Treatment of the Porphyrias: Mechanisms of Action

DAVID R. BICKERS, M.D. Depa.rtm.ent of Derma.tology, Case Western R e"erve University, Cleveland, Ohio, U.S.A.

The porphyrias are diseases that result from inherited activity of certain enzymes in t he heme pathway by the admin or acquired abnormalities of porphyrin-heme synthesis istration of certain drugs, no permanent alteration can be in the liver and the bone marrow_ Only the hepatic achieved with t he modalities now available. There are, however, porphyrias are known to be aggravated by exposure to a number of t reatments of the various types of porphyria. These a variety of exogenous drugs and chemicals_ Simple range from highly effective modalities such as phlebotomy and avoidance of these agents will reduce the risk of devel chloroquine for porphyria cutanea tarda to marginally effective oping hepatic porphyria and may lead to clinical im measures such as photoprotection of the skin. Fwthermore, proveme nt in patients with active disease. Some types avoidance of exposure to dJ'ugs and environmental chemicals of therapy of the hepatic porphyrias are effective be that can alter heme pathway enzym e activity may be most cause of their ability to modulate the activity of <'l-ami helpful in preventing the clinical expression of porphyria. nolevulinic acid synthetase, the rate-limiting enzyme for heme synthesis. Most of the porphyrias are associated PORPHYRIAS AS DISORDERS OF THE REGULATION with cutaneous photosensitivity, the treatment of which OF HEME SYNTHESIS centers about either reducing the excessive production The porphYl'in-heme pathway is ubiquitous in biological sys of porphyrins or of inhibiting the photobiological re tems. Its activi ty is carefully regulated such that large amounts sponse to these photosensitizing chemicals in the skin. of the end-product heme are formed daily whereas pathway intermediates accumulate and are excreted only in trace amounts. It is currently thought that the bone marrow and the Each of the porphyrias represents the clinical expression of li ver are the major body compartments in which heme synthesis diseases that result from abnormalities in the control of heme occurs. Bone marrow heme is needed for daily erythrocyte syn thesis due to aberrations in the activities of enzymes in t he hemoglobin production and hepatic heme for a variety of heme heme pathway. Both inherited and acquired factors play major proteins with relatively rapid tumover. Since heme cannot be roles in the development of these diseases. The clinical mani reutilized a nd is broken down into linear tetrapyrroles that festation of the porphyrias appear to be due to the toxic eventuate in bilirubin production, the body must continuously properties of porphyrins and porphyrin precursors. In normal synthesize heme. Heme is required as a prosthetic group by individuals these biochemical intermediates are present only in various apoproteins such as globin and apo-cytoc!11'ome P-450. trace amounts and are therefore virtually innocuous. In patients As cellula]' heme binds to these proteins, heme levels diminish. with porphyria, the presence of excessive amounts of these This decrease in cellular heme leads to enhancement of heme chemicals results in pathologic changes that in tum account for synthesis until "normal" levels are restored. t he recognizable clinical featw-es of these diseases. The rate-limiting step for regulating hepatic heme synthesis Rational therapy of the porphyrias requires detailed knowl is the initial enzyme in the pathway, o-aminolevulinic acid edge of porphyrin-heme biosynthesis a nd the genetic and en synthetase (ALAS) (Fig 1) [1]. There are everallines of exper vironmental factors that influence the activity of this pathway. imental evidence that support the role of mitochondrial ALAS Ideal therapy of the porphyrias would restore a berrant enzyme in controlling the rate of heme synthesis. (1) The activity of activity to normal, thereby reducing the level of the potentially this enzyme is relatively low compared to that of the other toxic porphyrins and porphyrin precw-sors to normal. Unfor enzymes in the pathway. (2) The half-life of ALAS is relatively t unately this highly desirable therapeutic endpoint is currently short in mammalian liver (60-180 mins). This is considera bly not attainable. While it does appear possible to influence the less than that of many mitochondrial proteins which have half lives of 3-5 days. (3) Activity of the enzyme can be induced or This work was supported by U.S. Public Health1'ervice Grants ES- enhanced by certain types of drugs and other environmental 1900, OH-1l47 and by the Medical Research ServIce of the Veterans Administration. chemicals as well as selected endogenous substances, particu Reprint requests to: Dav id R. Bickers, M.D., Professor and Chair larly steroid hormones and their metabolites. This "enzyme man, Department of Dermatology, Case Western Reserve University, induction" permits the synthesis of larger amounts of heme Cleveland, Ohio. upon demand particularly for t he production of hepatic cyto Abbreviations: chl'Ome P-450, the heme-protein that is an important compo AlA: allylisopropylacetamide nent of t he microsomal enzyme system that functions in the ALA: c5 -aminolevulinic acid metabolism of drugs and exogenous chemicals. ALAS: c5-a minolevulinic acid synthetase The hepatocyte appears to be quite sensitive to heme levels: COPRO-O: coproporphyrinogen oxidase as heme falls the strLlctural gene coding for ALAS is dere EP: erythropoietic porphyria EPP: erythropoietic proto porphyria pressed. This results in an increased rate of synthesis of this HCP: