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Background
This group of bullous disorders are caused by abnormalities in the synthesis of heme. Various enzyme deficiencies lead to accumulation of porphyrin precursors. Clinically, there are three main categories.
Acute episodes and no skin changes Acute intermittent porphyria
ALA-dehydratase deficiencyAcute episodes and skin changes Hereditary coproporphyria
Vareigate porphyriaSkin changes only Congenital erythropoietic porphyria
Erythropoietic protoporphyria
Porphyria cutanea tarda
Hepatoerythropoietic porphyriaAcute cases are characterized by abdominal pain, neurologic, and psychiatric disturbances. Skin changes include acute flares with erythema and edema with pain and burning. This pattern is common with erythropoietic protoporphyria. A second pattern has skin fragility with blisters, erosions, and scars. This pattern is seen the other types.
Heme porphyrin synthesis follows a sequence of enzymatic changes. The following table lists the sequence of changes and corresponding porphyria associated with the enzyme deficiency.
Metabolite Enzyme Porphyria Laboratory Findings Inheritance Glycine+Succinyl CoA ALA-synthase Aminolevulinic acid ALA-dehydratase ALA-dehydratase deficiency Autosomal recessive Porphobilinogen Porphobilinogen deaminase Acute intermittent porphyria Increased porphobilinogen and ALA in urine during and between attacks Autosomal dominant Hydroxymethylbilane Uroporphyrinogen III cosynthase Congenital erythropoietic porphyria Accumulation of uroporphyrinogen I and III in the bone marrow, blood, and organs Autosomal recessive Uroporphyrinogen III Uroporphyrinogen decarboxylase Porphyria cutanea tarda
Hepatoerythropoietic porphyriaIncreased uroporphyrins in urine and plasma
Increased coproporphyrins in feces
Unique isocoproporphyrin in fecesHepatoerythropoietic porphyria has similar findings in PCT but also elevated levels of protoporphyrins in erythrocytes
Autosomal dominant Coproporphyrinogen III Coproporphyrinogen oxidase Hereditary coproporphyria Porphobilinogen and ALA increased
Elevated urine and fecal coproporphyrinsAutosomal dominant Protoporphyrinogen IX Protoporphyrinogen oxidase Variegate porphyria Elevated fecal protoporphyrin and coproporphyrin
Urine ALA and porphobilinogen increasedAutosomal dominant Protoporphyrin IX Ferrochelatase Erythropoietic protoporphyria Normal urine porphyrins
Increased protoporphyrins in feces and bloodAutosomal dominant
Rare autosomal recessiveHeme OUTLINE
PATHOGENESIS CHARACTERIZATION HEPATO-
ERYTHROPOIETIC
Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus.Ged C, Ozalla D, Herrero C, Lecha M, Mendez M, de Verneuil H, Mascaro JM.
Laboratoire de Pathologie Moleculaire et Therapie Genique, Universite Victor Segalen-Bordeaux 2, 146, rue Leo Saignat, 33076 Bordeaux CEDEX, France
Arch Dermatol 2002 Jul;138(7):957-60 Abstract quote BACKGROUND: Hepatoerythropoietic porphyria (HEP) is usually a severe form of cutaneous porphyria, characterized biochemically by an increased urinary excretion of polycarboxylated porphyrins. The disease is the result of a profound deficiency (<10% of normal activity) of uroporphyrinogen decarboxylase (UROD) activity. Hepatoerythropoietic porphyria is inherited as an autosomal recessive trait, whereas familial porphyria cutanea tarda is dominant. At least 30 different mutations of the UROD gene have been identified in patients with HEP and familial porphyria cutanea tarda, with 1 predominant missense mutation (glycine-to-glutamic acid substitution at codon 281) in Spanish patients with HEP.
OBSERVATION: A 5-year-old patient with first-degree-related parents presented with HEP and mild symptomatology. We found low levels of UROD enzymatic activity and a new homozygous mutation of the UROD gene, a phenylanine-to-leucine substitution at codon 46 (F46L). Both parents were healthy carriers of the mutation. The mother had reduced UROD activity (50% of normal), whereas the father had normal UROD activity. Prokaryotic expression of the F46L mutation using a pGEX vector has been used to confirm the deleterious effect of the mutation. When the mother started a new pregnancy, a prenatal study showed the absence of F46L mutation in the fetus and no accumulation of porphyrins in the amniotic fluid.
CONCLUSIONS: A new mutation in the UROD gene causes a mild HEP phenotype. A normal UROD enzymatic activity was observed in the father, despite the presence of the heterozygous mutation. To our knowledge, this observation is the first description of a prenatal exclusion of HEP.
DISEASE ASSOCIATIONS CHARACTERIZATION HEMOCHROMATOSIS Association of porphyria cutanea tarda with hereditary hemochromatosis.
Mehrany K, Drage LA, Brandhagen DJ, Pittelkow MR.
