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Porphyria cutanea tarda with menopausal exacerbation: The possible role of menstruation as natural phlebotomy
Abstract
We describe a 48-year-old woman with a 12-year history of porphyria cutanea tarda who showed a remarkable exacerbation of her eruptions accompanied by high serum levels of iron and ferritin at menopause. As iron storage is known to be a triggering factor of porphyria cutanea tarda, the possible role of menstruation as natural phlebotomy to prevent porphyria cutanea tarda exacerbation is discussed.
... 63 Because PCT is related to iron storage, its symptoms become more severe in women after menopause, when this natural means of blood loss ceases. 64,65 Polycythemia vera and secondary polycythemias (erythrocytosis) ...
Orally administered ferric citrate exerts a pronounced synergistic effect on the induction of hepatic δ-aminolevulinic acid
synthetase produced by two compounds. The effect appears to be specific for iron citrate, as opposed to other metals in complex
with citrate, and specific also in affecting the level of δ-aminolevulinic acid synthetase as compared with another induced
enzyme, tyrosine transaminase. Inorganic iron salts did not produce augmentation of the induction of hepatic δ-aminolevulinic
acid synthetase. The data suggest that iron augments the rate of synthesis of the enzyme during induction rather than activating
or stabilizing the enzyme.
Iron deficiency is a frequent complication in chronically hemodialyzed patients because of the significant blood losses associated with this technique. Quantitating iron stores (by marrow examination or serum iron and total iron-binding capacity) on a repetitive basis has been difficult or unreliable, often resulting in failure to recognize iron deficiency superimposed on the existing anemia of chronic renal failure, or overtreating, which can lead to iron excess. Use of the serum ferritin allows easier quantitation of iron stores and, when measured serially in dialysis patients, can predict the emergence of iron deficiency. There was no correlation between serum ferritin levels and serum iron, total iron-binding capacity, or percent transferrin saturation. Iron absorption studies show that food iron absorption is physiologic, increasing when the serum ferritin is below 30 ng/ml, decreasing when more than 300 ng/ml. Treatment of iron deficiency with oral iron compounds increases serum ferritin levels and usually can maintain iron balance.
We report the cases of 4 male subjects, 29, 32, 41 and 44 years old, presenting isolated seropositivities for the human immunodeficiency virus (HIV), or full-blown acquired immunodeficiency syndrome, associated with a typical porphyria cutanea tarda (PCT). The 4 patients are in the usual risk groups for HIV infection. Viral hepatitis was observed in 3 of the 4 cases. Over the past 3 years, 15 cases associating HIV infection and PCT have been reported; almost all had the usual risk factors for HIV infection and hepatopathy. We speculate that HIV infection may have favored the occurrence of early PCT in these cases by altering the metabolism of the porphyrins, either directly or by means of the associated hepatopathy.
Eleven patients with porphyria cutanea tarda were studied. Biochemical confirmation of the clinical diagnosis required only determination of the total urine porphyrin concentration in a sample of urine voided on rising in the morning. The patients were divided for convenience of discussion into four groups differing in age, sex and etiologic factors. Of the six patients in whom a liver biopsy was done one was shown to have micronodular cirrhosis. Except for a modest elevation in the serum glutamic oxaloacetic transaminase values when the patients were first seen, no evidence was found for liver disease apart from the presence of porphyria cutanea tarda. One patient recovered solely by abstaining from alcohol consumption. Five patients underwent phlebotomy; their iron stores had been found to be between 2 and 3 g. Decreasing urine porphyrin values correlated well with decreasing serum ferritin values during the course of phlebotomy. Porphyria cutanea tarda, which is due to a deficiency of uroporphyrinogen decarboxylase, is manifested in association with alcohol abuse, estrogen therapy, exposure to chlorinated hydrocarbons or increased tissue iron stores, or a combination of these factors. Although relatively uncommon, this condition raises important and unresolved issues regarding the hepatotoxicity of alcohol, estrogens, chlorinated hydrocarbons and iron.