hereditru'y coproporphyria protein. In response to enhanced ALAS activity cellular heme PBG: porphobilinogen increases. It is utilized for varioLls proteins and also functions PCT: porphyria cutanea tarda as a co-repressor by binding to a putative aporepressor protein PROTO: protoporphyrinogen which is capable of repressing the synthesis of ALAS (Fig 2). It PROTO-O: protoporphyrinogen ox idase is currently thought that only a relatively small fraction of RBC: red blood ce ll hepatocyte heme (which is not bound to apo-proteins) partici TCDD: tetrachlorodibenzo -p-d ioxin pates in this regulatory process (the so-called regulatory heme URO: uroporphyrin or free heme pool) . Certain dJ'ugs which are potent inducers of UROD: uroporphyrinogen decarboxylase UROS: Ul'oporphyrinogen synthetase hepatic ALAS may trigger this effect by competing with heme UROCOS: Ul'oporphyrinoge n cosy nthetase for binding to the aporepressor; fw-thermore, drugs with phar VI': vru'iegate porphyria macologic effects that result in reduced cellular heme levels will

107 108 BICKERS Vol. 77, No_ 1

MITOCHONDRION ------, Thus in the liver the activity of the heme pathway is la.rgely r------determined by ALAS which in turn is directly regulated b y , ~ heme levels within the cell. A variety of inherited or acquired fa ctors may influence heme levels and thus interfere with this SUCCINATE GL YCINE ! + I' normally efficient regulatory scheme. Although most experi I HOOC-CH2 -CH2 COOH. NH2 CH 2 COOH m ental evidence points to a repression-derepression mecha.nism , . for controlling hepatic ALAS activity, it is also possible that heme could directly inhibit the enzyme. However, the levels I,' 8 - Aminolevulinic acid i required for direct enzyme inhibition (_lO- fiM ) are unlikely to synthetase , occur in vivo. ', (ALAS), The regulation of heme synthesis in the bone marrow is poorly understood but in general ALAS does not appear to be i ! rate-limiting in this tissue. There is experimental evidence to , , indicate that the activity of several enzymes in the h em e ~ HOOC CH CH CCH, NH2 " pathway increases slightly with accelerated demand for bemo , 2 2 II , 0 I globin synthesis; furthermore, bone marrow heme pathway enzymes normally function at or near their peak levels and ~ 8 - AMINOLEVULINIC ACID , , (ALA) . cannot be further stimulated by drugs. Recent studies indicate I that in experimental systems, ferrochelatase may become the rate-limiting enzyme for heme synthesis in bone marrow [5]. L~-~-~------~----'l----~------_J8- Aminolevulinic acid Since the porphyrias are diseases due either to inherited COOH dehydratase abnormalities in heme pathway enzymes or to the effects of HOOC CH (ALAD) certain drugs and environmental chemicals on these enzymes, I I 2 specific treatment should be capable of correcting these aber H 2C CH 2 rations. Furthermore because cutaneous photosensitivity is a major manifestation of th e majority of the porphyrias, nonspe 1 PORPHOBILINOGEN cific treatment modalities which have no demonstrable effect upon a bnormal porphyrin-heme synthesis may nonetheless be H C (PSG) 2 beneficial to the patient. H2 N' N The porphyrias are basically of 2 types: hepatic and eryth 0H ropoietic. These are listed in Table I. Currently available treat FIG 1. o-aminolevulinic ac id synthetase (ALAS) is the rate-limiting ment for each of these will be discussed. enzyme for heme sy nthesis. TREATMENT OF THE PORPHYRIAS Acute Hepatic Porphyrias .9" " 0 REGULATOR OPERATOR STRUCTURAL The acute hepatic porphyrias include acute intermittent por \--_.. 8APO ' • • 8mRNA GENE GENE GENE phyria, variegate porphyria and hereditary coproporphyria. These disorders share 2 fundamental characteristics: (1) ele c. ~~:~ .., t vated hepatic ALAS and (2) deficient activity of specific en- \. -Feedback Repression Protem Syntt\9SIS _ \ on Ribosomes

FEEDBACK INHIBITION aLA r---f--- HEME • s : CYTOCHROME n l tll ''" 8• F."FI"Otlh .,.,... ~ OJ~ejn . P-450 PROTO SUI;CI!YI COA I Proleln • PROTO.O Synlh,Osls PROTOGEN ALA HEME t IoIl1 ochOlld,IOII 1 I CO'R O' O ~ '''' 0,"''", •• • n ALLYLISOPROPYLACETAMIDE " \ 1// / COPROGEN ill +--UROGEN ill +--PBG I URO- D URO- S + ....- URO- COS ------'» ---- '0 EMf:-_ /I/I}\\ FIG 2. Schematic for hypothetica l m'ec hanisms whereby heme syn 11 thesis is regulated. Heme may directly inhibit ALAS or may function APO-CYTOCHROME! p?GRJf~,s as a co-repressor to repress the synthesis of ALAS. !_ P-450 _ FIG 3. Some drugs may induce hepatic ALAS by dest.roying heme_ also derepress ALAS. This can occur either by enhancing the This cou ld depl ete the regula to ry heme poo l. destruction of existing heme (Fig 3) or by inhibiting the con ,version of protoporphyrin to heme (Fig 4) [2,3]. It is importa nt to emphasize that certain of the hepatic porphyrias, the acute hepatic porphyrias (acute intermittent ALA IFERROCHELATASE> HEME porphyria, variegate porphyria and hereditary coproporphyria), are each characterized by elevated hepatic ALAS activity [4). It is though t that deficient enzyme activity a~ one 01' a nother of the steps in the porphyrin-heme pathway leads. to a decrease in the regulatory or free heme pool. This in turn results in chronic ALA HEME overact.ivity (derepression) of hepatic ALAS in these patients. Hepatic ALAS may also be slightly increased in porphyria cutanea tarda perhaps due to defi cient activity of uroP0l'phYl' inogen decarboxylase (UROD) (inherited or acquil'ed), which FIG 4. Some drugs may induce hepatic ALAS by blocking h eme might also result in diminished heme levels in the liver cell. synthesis. This could deplete the reg ulatory heme pool. July 1981 TREATMENT OF PORPHYRIAS 109 zyme(s) in the