Department of Dermatology, Mayo Clinic, Rochester, MN 55905, USA.
J Am Acad Dermatol. 2004 Aug;51(2):205-11. Abstact quote
BACKGROUND: An increased frequency of hereditary hemochromatosis gene mutations occurs in patients with porphyria cutanea tarda. Polymerase chain reaction analysis of peripheral blood for hemochromatosis gene (HFE) mutations is available for clinical use. Early detection and treatment of hereditary hemochromatosis limit disease progression and improve life expectancy.
OBJECTIVE: We present 8 patients with porphyria cutanea tarda subsequently found to have hereditary hemochromatosis or mutations in the HFE gene.
METHODS: Retrospective review of patients in whom both porphyria cutanea tarda and hereditary hemochromatosis or HFE gene mutations were diagnosed between 1976 and 2000.
RESULTS: Eight patients with porphyria cutanea tarda (6 males, 2 females; age range, 4-60 years; mean age at diagnosis of porphyria cutanea tarda, 42 years) were subsequently found to have hepatic iron overload or HFE gene mutations. Two patients had liver biopsy findings compatible with homozygous hereditary hemochromatosis. In the other 6 patients, HFE gene analysis revealed 3 homozygous C282Y, 1 compound heterozygous C282Y/H63D, and 2 heterozygous C282Y mutations. Seven patients (88%) had no specific signs or symptoms of hereditary hemochromatosis at diagnosis. In 5 patients (63%), the diagnosis of hereditary hemochromatosis or HFE gene mutation was initially suspected by the dermatologist.
CONCLUSION: Porphyria cutanea tarda can be an important cutaneous marker for patients with mutations of the HFE gene. HFE gene analysis should be done in patients who present with porphyria cutanea tarda. The dermatologist may play a key role in the early diagnosis of subclinical hereditary hemochromatosis in patients who present with porphyria cutanea tarda.LUPUS ERYTHEMATOSUS Coexistence of lupus erythematosus and porphyria cutanea tarda in fifteen patients.
Gibson GE, McEvoy MT.
Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
ients with coexistent disease.
J Am Acad Dermatol 1998 Apr;38(4):569-73 Abstract quote
BACKGROUND: Lupus erythematosus (LE) and porphyria cutanea tarda (PCT) may have similar clinical presentations, and their coexistence presents special problems in diagnosis and management.
OBJECTIVE: The purposes of this study were to describe a patient with discoid LE and PCT and to present a review of 15 patients with coexistent LE (all variants) and PCT.
METHODS: The medical records of all patients with coexistent LE and PCT seen between 1976 and 1995 were retrospectively reviewed.
RESULTS: Of 6179 cases of LE and 676 cases of porphyria (all variants), there were 15 patients, 6 men and 9 women, with coexistent LE and PCT. The mean age at diagnosis of LE was 42.8 years and of PCT was 48 years. Nine patients had discoid LE; five patients had systemic LE, and one patient had subacute cutaneous LE. The initial diagnosis was LE in eight patients, PCT in five patients, and simultaneous LE and PCT in two patients. Precipitating factors for PCT included alcohol in seven patients, iron overload in one patient, and estrogen in one patient. Treatment of LE with hydroxychloroquine 200 mg daily precipitated PCT in two patients. Patients were treated with phlebotomy or low-dose antimalarials for PCT. Patients with systemic LE received systemic glucocorticoid therapy. Patients with discoid LE and subacute cutaneous LE were treated with topical glucocorticoids.
CONCLUSION: The association of LE and PCT poses therapeutic challenges. The preferred treatment for one may exacerbate the other. Use of standard dose antimalarials for LE is inadvisable, and phlebotomy or low-dose antimalarials should be used cautiously in patients with coexistent disease.
LABORATORY/
RADIOLOGICCHARACTERIZATION Bile porphyrin analysis in the evaluation of variegate porphyria.
Logan GM, Weimer MK, Ellefson M, Pierach CA, Bloomer JR.
Department of Medicine, University of Minnesota, Minneapolis.
N Engl J Med 1991 May 16;324(20):1408-11 Abstract quote
BACKGROUND: Variegate porphyria is a genetic disorder of porphyrin metabolism in which patients may have both neurologic dysfunction and photocutaneous lesions. Biochemical confirmation of the diagnosis can be difficult, particularly in patients without neurologic dysfunction at the time of testing. The demonstration of increased fecal excretion of porphyrin is frequently used for this purpose, but levels may be normal. Since elevated fecal porphyrin levels in variegate porphyria are presumably a consequence of increased biliary excretion, we evaluated whether analysis of porphyrins in bile distinguishes better between patients with variegate porphyria and controls.
METHODS: Bile samples were collected by duodenal aspiration from 10 patients with proved variegate porphyria who had no neurologic symptoms when they were studied and 17 control subjects. Bile and fecal porphyrin levels were measured fluorometrically.
