaneous and systemic manifestations (pathophysiologic aspects), porphyrin profiles (as diagnostic aids), and effective therapeutic modalities have all played a part. In the past 15 years, there has been a virtual explosion in our knowledge of the defective enzymes as well as the cloning and chromosomal mapping of the affected genes. Functional correction of defective genes has been successfully done in vitro, and prenatal diagnosis is now possible for AIP and CER The above have laid an excellent foundation for further advances in the use of gene therapy in affected
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patients, screening of gene carriers for counseling, and ensuring a wider availability of prenatal diagnosis.
REFERENCES 1. Fritsch C, Bolsen K, Ruzicka T, et al. Congenital erythropoietic porphyria. J Am Acad Dermatol 1997;36:594-610. 2. Elder GH. Update on enzyme and molecular defects in porphyria. Photodermatol Photoimmunol Photomed 1998;14: 66-9. 3. Ged C, Morean-Gandry F, Taine L, et al. Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis. Prenat Diagn I996; 16:83-6. 4. de Verneuil H, Ged C, Boulechfar S, et al. Porphyrias: animal models and prospects for cellular and gene therapy. J Bioenerg Biomembr 1995;27:239-48. 5. Bonkovsky IlL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998;27:1661-9. 6. Lim HW, Pereira A, Sassa S, et al. Early-stage HIV infection and hepatitis C virus infection are associated with elevated serum porphyrin levels. J Am Acad Dermatol 1998;39:9569. 7. Peces R, de Salamanca E, Fontanellas A, et al. Successful treatment of haemodialysis-related porphyria cutanea tarda with erythropoietin. Nephrol Dial Transplant 1994;9:4335. 8. Roberts AG, Eider GH, de Salamanca RE, et al. A mutation (G218E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. J Invest Dermatol 1995;104: 500-2. 9. Meguro K, Fujita H, Ishida N, et al. Molecular defects of uroporphyrinogen decarboxylase in a patient with hepatoerythopoietic porphyria. J Invest Dermatol 1994;102:6815. 10. Martesak P. Hereditary coproporphyria. Semin Liver Dis 1998;18:25-32. 11. Tenhunen R, Mustajok P. Acute porphyria: treatment with heme. Semin Liver Dis 1998;18:53-5. 12. Schreiber W, Zhang X, Senz J0 et al. Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene. Hum Mutat 1997;10:196-200. 13. Kirsch RE, Meissner PN, Hilt RJ. Variegate porphyria. Semin Liver Dis 1998;18:33-41. 14. Frank J, McGrath J, Lam H, et al. Homozygous variegate porphyria: identification of mutations of both alleles of the protoporphyrinogen oxidase gene in severely affected proband. J Invest Dermatol 1998;110:452-5. 15. Gouya L, Deybach J, Lamoril J, et al. Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele. Am J Hum Genet 1996;58:292-9. 16. Gross, U, Frank M, Doss MO. Hepatic complications of ery-
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thropoietic protoporphyria. Photodermatol Photoimmunol Photomed 1998;14:52-7. 17. Mascaro JM. Management of the erythropoietic porphyrias. Photodermatol Photoimmunol Photomed 1998;14:44-5. 18. Rufenacht UB, Gouya L, Schneider-Yin X, et al. Systemic analysis of molecular defects in the ferrochelatase gene from
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patients with erythropoietic protoporphyria. Am J Hum Genet 1998;62:1341-52. 19. Mathews-Roth MM, Michel JL, Wise RJ. Amelioration of the metabolic defect in erythropoietic protoporphyria by expression of human ferrochelatase in culture cells. J Invest Dermatol 1995;104:497-9.
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