heme pathway. As a result of these individual Carbohydrate Loading enzyme defects it has been proposed that regulatory heme It is known that the induction of hepatic ALAS in experi levels in the hepatocytes of these patients are low, thereby mental a nimals by certain drugs such as aUylisopropylacetam resulting in elevated ALAS activity [6]. Furthermore it appears ide (AlA) is lru'gely abolished by prior cal'bohydl'ate feeding of that th e regulation of h eme synthesis in these diseases is t he animal [14]. Furthermore, h epatic ALAS activity decreases abnormal such that there is a particulal' susceptibility to drugs in rats fed high doses of carbohydrate. These experimental like t he barbitUl'ates which evoke increased heme synthesis by observations provide a rationale for the use of high doses of a ugmenting hepatic cytochrome P-450. Following ingestion of carbohydrate in patients suffering from acute attacks of por such drugs a cycle of increased demand for heme is coupled phyria. Glucose (200-500 grams pel' day) administered orally or with the inability of the li ver cell to raise heme levels sufficiently intravenously may be required. A recent study suggested that high to restore the regulatory (free) heme pool to normal which the use of laevulose (20%) infusions may be helpful [15]. Careful would repress ALAS activity. monitoring of urinary ALA and PBG excretion in selected It is of historical interest that elevated ALAS activity was patients has shown a marked decrease after carbohydrate load t h e first enzyme abnormality identified in patients with acute ing suggesting that hepatic ALAS activity has decreased. intermittent porphyria [7,8]. S ubsequentiy, it was shown that The mechanism of the "glucose-effect" is unknown. It was t h ere was an inherited deficiency of uroporphyrinogen synthe fu'st thought that the elevated carbohydrate generated large tase (UROS) in patients with this disease and it is thought that amounts of catabolites that coul d nonspecifically repress pro t his results in diminished heme levels in the liver of these tein synth esis in cells. More recently it has been suggested that patients coupled with d e r e pre ss i ~ n of A~AS [~]. . high carbohydrate levels in the ceU may block messenger RNA It is cUl'rentiy thought that patients With variegate porphyn a or may interfere in some way with the induction effects of have increased hepatic ALAS and decreased ferrochelatase or steroid hormones on hepatic ALAS [1 6, 17]. protoporphyrinogen oxidase (PROTO-O) [10,11]. ~atients with hereditary co pro porphyria have increased hepatic ALAS and Hematin Infusions decreased copl'Oporphyrinogen oxidase (COPRO-O) [12]. In all The rationale for t he administration of heme li es in the 3 of t he acute hepatic porphyrias, t he deficient enzyme activity abili ty of this substance to both repress the synthesis of ALAS is inherited in an autosomal dominant pattern. Each of these and to directly inhibit the enzyme [18,19]. Hematin is prepared diseases is characterized by intermittent "attacks" of abdominal by crystallizing and recrystallizing hemin which is diss?lved In pain, autonomic dysfunction, n e urop~yc hi at ri c syml?toms, pe 0.25% NazCO: [20]. Watson et al ad mini tered hematm as an riph eral neuropathy and paresis. Variegate p.orphyn a and he 1 intravenous infusion in physiologic saline (3-5 mg/ kg) once or reditary coproporphyria are often accompamed by cutaneous twice daily. The compound is given in a bolus over 30- 60 min. p hotosensitivity. It is important to emphasize that a la.l·ge Prompt and dramatic recovery has been reported following number of drugs and steroid hormones a nd theu' metabohtes hematin infusions in 2 series of 20 a nd 11 patients [21 ,22]. ThIS appear capable of triggering "attacks" of these diseases (Table was accompa nied by a rapid decrease in urinary ALA and PBG. II). Studies have also shown that elevated leukocyte ALAS de The treatment of the acute hepatic porphyrias includes: (1) creased following hematin infusions [23]. This method of treat avoida nce of inducer drugs, (2) carbohydrate loading, and (3) ment appears to be effective by making heme accessible to liver hematin infusions. ceUs which results in repression and/ or inhibition of ALAS Avoidance of Inducer Drugs activity. It should be pointed out that hematin infusions are only Drugs which have been incriminated as capable of exacer effective in ameliorating the neuropsychiatric manifestations of bating the acute hepatic porphyrias ru'e listed in Table II: ~he the acute hepatic porphYl'ias. No evaluation of the efficacy of role of t hese agents has been deduced either from the chmcal this modality on the photocutaneous syndl'ome of VP and HCP o bservation of patients or from studies in experimental systems, is currently available. primaril y the chick embryo liver ceU culture sys~e m developed by Granick [13]. Avoidance of these drugs will reduce the POIphyria Cutanea T arda (PCT) number of acute attacks of porphyria in many though not all Porphyria cutanea tarda is a different form of hepatic por patients. This is simply preventive therapy. ~e r ta in . p~ti e n ts phyria in which acute attacks do not occur. This disease oCC Ul.'S will suffer repeated attacks of porphyria despite aVOIding ex primarily in middle-aged individuals (male == female) and IS posure to these agents. These may be due to horm?