RESULTS: The mean total porphyrin concentration in bile in the patients with variegate porphyria was significantly higher than that in the controls (67.8 vs. 0.71 mumol per liter; P less than 0.00002). There was more than a ninefold difference between the highest level in any control subject and the lowest level in any patient with variegate porphyria. The mean fecal porphyrin level in the patients with variegate porphyria also differed significantly from that in the controls (0.79 vs. 0.14 mumol per gram of dry weight; P less than 0.007), but four patients had levels within the control range.
CONCLUSIONS: The concentration of porphyrin in bile is higher in patients with variegate porphyria than in controls, and the difference is greater than that for fecal porphyrin. Bile porphyrin measurements may be helpful in the evaluation of asymptomatic patients suspected of having variegate porphyria.
Reference intervals for 24-hour and random urine porphyrins.
Nuttall KL, Pingree SS, Ashwood ER.
Department of Pathology University of Utah School of Medicine Salt Lake City 84132, USA.
Ann Clin Lab Sci 1996 Jul-Aug;26(4):313-22 Abstract quote
Urine porphyrin analysis is an important part in evaluation of photosensitivity. Since porphyrin excretion is variable throughout the day, analysis is traditionally based on 24-hour collections. To facilitate the use of random specimens, as well as poorly collected 24-hour specimens, reference limits based on the porphyrin to creatinine ratio have been developed.
Based on 1,171 adult specimens, it is estimated that the 95 percent reference limit (90 percent confidence interval) is < or = 3.9 (3.5-5.7) mumol/mol of creatinine for uroporphyrin and < or = 22 (19-34) mumol/mol for coproporphyrin. These values apply to both 24-hour and random specimens, although random specimens show a higher degree of variability. Modest differences exist between males and females, but they are not significant given the degree of uncertainty in the confidence intervals. In terms of more traditional 24-hour units, reference limits correspond to < or = 37 (32-63) nmol/day for uroporphyrin and < or = 221 (195-320) nmol/day for coproporphyrin.
Biochemical differentiation of the porphyrias.
Hindmarsh JT, Oliveras L, Greenway DC.
Division of Biochemistry, The Ottawa Hospital and the Department of Pathology and Laboratory Medicine, University of Ottawa, Ontario, Canada.
Clin Biochem 1999 Nov;32(8):609-19 Abstract quote
OBJECTIVES: To differentiate the porphyrias by clinical and biochemical methods.
DESIGN AND METHODS: We describe levels of blood, urine, and fecal porphyrins and their precursors in the porphyrias and present an algorithm for their biochemical differentiation. Diagnoses were established using clinical and biochemical data. Porphyrin analyses were performed by high performance liquid chromatography.
RESULTS AND CONCLUSIONS: Plasma and urine porphyrin patterns were useful for diagnosis of porphyria cutanea tarda, but not the acute porphyrias. Erythropoietic protoporphyria was confirmed by erythrocyte protoporphyrin assay and erythrocyte fluorescence. Acute intermittent porphyria was diagnosed by increases in urine delta-aminolevulinic acid and porphobilinogen and confirmed by reduced erythrocyte porphobilinogen deaminase activity and normal or near-normal stool porphyrins. Variegate porphyria and hereditary coproporphyria were diagnosed by their characteristic stool porphyrin patterns. This appears to be the most convenient diagnostic approach until molecular abnormalities become more extensively defined and more widely available.
Plasma porphyrins in the porphyrias.
Hindmarsh JT, Oliveras L, Greenway DC.
Division of Biochemistry, Ottawa Hospital, General Campus, 501 Smyth Rd., Ottawa, Ontario, Canada K1H 8L6.
Clin Chem 1999 Jul;45(7):1070-6 Abstract quote
BACKGROUND: As an aid in the diagnosis and management of porphyria we have developed a method to fractionate and quantify plasma porphyrins and have evaluated its use in various porphyrias.
METHODS: We used HPLC with fluorometric detection to measure plasma concentrations of uroporphyrin I and III, heptacarboxyl III, hexacarboxyl III, pentacarboxyl III, and coproporphyrin I and III. We studied 245 healthy subjects, 32 patients with classical porphyria cutanea tarda (PCT), 12 patients with PCT of renal failure, 13 patients with renal failure, 8 patients with pseudoporphyria of renal failure, 3 patients with acute intermittent porphyria, 5 patients with variegate porphyria, 5 patients with hereditary coproporphyria, and 4 patients with erythropoietic protoporphyria.
RESULTS: Between-run CVs were 5.4-13%. The recoveries of porphyrins added to plasma were 71-114% except for protoporphyrin, which could not be reliably measured with this technique. Plasma porphyrin patterns clearly identified PCT, and its clinical sensitivity equaled that of urine porphyrin fractionation. The patterns also allowed differentiation of PCT of renal failure from pseudoporphyria of renal failure.