PIP
Porphyria cutanea tarda is the most common disorder of porphyrin metabolism in the United States and Europe. This report presents the clinical, laboratory and pathologic features of 40 patients with porphyria cutanea tarda. Each patient was followed up for variable times during 1960-76 at the Clinical Research Center and the Dermatology Service of the Columbia-Presbyterian Medical Center; at the New York University Medical Center; or at the Rockefeller University Hospital. Earlier age at onset; diminution of alcohol ingestion as the major etiologic factor; and, an increased incidence in females indicate new environmental influences. The most frequently associated etiologic factor, aside from alcohol intake, was use of estrogens for contraception; postmenopausal syndrome; or treatment of prostatic carcinoma. Cutaneous findings in the patients included bullae (85%); increased skin fragility (75%); facial hypertrichosis (63%); hyperpigmentation (55%); sclerodermoid changes (18%); and, dystrophic calcification with ulceration (8%). Diabetes mellitus was found in 15%; systemic lupus erythematosus in 5%; elevated serum iron level in 62%; and, abnormal liver function test results in 60%. Histologic abnormalities were seen in liver biopsies of 34 patients. Phlebotomy is the treatment of choice. In 32 patients so treated, clinical remissions averaged 30.9 months. 31% (10 patients) had a relapse but additional phlebotomies resulted in 2nd remissions. Chloroquine and plasmaphoresis treatments were also briefly discussed.
Iron deficiency is a frequent complication in chronically hemodialyzed patients because of the significant blood losses associated with this technique. Quantitating iron stores (by marrow examination or serum iron and total iron-binding capacity) on a repetitive basis had been difficult or unreliable, often resulting in failure to recognize iron deficiency superimposed on the existing anemia of chronic renal failure, or overtreating, which can lead to iron excess. Use of the serum ferritin allows easier quantitation of iron stores and, when measured serially in dialysis patients, can predict the emergence of iron deficiency. There was no correlation between serum ferritin levels and serum iron, total iron-binding capacity, or percent transferrin saturation. Iron absorption studies show that food iron absorption is physiologic, increasing when the serum ferritin is below 30 ng/ml, decreasing when more than 300 ng/ml. Treatment of iron deficiency with oral iron compounds increases serum ferritin levels and usually can maintain iron balance.
Porphria cutanea tarda is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I and 7-carboxylporphyrins. This pattern of excretion suggest an impaired ability to decarboxylate uroporphyrinogen to the paired ability to decarboxylate uroporphyringen to the 4-carboxyl porphyrinogen, coproporphyrinogen, a reaction catalyzed by the enzyme uroporphyringen decarboxylase. Because clinical evidence has implicated iron in the pathogenesis of porphyria cutanea tarda, these experiments were designed to study the effect of iron on uroporphyrinogen decarboxylase in procine crude liver extracts. Mitochondria-free crude liver extracts were preincubated with ferrous ion and aliquots were assayed for uroporphyrinogen decarboxylase activity. Uroporphyrinogens I and III, the substrates for the decarboxylase assay, were prepared enzymatically from (3H)porphobilinogen. The products of the decarboxylase reaction were identified and quantitated by three methods: (a) extraction into 1.5 N HCl and spectrophotometric quantitation; (b) adsorption onto talc, esterification, paper chromatographic identification, and quantitation by liquid scintillation counting; and (c) adsorption onto talc, esterification, thin-layer chromatographic identification on silica gel, and quantitation by liquid scintillation counting. The thin-layer scinllation method proved most sensitive as it was the only method which accurately identified and quantitated the 7-carboxyl porphyrin reaction product. Uroporphyrinogens I and III were decarboxylated at the same rate by porcine hepatic uroporphyrinogen decarboxylase, and the addition of iron induced marked inhibition of the decarboxylase activity. Ortholpehanthroline blocked the inhibitory effect of iron. The inhibition of uroporphyrinogen decarboxylase by ferrous ion, coupled with its previously reported inhibitory effect on uroporphyrinogen III cosynthetase, provides a possible biochemical explanation for the pattern of urinary porphyrin excretion observed in patients with porphyria cutanea tarda and the clinical association with disordered iron metabolism.
The prevalence of HCV antibodies in IH and PCT patients was examined. It was found that both groups are characterized by increased incidence of HCV infection. These results suggest a possible connection between HCV and iron overload.