~al factor~, frequently associated with the ingestion of drugs, such as ~lco intercurrent infection, stru'vation, etc. Often a specIfiC etlOloglc hoI and estrogens or exposure to environmental chemicals, factor for an acute attack cannot be identified in the individual particulru'ly selected halogenated hydrocarbons. . . . patient. There now appeal' to be two major types ofPCT: (1) Inhen te.d and (2) acquired or sporadic. In the inherited ty~e, there IS defi cient activity of UROD [24]. This is transmitted as an TABLE I. The porphyrias a utosomal dominant trait a nd defici ent UROD activity has been detected in both the li ver a nd in red blood cells of t~ese E rythropoietic E rythl'opoietic porphyria E rythropoietic protoporphYl'ia patients. A second type of porphyria cutanea tarda, the acquu'ed H epatic Acute intermittent porphyria or sporadic type, is indistinguishable clinically from the 1I1her Vari egate porphyria ited type. However, deficient UROD activity may only be Hereditary coproporphyria detectable in the li ver of these patients [25]. Felsher, Norl'ls, Porphyria eu tanea tal·da and Shih have shown that UROD is deficient in the red blood cell s of patients with the sporadic type [26]. Th~ reason for these different findings could relate to differences 111 the meth TABLE II. Dmgs that may induce aCllte atlaclls o(polphyria odology used to meaSUl'e the enzyme. FUl'ther studies are cl.early Barbiturates Sulfo namides needed to explain t hese apparent differences In enzymatic ac- Methyprylone Dapsone tivities. . Meprobamate Griseofulvin T he role of alcohol, estrogens, hexachlorobenze ne a nd o~h ~ r Amidopyrene Sulfonylureas chlorinated hydrocarbons in the clinical expressIO n of PC r IS Glu tethimide Estrogens weU documented [27]. Furthermore, there is good evidence that Diphenylhydantoin E rgot preparations PCT is usually accompa ni ed by iron overload in the liver. ~he M esantoin mecha nism of the iron overload is unclear a nd the excesSIVe 110 BICKERS Vol. 77, No.1 hepatic iron may result in diminished activity of hepatic U)'O 16 porphyrinogen cosynthetase (UROCOS) and UROD [28,29]. T he former would explain the predominance of I-isomer por 1 phyrin excretion and the latter could explain the elevated URO 15 CLINICAL BIOCHEMICAL and 7-carboxyl porphyrins chamcteristic of the disease. Treatment of experimental animals with chlorinated hydro 14 carbons such as hexachlorobenzene and tetrachlorodibenzo-p dioxin (TCDD) causes inhibition of hepatic UROD after a latent period of several weeks [30]. Iron may also play a 13 permissive role in the inhibitory effect of selected halogenated hydrocarbons on hepatic UROD (Fig 5) [31]. In addition recent 12 studies indicate that iron-depleted mice are resistant to the porphyrinogenic effect of tetrachlorodibenzo-p-dioxin (TCDD) the most potent porphyrinogen yet identified [32]. These da ta 1 1 aU support a fundamental role for iron in the clinical and biochemical expression of PCT. Treatment measures for PCT 10 include: (1) avoidance of exposure to drugs and chemicals that eli cit the disease, (2) phlebotomy, (3) the antimala rial drugs, en I 9 chloroquine and hydroxychloroquine, (4) metabolic alkaliniza t- tion, and (5) i.ron chelation. Z The simple avoida nce of alcohol, estrogens and exposme to 0 8 chlorinated hydrocal'bons will result in clinical and biochemical ~ n = 33 n=29 remission of PCT. However, this usually requires years. 7 Phlebotomy is the treatment of choice for PCT. This modal ity was first shown to be effective in PCT by Ippen [33]. Numerous reports from throughout the world have subse 6 quently verified the effi cacy of this modality in PCT [34-36]. The rationale, though never proven directly, rests upon certain 5 critical observations: (1) hepatic siderosis frequently improves following phlebotomy therapy, and (2) readministration of iron 4 to phlebotomy-treated patients results in clinical and biochem ical exacerbation of the disease [37]. Phlebotomy therapy can be performed in the physician's 3 office. In general, it has been the experience of most investiga tors that the removal of 2 to 4 liters of blood is required. This 2 can be done at biweekly intervals (-500 ml per phlebotomy). The hemoglobin is monitored until it faU s to 10-11 gm%. This is quite variable in the individual patient and recently it has 1 been suggested that monitoringserum ferritin may be the best guide for assessing activity of the disease [38]. This observation requiTes confirmation. FIG 6. Clinical and biochemical remission of PCT foUowing phle The response of PCT to phlebotomy is usually highly satis botomy therapy is usually delayed. fa ctory in most patients. Clinical remission does not occur for 6-9 mos and biochemical remission may not be complete for 12-24 mo (Fig 6). The response to therapy varies in individual '" patients. As shown in Fig 7 and 8, a single coune of phlebotomy =- 3200 (/) z may bring about a long-term remission of the disease whereas 2600 a: t = PHLEBOT OMY repeated courses of phlebotomy may be required in selected >- J: (400- 500 ML a. WHOLE patients. In the latter situation careful evaluation may reveal cr 2400 BLOOD 0 REMOVED, that the patient has not adhered to avoidance of exposure to a. 2000 porphyrinogenic agents, particularly alcohol. Extensive clinical >- cr experience with phlebotomy indicates that this treatment is « ~ 1600 safe, well- tolerated and effective in the vast majority of patients cr with PCT. :::> cr 1400 Treatment with the antimalarial drugs chloroquine and hy :::> 0 dJ'oxychloroquine is a satisfactory alternative in selected pa J: 1000 cr ti ents with PCT. Chloroquine is an antimalarial agent that was :::> 0 initially thought to evoke acute attacks of porphyria, since its u. 600 >- >- z 200 w I!!ll HALOGENATED ...~ I I I IRON 3 6 9 12 16 24 30 36 4 2 46 54 60 66 72 HYDROCARBONS MONTHS FIG 7. The clinical response of PCT Lo phlebotomy may be rapid wiLh prolonged remission.