CONCLUSIONS: The assay of plasma porphyrins identifies patients with PCT and appears particularly useful for differentiating PCT of renal failure from pseudoporphyria of renal failure.
On accuracy and precision of a HPLC method for measurement of urine porphyrin concentrations.
Zuijderhoudt FM, Koehorst SG, Kluitenberg WE, Dorresteijn-de Bok J.
Department of Clinical Chemistry, Deventer Ziekenhuis, The Netherlands.
Clin Chem Lab Med 2000 Mar;38(3):227-30 Abstract quote
We studied the accuracy and precision of a HPLC method for determination of porphyrins in urine.
A commercial standard solution appeared to contain less porphyrins than indicated by the manufacturer, since calibration resulted in lower concentrations of uroporphyrin and coproporphyrin: 16% and 8%, respectively. Coefficients of variation for the measurement of uro-, hepta-, copro I and copro III porphyrins in samples of patients with and without porphyria were often much less than 15%. Comparison of measurements with and without calibrated standards revealed differences for uroporphyrin and coproporphyrin of 27% and 5%, respectively. Recovery of added uroporphyrin and coproporphyrin was 99%. The main cause of the variability in test results was apparently the improperly calibrated standard solutions. The precision of porphyrin measurements was not influenced by the type of porphyria.
Abnormal chromatographic patterns of porphyrins in urine.
Nuttall KL.
Department of Pathology and Laboratory Medicine, Children's and Women's Health Centre of British Columbia, Vancouver, Canada.
Ann Clin Lab Sci 2001 Jul;31(3):259-64 Abstract quote
Urine is the most frequent specimen used in the initial evaluation of adult patients who present with photosensitivity. When urine porphyrins are abnormal, characterization of the chromatogram is facilitated by calculation of uroporphyrin-to-heptacarboxylate porphyrin (uro/hepta) and uroporphyrin-to-isocoproporphyrin (uro/iso) ratios.
The most frequent abnormal pattern, and that most consistent with porphyria cutanea tarda (PCT), is an uro/hepta ratio < or =2.0 and an uro/iso ratio < or =18. When the uro/hepta or uro/iso ratios are less consistent with PCT, other less common porphyrin disorders should be considered. These include variegate porphyria, coproporphyria with manifestations of photosensitivity only, adult onset congenital porphyria, mixed porphyrias, and other less frequent porphyrin disorders. After initial evaluation, the diagnosis should ideally be confirmed by additional testing of blood and fecal specimens. Most attacks of the acute porphyrias are associated with a uro/hepta ratio >4, and can be confirmed by an elevated urine porphobilinogen concentration.
CLINICAL APPEARANCE/
GROSS DISEASECHARACTERIZATION Congenital erythropoietic porphyria
Erythropoietic protoporphyria
Acute intermittent porphyria
ALA-dehydratase deficiency
Hereditary coproporphyria
Variegate porphyria
Porphyria cutanea tarda
Hepatoerythropoietic porphyriaSPECIFIC VARIANTS ALA-dehydratase deficiency Laboratory abnormalities resemble severe lead poisoning Acute intermittent porphyria Drugs such as barbiturates, sulfonamides, and griseofulvin may precipitate acute episodes
Congenital erythropoietic porphyria Also known as Gunther's disease
Classic presentation in infancy with red urine in diaper
Porphyria cutanea tarda
Commonest form of porphyria in North America and Europe
Familial form
Sporadic form
>70% associated with alcohol abuse and liver damage
Toxic form
Exposure to polychlorinated aromatic hydrocarbonsHepatoerythropoietic porphyria Childhood
Similar enzyme deficiency as in PCT but with less activity in the enzyme
Similar lab findings to PCT but also elevated levels of protoporphyrins in erythrocytesHereditary coproporphyria Latent disease more common
Acute disease has been induced by anabolic steroid methandrostenoloneVariegate porphyria Common in white Afrikaaners
Onset after pubertyErythropoietic protoporphyria Early childhood with edema and erythema
Chronic stages present with scarring and cobblestone thickening of the dorsum of handsCLINICAL VARIANTS ERYTHROPOIETIC PROTOPORPHYRIA
Department of Biochemistry and Molecular Genetics, Villarroel 170, Hospital Clinic Barcelona, 08036 Barcelona, Spain.
OBJECTIVE: To study the mutations in the ferrochelatase gene (FECH) and the phenotypic expression of erythropoietic protoporphyria (EPP) in a group of Spanish patients.
DESIGN: Case series.
SETTING: University-based hospital. Patients Eleven unrelated patients with EPP and 19 asymptomatic relatives from 10 families. Main Outcomes Measures Measurement of protoporphyrin concentration in red blood cells and feces by fluorometry and chromatography. Analysis of the mutations of the FECH gene by single-strand conformation analysis. Expression of mutations in Escherichia coli.