We report the cases of 4 male subjects, 29, 32, 41 and 44 years old, presenting isolated seropositivities for the human immunodeficiency virus (HIV), or full-blown acquired immunodeficiency syndrome, associated with a typical porphyria cutanea tarda (PCT). The 4 patients are in the usual risk groups for HIV infection. Viral hepatitis was observed in 3 of the 4 cases. Over the past 3 years, 15 cases associating HIV infection and PCT have been reported; almost all had the usual risk factors for HIV infection and hepatopathy. We speculate that HIV infection may have favored the occurrence of early PCT in these cases by altering the metabolism of the porphyrins, either directly or by means of the associated hepatopathy.
Immunoreactive and catalytic uroporphyrinogen decarboxylase were measured in liver from 15 patients with sporadic porphyria cutanea tarda (PCT) and 4 patients with familial PCT at different stages of the disorder. In sporadic PCT, catalytic activity was lowest and immunoreactive enzyme concentration was highest when active skin lesions were present; this pattern was also seen in the one familial PCT patient who had skin lesions. During remission, the ratio of catalytic activity to immunoreactive enzyme concentration returned towards normal. Immunoreactive enzyme was increased by comparison with controls in sporadic patients with skin lesions; in familial PCT mean concentration was 59% of the overall sporadic value. In 4 sporadic patients in prolonged (4-8 years) remission (following venesection) enzyme activity and immunoreactive enzyme concentrations were normal. It is suggested that clinically overt PCT is precipitated by an iron-dependent process which inactivates the active centres of uroporphyrinogen decarboxylase molecules in the liver. Treatment by venesection eventually leads to complete reversal of this biochemical defect in at least some patients with sporadic PCT. The findings are consistent with the view that sporadic PCT is an acquired disorder.
Serum markers of hepatitis B virus (HBV) infection were determined in 82 patients with porphyria cutanea tarda (PCT). Pathogenetic factors (alcohol, thalassemia minor, drugs) and clinical and histologic findings of PCT were taken into account. The prevalence of HBV infection was very high (70.7%). Hepatitis B surface antigen (HBsAg) was positive in 14 patients (17%). Eight patients had HBV infection as the only documented acquired factor. The clinical picture and histologic findings were aggravated by HBV infection; primary hepatic carcinoma occurred in four patients with HBV infection. Liver siderosis was histologically documented in 82.6% of cases, serum ferritin was pathologically increased in 91%, confirming the role of iron overload in PCT. A correlation (p less than 0.02; chi-squared method) was found between increased serum ferritin levels and HBV infection, suggesting a possible relationship between liver siderosis and HBV clearance. HBV infection appears to be a relevant additional factor in the pathogenesis of PCT liver disease.
Serum ferritin was measured in 9 patients with overt porphyria cutanea tarda. In 6, the level was higher than normal. We confirm that moderate, but not gross iron overload is a feature of such patients.
Radio-iron kinetic tests were performed in 7 patients with end-stage renal disease treated by hemodialysis; the study could be completed in 6 patients. The incorporation of radio-iron into the erythrocytes was 21% on average in patients with acute anemia. The red cell life-span determined in 4 patients became significantly shorter in 3 patients. Iron turnover in the bone marrow was significantly lower than normal, the rate of ineffective erythropoiesis being higher. Serum ferritin levels were significantly higher, and tissue and extravascular iron turnover was found to be enhanced compared to normal. At the same time, serum iron level was normal. The data on iron turnover indicated deficient hemopoiesis in the bone marrow, due partly to the lack of erythropoietin and partly to the insufficiency of the BFU-E (burst forming units) and CFU-E (colony-forming units) reserves. Undoubtedly, this was a consequence of the uremia.
We have studied the prevalence of hepatitis C virus antibodies (anti-HCV) in 13 patients suffering from sporadic porphyria cutanea tarda. The sera were tested by Abbott second-generation enzyme immunoassay; seropositivity was confirmed by Ortho second-generation recombinant immunoblot assay. Ten cases (76.1%) were anti-HCV positive; one patient was also seropositive for HIV. This preliminary study suggests that HCV could be a frequent triggering factor for sporadic porphyria cutanea tarda.