UROGEN administration was followed by "attacks" of nausea, vomiting, COPROGEN abdominal pain, and biochemical evidence of severe hepatocel FIG' 5. Iron is capable of enhancing Lhe inhibitory effect of chlori lular necrosis [39). It has subsequently been shown that chlo nated hydl"ocru'bons on UROD. roquine does not exacerbate acute hepatic porphyria; rather July 1981 TREATMENT OF PORPHYRIAS III 5000 Metabolic AlIwlinization This method of treating PCT is based upon the difference in pK of coproporphyrin and Ul'oporphyrin [46]. It has not been = PHLEBOTOMY uniformly successful and is not in current use, (400-500ML WHOLE BLOOD ~ 4000 REMOVED) Iron Chelation en While theoretically desirable, the use of iron chela tors has z not been satisfactory [47). The requirement for repeated painful a: injections of desferroxamine has greatly limited its use partic ~ :I: ularly since other highly effective modalities such as phlebo a.. tomy and the antinlalarial drugs are avail able, It is entirely g 3000 a.. possible t hat newly developed less toxic iron chelators could w offer an effective approach to the treatment of PCT. z a: Elylhl'Opoietic Porphyria (EP)-(Giinther's Disease) ::> a: This is a rare type of porphyria charactel'i zed by mutilating o::> 2000 cutaneous photosensitivity and abnormal porphyrin-heme syn :I: thesis in the bone marrow. This disease usually is ma nifest a: early in life as severe photosensitivity with red-stained fluores ::> o cent teeth (erytru'odontia) and reddish discoloration of the u.. urine. The photosensitivity is associated with hypertrichosis

~ combined with scarring. Repeated episodes of cutaneous pho I 1000 Z tosensitivity result in sclerotic changes in light-exposed skin W 800 that may resemble scleroderma. ~ I- 600 In addition to photosensitivity, many patients suffer from 400 hemolytic anemia. Circulating "erythroblasts" are rich in por 200 phyrins and therefore, highly fluorescent RBC's are detectable. WII HIij !!II The life span of the erytlU'ocyte is frequently shortened and i splenomegaly often develops. Whether the hemolytic a nemia is o 4 8 12 16 20 24 28 32 36 due to "photo-hemolysis" of circulating porphyrin-laden eryth MONTHS rocytes remains controversial [48]. FIG 8. The clinical response of pe l' to repeated CO Ul'ses of phlebo tomy is shown here. The enzymatic abnormality in EP is unclear. Romeo and Levin have shown that UROCOS activity is decreased to 1/ 3 to 1/ 10 of the normal level in pa ti ents with EP [49]. Others have t he drug causes a selective type of hepatotoxicity in PCT [40]. shown that there is a general increase in the activity of several This selective toxic effect is due to binding of the drug to the heme pathway enzym es in EP [50]. This has led to the hypoth elevated porphyrins in the hepatocyte forming a porphyrin esis that the primary control of heme biosynthesis in EP is at chloroquine complex [41]. This complex is highly water soluble the level of ALAS with a secondary control point at the level of and is rapidly "flu shed" from the li ver resulting in massive UROCOS. Further studies are needed to clarify the specific increases in urinary porphyrin excretion. It has also been sug enzyme defect(s) in EP. gested that the mechanism of chloroquine action for PCT is the The treatment of EP remains unsatisfactory. Splenectomy in drug associated removal of iJ'on [42]. Initially it was felt that patients with hemolytic anemia a nd splenomegaly is said to be t h e hepatotoxic reaction was necessary for the therapeutic helpful in diminishing hemolysis and thereby perhaps reducing effect. It is now clear however that low-doses of the drug (125 the circulating porphyrin load [51]. Chloroquine administration mg) administered intermittently (twice weekly) will bring about (125 mg twice weekly) has been advocated as a method to remission of the disease lasting months to years without hepa improve erytru'ocyte fragility and thereby diminish hemolysis totoxicity [43,44]. [52]. Shielding in light-opaque celluloid is said to reduce cuta The onset of remission of PCT induced by the antimalal'ial neous photosensitivity [53]. Hematin infusions have been uti drugs is generally similar to that evoked by phlebotomy, How lized with paJtial reduction of porphyrin production in a single ever, there is a dose-response relationship in that higher initial patient [54]. No long-term studies have been performed to doses of these drugs do result in a more rapid onset of clinical evaluate the usefulness of this modality. Metabolic' alkaliniza and biochemical remission, The length of remission may be tion was attempted in 2 patients without success [55]. shorter than that associated with phlebotomy. Malkinson and Levitt treated 6 patients with PCT using hydroxychloroquine Elythropoietic Protoporphyria (EPP) [45]. Initial doses were 100 mg 3 times weekly for 1 mo, then 200 mg 3 times weekly for 1 mo and then 200 mg daily, This is one of the more common types of porphyria and is Thereafter the daily dose was increased to 300 mg 01' 400 mg characteri zed by a milder form of cutaneous