RESULTS: FECH gene mutations were found in all 11 patients. Ten were heterozygous and carried the IVS3-48C low-expression allele. Three novel mutations were found: IVS4 + 1delG, 347-351delC, and 130_147dupl 18. One patient did not present the IVS3-48C polymorphism and was found to harbor a novel A185T missense mutation in both alleles. The familial study confirmed a recessive mode of inheritance of the disease. The A185T mutation showed a residual activity 4% of normal when expressed in E coli. This patient presented cutaneous photosensitivity similar to the heterozygous cases, but a higher protoporphyrin accumulation in erythrocytes, microcytic anemia, and early signs of liver engagement. FECH mutations were found in 10 healthy relatives, none of whom carried the low-expression allele. The frequency of the IVS3-48C allele among 180 nonporphyric Spanish individuals was 5.2%.
CONCLUSIONS: These findings confirm, among a group of Spanish patients, that most cases of EPP result from the coinheritance of IVS3-48C and a mutation in the FECH gene, and also document the existence of patients with mutations in homozygosity that may present a more severe form of the disease.
Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations.Poh-Fitzpatrick MB, Wang X, Anderson KE, Bloomer JR, Bolwell B, Lichtin AE.
Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
J Am Acad Dermatol 2002 Jun;46(6):861-6 Abstract quote Acute myelogenous leukemia occurred in a 47-year-old woman whose 25-year history of cutaneous photosensitivity had been undiagnosed until abnormally high erythrocyte, plasma, and fecal protoporphyrin levels were discovered during evaluation for her hematologic disorder.
She was found to be heteroallelic for ferrochelatase gene mutations, bearing a novel missense mutation caused by a C185-->G (Pro62-->Arg) transversion in exon 2 of one allele, and a previously described g-->a transition at the +5 position of the exon 1 donor site of the other allele, confirming a diagnosis of erythropoietic protoporphyria.
Successful bone marrow transplantation from her brother, who is a mildly affected bearer of the second mutation, resulted in remission of the leukemia and in conversion of the protoporphyria phenotype of the recipient to one resembling that of the donor.
HISTO-PATHOLOGICAL VARIANTS CHARACTERIZATION SKIN All of the porphyria variants show similar histologic features. There is eosinophilic hyaline material around the capillaries in the papillary dermis.
This material is reduplication of the basement membrane of the vessels and epidermal basement membrane. The blisters that form are subepidermal with characteristic festooning of the dermal papillae projecting into the floor of the blister.
The PAS positive basement membrane is present in the roof of the blister.Porphyria cutanea tarda PAS positive thickening of basement membrane
Solar elastosis
Sclerodermoid lesions have dermal thickening
Subepidermal blisters with festooning of dermal papillaeErythropoietic protoporphyria Hyaline material in the wall of the small vessles and also as an irregular cuff
Occasional neutrophils with nuclear dust within the papillary dermis
CHARACTERIZATION DIRECT IMMUNO-FLUORESCENCE Direct immunofluorescence (DIF) reveals IgG and less commonly IgM and C3 around the papillary dermal blood vessels.
BACKGROUND: The cutaneous lesions of diabetes mellitus (DM) and porphyria cutanea tarda (PCT) exhibit distinctive microvascular changes including basement membrane zone thickening and lamellation, morphologically appearing as hyaline-like alterations of the vessel wall. Immunofluorescence demonstrates homogeneous mantles of immunoglobulin in the microvasculature. The staining intensity is variable and in some cases can closely approximate those immunofluorescent changes seen in photoaged skin.
OBJECTIVE: The purpose of this study was to establish an association between the microvascular changes seen in the skin from patients with DM and PCT and the presence of C5b-9 deposition, potentially defining the C5b-9 assay as an additional diagnostic adjunct.
METHODS: Routine light microscopy and immunofluorescence studies were conducted on skin biopsy specimens from 14 patients with cutaneous manifestations of DM and 17 patients with PCT. The immunofluorescence profile included IgG, IgM, IgA, C3, C3d, C4d, and C5b-9.
RESULTS: Fourteen of 14 DM and 17 of 17 PCT skin biopsy specimens revealed extensive granular and homogeneous vascular deposition of C5b-9; a similar pattern was observed for C3d and C4d. Control specimens from patients without DM and PCT, where C5b-9 was not an expected immunoreactant, were negative. Positive controls were cases of vasculitis, scleroderma, and dermatomyositis without DM and PCT where C5b-9 deposition was expected. C5b-9 deposition was observed and was of lesser magnitude than that encountered in patients with PCT or DM.
LIMITATIONS: We were unable to obtain detailed clinical information on some of the diabetic patients in regards to significant extracutaneous vascular complications. In addition, a correlation between hemoglobin 1 Ac levels and the extent of C5b-9 deposition could not be ascertained as the serum levels for hemoglobin 1 Ac were unknown.