Hepatoerythropoietic porphyria is a severe cutaneous porphyria caused by deficiency of uroporphyrinogen decarboxylase and is considered to be the homozygous form of familial (type II) porphyria cutanea tarda. To elucidate further the relation between these conditions, we studied five Spanish families with hepatoerythropoietic porphyria and nine unrelated Spanish patients with familial porphyria cutanea tarda. Immunoreactive and catalytic uroporphyrinogen decarboxylase was decreased by greater than 95% in the five patients with hepatoerythropoietic porphyria. Hepatic uroporphyrinogen decarboxylase activity was decreased to 22% of normal. Four patients were homozygous for a mutation (G281E) originally identified in a Tunisian family; the fifth patient was a compound heterozygote for this mutation. The calculated carrier frequency for G281E in Spain is one in 1800. None of the nine familial porphyria cutanea tarda patients carried the G281E mutation. However, one G281E heterozygote in a family with hepatoerythropoietic porphyria had overt porphyria cutanea tarda. These findings suggest that the G281E mutation is functionally less severe than erythrocyte measurements indicate, that its clinical penetrance is very low in heterozygotes, and that, for this particular mutation, hepatoerythropoietic porphyria is the homozygous form of familial porphyria cutanea tarda.
Recent reports have revealed the high prevalence of serological markers of viral hepatitis in porphyria cutanea tarda (PCT). We present two cases of PCT associated with hepatitis C and discuss the relationship between PCT and viral hepatitis. Case 1: A 50-year-old Japanese male noticed blisters, erosions, and fragility on sun-exposed areas of his skin in November of 1990. He had no history of excessive alcohol intake. He had been taking analgesics for eighteen years. Case 2: A 64-year-old Japanese male was referred in October of 1989 because of pigmentation on sun-exposed areas of his skin. He had been drinking alcohol excessively for 43 years. The hepatitis C virus (HCV) antibody was present in each case. Tests for the HCV antibody and hepatitis B serological markers were run in 5 other patients. HCV antibody was present in 3 of them. The two cases negative for the HCV antibody exhibited the hepatitis B antibody. We speculated that viral hepatitis infection may play an important role in precipitating PCT in cases with a history of a long term excessive intake of alcohol or chemicals.
Sporadic porphyria cutanea tarda (S-PCT) has been considered an acquired disease because of the generation of liver-specific inhibitors of uroporphyrinogen decarboxylase (URO-D) activity. Several families have been described with S-PCT in multiple generations, raising the possibility of an inherited basis for the disease. To determine if S-PCT is associated with mutant URO-Ds that might be sensitive to liver-specific inhibitors, a molecular analysis of genomic and hepatocellular URO-Ds was undertaken.
Total RNA from lymphoid cell lines from three unrelated patients with S-PCT and poly A+ RNA from liver biopsy samples from two additional patients was used as a template for single-stranded cDNA synthesis, and URO-D sequences were amplified and sequenced. DNA prepared from peripheral blood leukocytes was used as a template to polymerase chain reaction (PCR) amplify the promoter region of the URO-D gene. Sequencing of PCR products was performed completely in both directions by the chain termination method using a variety of custom oligonucleotide primers.
Ten URO-D alleles were sequenced, and no mutations were found. The promoter region of the URO-D gene was also normal.
It is concluded that S-PCT is not due to mutations at the URO-D locus. If inherited factors are involved, other loci must be affected.
Porphyria cutanea tarda (PCT) is a skin disease that results from decreased activity of uroporphyrinogen decarboxylase (UROD). About 80% of patients have the sporadic (type I) form in which UROD deficiency is restricted to the liver. Others have familial (type II) PCT in which mutations in the UROD gene are inherited in an autosomal dominant pattern with low clinical penetrance. PCT may also follow exposure to porphyrogenic chemicals. Clinically overt PCT (types I and II) is provoked by liver cell injury, particularly when associated with alcohol abuse, hepatitis C infection, or estrogens. Hepatic iron overload is common, depletion of iron stores produces remission, and their replenishment leads to relapse. In PCT, hepatic UROD is inactivated by a process targeted at its catalytic site, which is iron-dependent, requires a heme precursor, and may be accelerated by induction of cytochrome P450s. Susceptibility to develop PCT in response to common causes of liver injury may be determined by co-inheritance of genes that regulate components of this inactivation process.
Iron deficiency anemia is the most common cause of anemia worldwide and results from inadequate iron supply for erythropoiesis. Iron deficiency is most prevalent during periods of rapid body growth: in infancy and again at puberty. Insufficient intake accounts for most cases. The clinical manifestations of iron deficiency anemia can be subtle, but irreversible delayed psychomotor development may occur if the anemia is severe and prolonged. The optimal approach is prevention and early treatment.
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