Leonard C. Harber

Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients.

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.

Erythropoietic Protoporphyria: Lipid Peroxidation and Red Cell Membrane Damage Associated with Photohemolysis

The mechanism by which long wavelength ultraviolet light hemolyzes red cells obtained from patients with erythropoietic protoporphyria (EPP) was investigated. Previous studies had suggested that irradiation of these red cells with wavelengths of light capable of eliciting dermatological manifestations led to oxygen-dependent colloid osmotic hemolysis through the formation of peroxides. In the present report, lipid peroxidation during in vitro irradiation of EPP red cells with long ultraviolet light was demonstrated by: (a) the formation of 2-thiobarbituric acid reactants; (b) the presence of conjugated diene bonds in red cell lipid; and (c) the selective loss of unsaturated fatty acids proportional to the number of carbon-carbon double bonds in each. Irradiation of EPP red cells was also shown to result in the formation of hydrogen peroxide.Before photohemolysis there was a decline in cell membrane sulfhydryl groups and a loss in activity of the cell membrane enzyme acetylcholinesterase. These parameters provide further evidence suggesting that the cell membrane is a primary site of the photohemolytic effect of long ultraviolet light in EPP red cells. Further evaluation of the radiation-induced inactivation of EPP red cell acetylcholinesterase was performed by radiating mixtures containing bovine erythrocyte acetylcholinesterase and protoporphyrin IX. These studies revealed that the rate of decline in enzyme activity is accelerated by the addition of linoleic acid, an unsaturated fatty acid, but not by palmitic acid, a saturated fatty acid. Partial protection against both photohemolysis and acetylcholinesterase decline is provided by alpha-to-copherol. This lipid antioxidant loses its activity during the irradiation of EPP red cells suggesting that it is utilized in this process.

Erythropoietic protoporphyria 10 years experience

The clinical and laboratory findings in 32 patients with erythropoietic protoporphyria as well as a review of the pertinent literature on this relatively recently described form of porphyria are presented. The disease is thought to be transmitted in an autosomal dominant fashion with variable penetrance and was characterized in these 32 patients by the onset in childhood of burning (97 per cent) and itching (88 per cent) of the skin on exposure to sunlight. This was accompanied by edema (49 per cent) and erythema (69 per cent) of the exposed areas. Vesicles, petechiae and residual scarring occurred less frequently. Associated abnormalities included cholelithiasis (12 per cent), anemia (27 per cent) and abnormal liver function studies (4 per cent). Reports of associated liver disease including nine cases of fatal hepatic failure, are reviewed. Current methods of diagnosis as well as theories of pathophysiology of the disease are presented. Nineteen of 23 of these patients recently treated with beta-carotene responded with significant increase in their tolerance to sun exposure.

Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. I. Different rates of disappearance of protoporphyrin from the erythrocytes, both in vivo and in vitro.

In lead intoxication photosensitivity is usually absent, despite concentrations of protoporphyrin in the erythrocytes equal to or greater than in erythropoietic protoporphyria. Profound differences in the distribution of protoporphyrin in aging erythrocytes were demonstrated by age-dependent fractionation of cells on discontinuous density gradients. In erythropoietic protoporphyria the concentration of protoporphyrin declined extremely rapidly with erythrocyte age; the bulk of the protoporphyrin was lost in less than 3 days and the concentration of fluorescent erythrocytes in the gradient paralleled the decline of protoporphyrin. In lead intoxication the protoporphyrin concentration declined only slightly with cell aging and erythrocytes of all ages fluoresced. In the bone marrow from a patient with erythropoietic protoporphyria all reticulocytes, but only occasional late normoblasts, fluoresced, suggesting a single population. Sterile incubation in plasma (pH 7.5) demonstrated rapid diffusion of protoporphyrin from the erythrocytes in erythropoietic protoporphyria, but not in lead intoxication. Plasma protoporphyrin was elevated in erythropoietic protoporphyria, but not in lead intoxication. Estimates of the daily loss of protoporphyrin from erythropoietic tissue in erythropoietic proporphyria suggested an order of magnitude similar to the total blood protoporphyrin. Therefore, it is not necessary to postulate a preponderant extraerythropoietic source to explain the amount of fecal excretion. A significant amount of the diffused protoporphyrin probably reaches the skin with resulting photosensitivity. In contrast, in lead intoxication protoporphyrin remains within the erythrocyte throughout its life span ; there is no diffusion into the plasma and hence no photosensitivity.

Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. II. Different binding of erythrocyte protoporphyrin to hemoglobin.

Acidic solvents extract the same porphyrin-protoporphyrin-from the erythrocytes of patients with either erythropoietic protoporphyria or lead intoxication. However, extractable protoporphyrin disappears rapidly, both in vivo and in vitro, from erythrocytes in erythropoietic protoporphyria but slowly, if at all, in lead intoxication. Consistent with these observations, fluorescence spectroscopy revealed that the intracellular state of the erythrocyte protoporphyrin is different in the two diseases. Spectrofluorometric measurements coupled with fractionations and biochemical syntheses showed that in erythropoietic protoporphyria the protoporphyrin is bound as the free base to hemoglobin molecules at sites other than the heme binding sites. In lead intoxication the fluorescent porphyrin is also bound to hemoglobin but is present as zinc protoporphyrin. The data suggest that the zinc protoporphyrin is bound at heme binding sites. Acidic extraction solvents remove the chelated zinc, but zinc protoporphyrin may be extracted intact from erythrocytes with acetone, ethanol, or the detergent Ammonyx-LO.

PHOTOREACTIONS ASSOCIATED WITH IN VITRO HEMOLYSIS IN ERYTHROPOIETIC PROTOPORPHYRIA

Abstract— –Photohemolysis of erythrocytes. from patients with erythropoietic protoporphyria results from damage to the cell membrane following photoexcitation of the protoporphyrin molecule by 400 nm radiation. Photochemical reactions were assessed for their roles in initiating cell destruction in an in vitro model in which erythrocytes from patients with erythropoietic protoporphyria were irradiated. Electron transfer properties were demonstrated using 2,3,6‐trichloroindophenol as an electron acceptor. Photohemolysis of these abnormal cells is due to cell membrane damage initiating colloid osmotic hemolysis. Additional data are offered demonstrating that this type of photohemolysis is oxygen‐dependent, associated with peroxide formation, and preceded by increased osmotic fragility. An hypothesis explaining the interrelationship of the photochemistry of protoporphyrin with the photobiologic observation of hemolysis is offered.

Effect of continued ultraviolet B phototherapy on the duration of remission of psoriasis: A randomized study

Phototherapy using sunburn spectrum ultraviolet radiation (UVB) is now a frequently utilized treatment for psoriasis that is extensive or has not responded to topical preparations. Four university centers performed a prospective randomized clinical trial to compare remission times of patients with psoriasis who continued UVB phototherapy after initial clearing with this therapy and patients whose UVB phototherapy was discontinued within 3 weeks of clearing. As assessed by life table methods, the time to flare after initial clearing for patients on UVB maintenance therapy was significantly longer than for patients who discontinued UVB within 3 weeks after initial clearing. Our data suggest that continuing UVB phototherapy after initial clearing contributes to the duration of disease control and is justified for many patients.

PHOTOBIOLOGY OF LUPUS ERYTHEMATOSUS.

Ultraviolet radiation in the 2850 to 3150 angstrom range can produce abnormal cutaneous reactions and exacerbation of systemic manifestations in some cases of subacute and acute systemic lupus erythematosus. It may also be responsible for cutaneous lesions and systemic involvement in rare cases of chronic discoid lupus erythematosus--probably those with disseminated lesions. The pathophysiological mechanism producing these photobiological effects in lupus erythematosus remains unknown.

Photoallergic contact dermatitis to musk ambrette: Clinical report of two patients with persistent light reactor patterns

Two male patients with photoallergic contact dermatitis to musk ambrette, 2-methoxy-3,5-dinitro-4-methyl-t-butylbenzene, are reported. Musk ambrette is a synthetic fragrance material commonly used in foods and cosmetics. The clinical distribution of lesions presented by these patients strongly suggested an adverse reaction to light. Over a period of several years no etiology had been determined in these cases despite extensive testing and hospitalization. Photopatch tests to musk ambrette were positive. No other etiology for photosensitivity was found. This report emphasizes that exposure to household or cosmetic products represents a potential source of contact photosensitivity. Patients presenting with dermatoses of unknown origin confined to the light-exposed areas should have fragrances considered as possible etiologic agents.

Photosensitivity due to chlorothiazide and hydrochlorothiazide.

CHLOROTHIAZIDE and hydrochlorothiazide are aromatic sulfonamides differing from each other only in that in the hydrochlorothiazide the 3, 4 carbon-nitrogen bond is saturated by 2 hydrogen atoms whe...