CONCLUSION: Granular and homogeneous deposits of C5b-9 in vessels, along with homogeneous deposits of immunoglobulin within the blood vessels, are characteristic immunofluorescence findings in patients with DM and PCT. In regards to potential mechanisms of C5b-9 deposition, decreased metabolism of C5b-9 due to glycosylation of CD59 in the setting of DM and activation of complement by irradiated porphyrins in PCT are proposed. The extent of C5b-9 deposition suggests that this complex may play a pathogenetic role in the evolution of microvascular injury in patients with DM and PCT.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES CATERPILLAR BODIES
The sensitivity and specificity of "Caterpillar Bodies" in the differential diagnosis of subepidermal blistering disorders.Fung MA, Murphy MJ, Hoss DM, Berke A, Grant-Kels JM.
Am J Dermatopathol. 2003 Aug;25(4):287-90. Abstract quote. Caterpillar bodies are eosinophilic, elongated, segmented bodies located within the roofs of blisters and are considered to represent a specific histopathologic feature of porphyric bullous eruptions, including porphyria cutanea tarda and erythropoietic protoporphyria. The possibility that similar or identical bodies may be present in other disorders prompted further study exploring the specificity of caterpillar bodies in the differential diagnosis of subepidermal vesiculobullous disorders.
Seventy-six cases exhibiting subepidermal clefting were reviewed by light microscopy. "Classic" caterpillar bodies were present in porphyria cutanea tarda (6 of 14) and 1 case representing either venous stasis-associated bulla or possibly bullosis diabeticorum. Caterpillar body-like clusters were present in porphyria cutanea tarda (5 of 14), erythropoietic protoporphyria (1 of 3), bullous pemphigoid (7of 24), and junctional or dystrophic epidermolysis bullosa (3 of 5). In some cases, classic caterpillar body and caterpillar body-like clusters coexisted in a blister roof.
Caterpillar bodies or caterpillar body-like clusters were not identified in any cases of dermatitis herpetiformis, linear IgA bullous dermatosis, bullous erythema multiforme, epidermolysis bullosa acquisita, or wound-healing reactions. In contrast to caterpillar bodies, caterpillar body-like clusters were negative for PAS or Type IV collagen stains. In conclusion, caterpillar bodies appear to represent a specific feature of porphyria cutanea tarda (specificity, 98%) but were present in less than half of those cases in this study (sensitivity, 43%).
Caterpillar body-like clusters are less specific and may be present in porphyria cutanea tarda, erythropoietic protoporphyria, pseudoporphyria, bullous pemphigoid, epidermolysis bullosa, and epidermolysis bullosa acquisita.
PROGNOSIS CHARACTERIZATION HEMOCHROMATOSIS GENE MUTATIONS
Hemochromatosis (HFE) Gene Mutations and Response to Chloroquine in Porphyria Cutanea Tarda.Stolzel U, Kostler E, Schuppan D, Richter M, Wollina U, Doss MO, Wittekind C, Tannapfel A.
Medical Physics, Medizinische Klinik II, Klinikum Chemnitz gGmbH, Teaching Hospital of the University of Leipzig, Flemmingstr 2, D-09116 Chemnitz, Germany
Arch Dermatol 2003 Mar;139(3):309-13 Abstract quote OBJECTIVE: To examine the role of hemochromatosis (HFE) gene mutations, which are associated with porphyria cutanea tarda (PCT), in the therapeutic response to chloroquine.
DESIGN: We retrospectively analyzed a database (Excel version 2001 [Microsoft Excel, Redmond, Wash]; date range of search, 1985-1999) of chloroquine-treated patients with PCT on whether HFE mutations (C282Y and H63D) might have influenced the clinical response, urinary porphyrin excretion, liver enzyme activities, and serum iron markers. Serum samples and corresponding complete sets of data before and after therapy were available in 62 of 207 patients with PCT who were treated exclusively with chloroquine.
SETTINGS: Academic teaching hospital.
INTERVENTION: For treatment, low-dose chloroquine diphosphate, 125 to 250 mg twice weekly, was used during a median time of 16 months (range, 12-26 months).
RESULTS: Of the 62 German patients with PCT, 37 (60%) carries HFE mutations. Chloroquine therapy was accompanied by clinical remission and reduced urinary porphyrin excretion (P<.001) in the 24 patients (39%) with HFE wild type as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum iron markers following chloroquine therapy were limited to patients with PCT and HFE wild type. All patients homozygous for the C282Y mutation (3 [5%] of 62) had high serum iron, ferritin, and transferrin saturation and failed to respond to chloroquine treatment.
CONCLUSIONS: The therapeutic response to chloroquine was not compromised by C282Y heterozygosity and compound heterozygosity of HFE mutations. Because HFE C282Y homozygotes (+/+) did not respond to chloroquine and a decrease in serum iron concentration was limited to patients with PCT and HFE wild type, phlebotomy should be first-line therapy in patients with PCT and HFE mutations.