photosensitivity depending upon the clinical and biochemical response. Treat than that seen in EP. The disease usually begins in early ment periods ranged from 5 to 13 mo and both clinical and childhood and the primary complaint often is that of stinging, biochemical remission occurred. Four of 6 patients in remission burning and swelling of the skin during 01' shortly after sun followed for 9 to 24 mo had relapses. Three of the 4 were again exposure [56]. Repeated episodes result in wax-like lineal' SCal'S retreated with hydroxychloroquine and again improved or went on the bridge of the nose a nd on the bony prominences of the into remission, It was concluded that prolonged remissions may hands. Histopathologic examination of the skin from these not OCCUI' in PCT patients treated with the antimalarial drugs, areas shows massive amounts of PAS-positive material in and It is important to emphasize, however, that these patients were around the vessels of the upper dermis. In most patients cuta not instructed to discontinue alcohol ingestion, neous photosensitivity is the sole clinical manifestation of the It has also been suggested that the combination of phlebo disease [56]. tomy and chloroquine is effective in PCT and that phlebotomy Cholelithiasis occurs more frequently than in the normal prior to chloroquine administration reduces the risk of hepa population and the stones are rich in PROTO [57]. A minority totoxicity of the latter [46]. of patients have developed liver disease which may progress 112 B ICKERS Vol. 77, NO.1 inexorably to terminal hepatic failme [58]. The mechanism of REFERENCES this fatal complication is unclear. 1. Granick S, Sassa S: 8-a minolevulinic acid synthetase a nd the con Defective activity of ferrochelatase has been identified in trol of heme and chlorophyll synthesis, Metabolic Regulation. bone marrow, liver, cultured skin fibroblasts, nucleated red cells Edited by HJ Vogel. New York, Academic Press, 1971, pp 77-141 2. DeMatteis F: DistUJ'bances of liver porphyrin metabolism caused and mitogen stimulated lymphocytes of patients with EPP by drugs. P hal'macol Rev 19:523- 557, 1967 [59]. 3. DeMatteis F, Stonru·d M: Experimental porphyrias as models for It is important to point out that elevated erytlu'ocyte PROTO human hepatic porphyria. Sem Hemat 14 : 187-1 92, 1977 is not unique to EPP. In both lead poisoning and in severe iron 4. Brodie MJ, Moore MR, Goldberg A: E nzyme abnormalities in t h e porphyrias. Lancet 11:699-671, 1977 deficiency anemia, elevated levels of PROTO also occur and yet 5. Rutherford T, Thompson GG, Moore MR: Heme biosynthesis in no cutaneous photosensitivity develops. This has been ex Friend erythroleukemia cells: Control by ferrochelatase. PNAS plained by chemical differences in the PROTO in EPP as 76:833-836, 1979 compared to that in lead poisoning and iron-defi ciency anemia 6. Strand LJ, Mru'ver H: Determination of I>-am inolevulinic acid syn thetase (ALA-S) in cell culture: Naturally occurring inducers in [60]. In the latter 2 disorders, the excessive RBC PROTO is normal human plasma. Clin Res 18:345, 1970 chelated with zinc and is apparently unable to diffuse out of 7. Tschudy DP, Valsamis M , Magnussen CR: Acute in termittent the red cell. In EPP, the excessive PROTO is unchelated or porphyria: Clinical and selected research aspects. Ann Int M ed free a nd is capable of diffusing from the red cell into the plasma 83:85J -864, 1975 8. Nakao K, Wada 0 , Kitamuru T, et al: Activity of aminolaevulinic and ultimately into cutaneous tissue where it can absorb solar acid synthetase in normal and porphyrin human livers. Natw'e energy a nd resul t in cuta neous photosensitivity. 210:838-839, 1966 T he treatment of EPP centers about management of the 9. Bonkowsky HL, Sincla i.r PR, S inclair JF: Hepatic heme metabolism cutaneous photosensitivity and the hepatic failme that may and its control. Yale J BioI Med 52:13-37, 1979 JO. Becker DM, Viljoen JD, Katz J , et a l: Reduced ferrochelatase occur in a small number of patients with this disease. The single activity: A defect common to porphyria variegata and protopor effective treatment currently avail able for the cutaneous pho phyria. Br J Haematol 36:171-179, 1977 tosensitivity in EPP is beta-carotene. 11. Brenner DA, Bloomer JR: The enzyme defect in variegate porphy Orally administered beta-carotene has improved cutaneous ri a. New Engl J Med 302:765-769,1980 12. Brodie MJ, Thompson GG, Moore MR, et al: Hereditru'y copro photosensitivity in 84% of 133 patients [61]. T his was assessed porphyria: Demonstration of the abnormali ties in haem biosyn by determining the a bility of patients to tolerate sun exposure thesis in peripheral blood. Quart J Med 46:229- 241, 1977 before and after treatment with beta-carotene. The drug is 13. Granick S : The induction in vitro of the synthesis of 8-aminolevu available in 30 mg capsules (Solatene) which are usually ad linic acid synthetase in chemical porphyria. A response to certain drugs, sex hormones and foreign chemicals. J Bioi Chem 241: ministered in doses of 60 to 180 