TREATMENT CHARACTERIZATION BONE MARROW TRANSPLANTATION
Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation.Tezcan I, Xu W, Gurgey A, Tuncer M, Cetin M, Oner C, Yetgin S, Ersoy F, Aizencang G, Astrin KH, Desnick RJ.
Department of Pediatric Immunology and Hematology, Hacettepe University, Ankara, Turkey.
Blood 1998 Dec 1;92(11):4053-8 Abstract quote The long-term biochemical and clinical effectiveness of allogenic bone marrow transplantation (BMT) was shown in a severely affected, transfusion-dependent 18-month-old female with congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of heme biosynthesis resulting from mutations in the uroporphyrinogen III synthase (URO-synthase) gene.
Three years post-BMT, the recipient had normal hemoglobin, markedly reduced urinary porphyrin excretion, and no cutaneous lesions with unlimited exposure to sunlight. The patient was homoallelic for a novel URO-synthase missense mutation, G188R, that expressed less than 5% of mean normal activity in Escherichia coli, consistent with her transfusion dependency. Because the clinical severity of CEP is highly variable, ranging from nonimmune hydrops fetalis to milder, later onset forms with only cutaneous lesions, the importance of genotyping newly diagnosed infants to select severely affected patients for BMT is emphasized.
In addition, the long-term effectiveness of BMT in this patient provides the rationale for future hematopoietic stem cell gene therapy in severely affected patients with CEP.
Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation
Frederick A. Harada, MD Tor A. Shwayder, MD Robert J. Desnick, MD, PhD Henry W. Lim, MD
Detroit, Michigan, and New York, New York
J Am Acad Dermatol 2001;45:279-82 Abstract quote
Congenital erythropoietic porphyria (CEP), which is the result of a deficiency of uroporphyrinogen (URO) III synthase activity, is the most disfiguring porphyria in humans. Various methods of treatment have been used to treat CEP with varying success, including erythrocyte transfusion, hydroxyurea, and splenectomy. The only treatment that corrects the enzymatic defect resulting in a cure is bone marrow/stem cell transplantation, which has been reported previously in only 5 patients worldwide. We describe the first patient with CEP who underwent successful bone marrow transplantation performed in the United States and review the therapeutic options in the management of this challenging type of porphyria.
GENE TRANSFER
Metabolic correction of congenital erythropoietic porphyria by retrovirus-mediated gene transfer into Epstein-Barr virus-transformed B-cell lines.Moreau-Gaudry F, Mazurier F, Bensidhoum M, Ged C, de Verneuil H.
Laboratoire de Biochimie Medicale et Biologie Moleculaire, Universite de Bordeaux II, France.
Blood 1995 Mar 15;85(6):1449-53 Abstract quote Congenital erythropoietic porphyria (CEP) is an inherited metabolic disorder resulting from the accumulation of porphyrins because of defective uroporphyrinogen III synthase (UROIIIS).
This autosomal recessive disorder is phenotypically heterogeneous with respect to the age of onset and the severity of the symptoms. Different exonic point mutations in the UROIIIS gene have been identified, providing phenotype-genotype correlations in this disease. Severe cases may be treated by bone marrow transplantation and are potential candidates for somatic gene therapy. Epstein-Barr virus-transformed B-cell lines from patients with CEP provide a model system for the disease.
We have used retrovirus-mediated expression of UROIIIS to restore enzymatic activity in a B-cell line from a patient. We have also demonstrated the metabolic correction of the disease, ie, porphyrin accumulation into the deficient transduced cells was reduced to the normal level. These data show the potential of gene therapy for this disease.
Congenital erythropoietic porphyria: prolonged high-level expression and correction of the heme biosynthetic defect by retroviral-mediated gene transfer into porphyric and erythroid cells.Kauppinen R, Glass IA, Aizencang G, Astrin KH, Atweh GF, Desnick RJ.
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Mol Genet Metab 1998 Sep;65(1):10-7 Abstract quote Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder resulting from the deficient activity of the heme biosynthetic enzyme uroporphyrinogen III synthase (UROS). Severely affected patients are transfusion dependent and have mutilating cutaneous manifestations. Successful bone marrow transplantation has proven curative, providing the rationale for stem cell gene therapy.
Toward this goal, two retroviral MFG vectors containing the UROS cDNA were constructed, one with the wild-type sequence (MFG-UROS-wt) and a second with an optimized Kozak consensus sequence (MFG-UROS-K). Following transduction of CEP fibroblasts, the MFG-UROS-wt and MFG-UROS-K vectors increased the endogenous activity without selection to levels that were 18- and 5-fold greater, respectively, than the mean activity in normal fibroblasts. Notably, the MFG-UROS-wt vector expressed UROS activity in CEP fibroblasts at these high levels for over 6 months without cell toxicity. Addition of either delta-aminolevulinic acid (ALA) or ferric chloride did not affect expression of the transduced UROS gene nor did the increased concentrations of uroporphyrin isomers or porphyrin intermediates affect cell viability. Similarly, transduction of CEP lymphoblasts with the MFG-UROS-wt vector without G418 selection increased the endogenous UROS activity by 7-fold or almost 2-fold greater than that in normal lymphoblasts. Transduction of K562 erythroleukemia cells by cocultivation with the MFG-UROS-wt producer cells increased their high endogenous UROS activity by 1.6-fold without selection. Clonally isolated K562 cells expressed UROS for over 4 months at mean levels 4.7-fold greater than the endogenous activity without cell toxicity.
Thus, the prolonged, high-level expression of UROS in transduced CEP fibroblasts and lymphoblasts, as well as in transduced K562 erythroid cells, demonstrated that the enzymatic defect in CEP cells could be corrected by retroviral-mediated gene therapy without selection and that the increased intracellular porphyrin intermediates were not toxic to these cells, even when porphyrin production was stimulated by supplemental ALA or iron. These in vitro studies provide the rationale for ex vivo stem cell gene therapy in severely affected patients with CEP.
PLASMAPHERESIS
Plasmapheresis combined with somatostatin is a successful treatment of porphyrias.Medenica R, Lazovic G, Long P, Corbitt W, Powell D.
International Immuno-Biology Research Laboratory, Hilton Head Island, South Carolina, USA.
Ther Apher 1997 May;1(2):159-64 Abstract quote During acute attacks of hepatic porphyria, levels of polypeptides, vasoactive intestinal peptides, neurotensin, substance P, pancreatic polypeptide, gastrin releasing polypeptide, gastrin, and motilin increased in the circulation while the clinical symptoms were evident. However, somatostatin decrease was not detected. Somatostatin belongs to a group of regulatory peptides that antagonize the action of endogenous steroid hormones, and decreasing their bioavailability decreases the rate of synthesis of delta-aminolevulinate synthase, alpha-aminolevunilic acid (ALA), and polypeptides.
Plasma exchange was conducted in courses for 2 consecutive days every 28 days (total of 6 courses), removing more than 100% of the patient plasma each time. Between the 2 courses of plasmapheresis, subcutaneous injections of somatostatin (100-500 mcg) were administered. A lasting disappearance of pain and complete remission were obtained in all 7 patients treated.
Plasmapheresis combined with somatostatin may be considered as a treatment of porphyria exacerbation.
TRANSFUSION
Porphyrins in urine, plasma, erythrocytes, bile and faeces in a case of congenital erythropoietic porphyria (Gunther's disease) treated with blood transfusion and iron chelation: lack of benefit from oral charcoal.Gorchein A, Guo R, Lim CK, Raimundo A, Pullon HW, Bellingham AJ.
Department of Clinical Pharmacology, Imperial College School of Medicine at St Mary's, London, UK.
Biomed Chromatogr 1998 Nov-Dec;12(6):350-6 Abstract quote Congenital erythropoietic porphyria is a rare genetic disorder in which deficiency of uroporphyrinogen III synthase results in excessive production of Type I porphyrins.
The main clinical features are severe photodestruction of the skin and haemolytic anaemia. Treatment consists of shielding from light, blood transfusions and splenectomy, but is generally unsatisfactory. Previous studies have suggested that oral charcoal may be of benefit by binding porphyrins in the gut.
A trial was therefore undertaken to evaluate this possibility. Porphyrins in urine, plasma and erythrocytes were measured by HPLC in a 23-year-old male patient with congenital erythropoietic porphyria, during an 8 week "run-in" period, and for a further 3 weeks when oral charcoal was given. Total urinary porphyrin excretion was 79-283 mumol/24 h consisting of 75% uroporphyrin I, 15% coproporphyrin I and smaller amounts of hepta-, hexa-, and pentacarboxylic porphyrins. Similar proportions were found in plasma and erythrocytes. During the first 24 h of charcoal administration a minor decrease in plasma and erythrocyte porphyrins was detected but this was not maintained during the remainder of the trial. In bile and faeces coproporphyrin I constituted approximately 95% of the porphyrins, with 2-3% coproporphyrin III and smaller amounts of pentaporphyrins I and III, but only trace amounts of uroporphyrin I. Oral charcoal was of no value in this case.
Reasons are discussed in the context of biochemical differences between this patient with classical Gunther's disease and the similar clinical syndrome due to deficiency of uroporphyrinogen decarboxylase.
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Caterpillar bodies-Reduplicated basement membrane and colloid bodies deposited in the basal layer of the epidermis. Immunohistochemical analysis using antibodies directed against laminin and type IV collagen. Characteristic finding in porphyria cutanea tarda and some other subepidermal blistering diseases.
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