mg/day. Toxic reactions have 1359-1375, 1966 been limited to transient loose stools a nd to carotenodermia, a 14. Tschudy DP, Well and FH, Collins A, et al: The effect of cru'bohy yellow-orange discoloration of the skin due to cutaneous depo mate feeding on the induction of 8-aminolevulinic acid syn th e sition of the drug. tase. Metabolism 13:396-406, 1964 15. Brodie MJ, Moore MR, Thompson GG, et al: The treatment of The mechanism of action of beta-carotene in EPP is contro acute intermittent porphyria with laevulose. Clin Sci Mol M ed versial. Photo-excited PROTO is in the triplet state and may 53:364-371, 1977 destroy cellular components directly or react with oxygen to 16. Goldberg ML: The glucose effect: Cru'bohydrate repression of en form singlet oxygen wruch can oxidize lipid-rich membranes in zyme induction, RNA synthesis and glucocorticoid activity. A role for cyclic AMP and cyclic GMP. Life Sci 17:1747-1754, 1974 the cell. This in turn could result in the release of lysosomal 17. Brodie MJ, Goldberg A: Acute hepatic porphyrias. Clin H aemat 9: hydrolases that would produce. tissue damage. Beta-carotene is 253- 272, 1980 known to quench free radicals and singlet oxygen [62]. Whether 18. Bonkowsky HL, Tschudy DP, Collins A, et a l: Repression of th e these effects have a ny relationship to the clinical improvement overproduction of porphyrin precursors in acute intermitten t of photosensitivity seen in most patients with EPP is unknown. porphyria by intravenous infusions of hematin. PNAS 68:2725_ 2729,1971 It is of interest that beta-carotene apparently does not reduce 19. Watson CJ, Dhar GJ, Bossenmaier I, et al: Effect of hematin in the erythrocyte PROTO levels in EPP. In fact it has been acute porphyria relapse. Ann Int Med 79:80-83, 1973 shown that RBC PROTO actually increases slightly in patients 20. Dhar GJ, Bossenmaier I, Petryka ZJ: Effects of hematin in hepatic receiving beta-carotene [63]. The drug is known to protect porphyria. Further studies. Ann lnt Med 83:20-30, 1975 21. Watson CJ, Pierach CA, Bossenmaier I, et al: Use of hematin in against erythrocyte lysis by PROTO in vitro [64]. It is also the acute attack of the "inducible" hepatic porphyd as. Adv Int possible that leakage of PROTO may be prevented by beta M ed 23:265- 286, 1978 carotene. This migh t result in less diffusion of RBC PROTO 22. Lamon JM, Frykhold BC, Hess RA et a l: H ematin therapy for into the ski.n, thereby reducing the severity of th e cutaneous acute porphyria. Medicine 58:252-269, 1979 23. McCall KEL, Moore MR, T hompson GT : Hematin therapy and photosensitivity. It should be pointed out that one clinical study leucocyte 8-aminolevulinic acid synthase activity in prolonged concluded that beta-cal'otene was ineffective in preventing pho- attack of acute porphyria. Lancet 1:133-134, 1979 tosensitivity in EPP [65). . 24 . Benedetto AV, Kushner J P , Taylor J S: Porphyria cutanea tru'da in At least 15 cases of terminal hepatic failme in patients with three generations of the same family. New Engl J Med 298:358- 362, 1978 EPP have been reported [59). The liver disease is characterized 25. E lder GH, Lee GB, Tovey JA: Decreased activity of hepatic w'o by direct hyperbilirubinemia and mild-to-moderate increases in porphyrinogen decru'boxylase in sporadic porphyria cutanea transaminase and alkaline phosphatase. Liver biopsy demon tru·da. New Engl J Med 299:274-278, 1978 strates ci.rrhosis with massive deposits of dark brown pigment 26. Felsher BF, Norris ME, S hih JC: Red-cell ul'o porphyrinogen de carboxylase activity in porphyria cutanea tarda and other forms which may be precipitated PROTO. of porphyria. New Engl J Med 299:1095-1098, 1978 The treatment of hepatic disease in EPP is directed at 27. Smith AG, DeMatteis F: Drugs and the hepatic porphyrias. Clin , depleting the excessive PROTO stores in the liver by interrupt . Haemat 9:399- 425, 1980 ing the enterohepatic circulation of the porphyrin. Cholestyra 28. Kushner JP, Lee GR, Nacht S: The role of iron in the pathogenesis of porphyria cutanea tarda. An in vitro model. J Clin Invest 51: mine, a nonabsorbed binder of anions, has been used for this 3044-3051, 1972 pmpose. One patient was treated with cholestyramine (12 gm/ 29. Kushner JP, SteinmuLler DP, Lee GR: The role of u'on in th e day in divided doses) and the antioxidant vij;amin E (100 units pathogenesis of porphyria cutanea tru·da. II. Inhibition of uro daily) [59]. Over a period of 11 mos plasm a PROTO decreased porphyrinogen decarboxylase. J Clin Invest 56:661-667, 1975 30. Elder GH, Evans JO, Matlin SA: The efi'ect of the porphyrogenic and liver function tests returned to normal. Liver biopsy also compound, hexachlorobenzene, on the activity of hepatic UJ'opor showed a reduction in cellular necrosis and inflammalion phyrinogen decru'boxylase in the rat. Clin Sci Mol M ed 51:71-80, though cirrhosis persisted. Pigment deposition also diminished. 1976 This treatment should be attempted in additional patients. 31. S inclair P, Granick S: Uroporphyrin formation induced by chlori nated hydrocarbon (linda ne, polychlorinated biphenyls, tetrach loro-p-dioxin) Requirements for endogeneous u'on, protein syn T he author acknowledges the help of Ms. Betty Hickle and Ms. thesis and drug metabolizing activity. BBRC 61:124- 133, 1974 Karen Motuza who typed the manuscript. 32. Sweeney GD. J ones KG, Cole FM. et al: Iron deficiency prevents July 1981 TREATMENT OF PORPHYRIAS 113

liver toxicity of 2,3,7,8-tetrachloro-p-dioxin. Science 204 :332-335, 49. Ippen H, Fuchs T: Congenital porphyri a. Clin Haemat 9: 323-344, 1979 1980 33. Ippen H: Allgemein symptome der spiiten haut porphyrie (porphy 50. Romeo G, Levin EY: Uroporphyrinogen III-Cosynthetase in hu ria cutanea tarda ) als hinweise fijr deren behandlung. Deutsche man congenital erythropoietic porphyria. PNAS 63:856- 863, 1969 Med Wochschrift 86:1 27-133, 1961 51. Miyagi K, Petryka ZJ, Bossenmaier I. et al: T he activities of 34. Epstein JH, Redeker AG: Porphyria cutanea tru·da. A study of the w'oporphyrinogen-synthetase and cosynthetase in congenital effect of phlebotomy. New Engl J Med 279:1 301-1304, 1968 erythropoietic porphyria (EP). Am J Hematol 1:3- 21, 1976 35. Ramsay CA, M agnus lA, Turnbull A: The treatment of porphyria 52. Magnus IA: Cutaneous porphyria. Clin Haemat 9:273-302, 1980 cutanea tarda by venesection. Quru·t J Med 43:1 -24, 1974 53. lppen H , T illman K, Seubert S: Porphyria erythropoietica 36. Grossman ME, Bickers DR, Poh-Fitzpatrick MB et al: Porphyria (Gunther) and chloroquine. Klin Wochens 56:623-624, 1978 cutanea tru·da. Clinical features and laboratory findings in 40 54. Eriksen L, Hofstad F, Seip M: Congeni tal erythropoietic porphyria. pat ients. Am J Med 67:277- 286, 1979 The effect of light shielding. Acta Paed Scand 62:385-390, 1973 37. Lundvall 0: The effect of replenishment of iron stores after phle 55. Watson CJ , Bossenmaier I, Cardinal R, et a l: Repression by hematin botomy therapy in porphyria cuta nea tarda. Acta Med Scand of porphYl'in biosynthesis in erythrocyte precursors in conge nita l 189:51-63, 1971 erythropoietic porphyria. PNAS 71:278-282, 1974 38. Sweeney GD, J ones KG: Porphyria cutanea tru'da: clinical a nd 56. Stretcher GS: Erythropoietic porphyria (two cases and the results laboratory featW'es. Canad Med Assoc J 120:803-807, 1979 of metabolic alkalinization). Arch Dermatol 11 3: 1553-1557, 1977 39. London ID: Porphyria cutanea tru'da: report of a case successfully 57. DeLeo VA, Poh-Fitzpatrick MB, Mathews-Roth MM, et al: E ryth treated with chloroquine. Arch Dermatol 75:801-803, 1957 ropoietic protoporphyria. 10 years experience. Am J Med 60:8- 40. Felsher BF, Redeker AG: Effects of chloroquine on hepatic uro 22, 1976 porphyrin metabolism in patients with porphyria cutanea tarda. 58. Cripps DJ, Scheuer PJ: Hepatobiliary changes in erythropoietic Medicine 45:575-583, 1966 protoporphyria. Arch Pathol 80:500-508, 1965 41. Scholnick PL, Epstein J , Mru'Ver HS: The moleculru' basis of the 59. Bloomel' JR, P hillips MJ, Davidson DL, et a l: Hepatic disease in action of chloroquine in porphyria cutanea tru·da. J Invest Der erythropoietic protoporphyri a. Am J Med 58:869-882, 1975 matol 61: 226-232, 1973 60. Bloomer JR: Pathogenesis and therapy of liver disease in proto 42. Taljaard JJF, S hanley BC, Stewru·t-Wynne, EG, et a l: Studies on porphyria. Ya le J Bioi Med 52:39- 48, 1979 low-dose chloroquine therapy and the action of chloroquine in 61. LaMola AA , P iomelli S, Poh-Fitzpatrick MB, et a l: Erythropoietic symptomatic porphyria. Br J Dermatol 87:261- 269, 1972 protoporphyria and lead in toxication: the moleculru' basis for 43. Kordac V, Semnidova M: Treatment of porphyria cutanea tarda difference in cutaneous photosensitivity. J Clin Invest 56: 1528- with chloroquine. Br J Dermatol 90:95-100, 1974 1535, 1975 44. Kordac V, Papezova R , Semradova M: Chloroquine in the treat 62. Mathews-Roth MM: Erythropoietic protoporphyri a - diagnosis and ment of porphyria cutanea tru·da. New Engl J Med 296:949, 1977 treatment. New Engl J Med 297:98-100, 1977 45. Malkinson FD, Levit L: HydroxychloroQuine treatment of porphy 63. Foote CS, Denny RW: Chemistry of singlet oxygen. VII. Quenching ria cutanea tru·da. Arch DermatoI1l6:1147-1150, 1980 by beta-cru·otene. JAm Chem Soc 90:6233- 6235,1968 46. Swan beck G, Wennersten G: Treatment of porphyria cutanea tarda 64. Miao LL, Mathews-Roth MM, Poh-Fitzpatrick MB: Beta-carotene with chloroquine and phlebotomy. Br J Dermatol 97:77-81, 1977 treatment and erythrocytic protoporphyrin levels. Arch Derma 4 7. Perry HO, Mullanax MG, Wiegand SE: Meta bolic alkalinization tol 115:818, 1979 therapy in porphyria cutanea tru·da. Arch Dermatol 102:359- 367, 65. Swanbeck G, Wennersten G: Effect of beta-carotene on photohem 1970 olys is. Acta Derm Venera l 53:282-289, 1973 48. Donald GF, Hunter GA, Roman W: Current concepts of cutaneous 66. Corbett MF, Herxheimer A, Magnus IA: The long-term treatment porphyria and its treatment with particular reference to the use with beta-carotene in erythropoietic protoporphyria. A con of sodium calciumedetate. Br J Dermatol 82:70-75, 1970 troll ed tria l. Br J Dermatol 97:653-658, 1977