Concise Review for Primary-Care Physicians

Concise Review for Primary-Care Physicians Acute Porphyrias: Diagnosis and Management AYALEW TEFFERI, M.D., JOSEPH P. COLGAN, M.D., AND LAWRENCE A. SOLBERG, JR., M.D. To summarize recent information about acute porphyrias and to provide clinicians with a practical diagnostic and management approach, we reviewed the pertinent literature and our clinical experience. The acute porphyrias are characterized by recurrent attacks of abdominal pain with or without additional manifestations of autonomie dysfunction or neuropsychiatrie symptoms. On the basis of the potential of these disorders to affect the skin, they are further subdivided into neuroporphyrias and neurocutaneous porphyrias. During acute attacks, acute porphyria is always associated with increased levels of urinary porphyrin precursors. Between attacks, patients with neurocutaneous porphyrias may have normal urinary porphyrins; therefore, stool porphyrins, which are invariably increased, are the most helpful. Latent disease can be detected by the measurement of either urinary and stool porphyrins or cellular enzyme activity. Specific intravenous therapy with hematin has resulted in biochemical remissions, but its clinical benefit remains controversial. Measurement of urinary and stool porphyrins or porphyrin precursors is critical for the diagnosis of clinically overt acute porphyria. Enzyme assays are helpful in supporting the diagnosis but are best used to identify family members with latent disease. Preventive measures and supportive therapy are the mainstays of current management of patients with porphyria. (Mayo Clin Proc 1994; 69:991-995) AIP = acute intermittent porphyria; ALA = δ-aminolevulinic acid; HCP = hereditary coproporphyria; PBG = porphobilinogen; PP = plumboporphyria; VP = variegate porphyria The porphyrias, which are inherited enzyme disorders, affect the biosynthesis of heme and result in accumulation of excessive porphyrins or porphyrin precursors. Most of these disorders are inherited as autosomal dominant traits; however, disease penetrance is low, and most carriers of the genetic abnormality have latent porphyria and are clinically asymptomatic.1 Patients who are carriers of the genetic defect may be identified by measuring the defective enzyme activity in blood cells or by quantifying porphyrins in urine or stool specimens. Clinicians should be aware that carriers of the genetic defect do not necessarily have clinically overt disease; in patients with latent porphyria, substantial excretion of porphyrins or decreased cellular enzyme activity may be noted. Symptoms and signs of porphyria, however, are always associated with increased excretion of porphyrins or porphyrin precursors. Therefore, even in the presence of reduced cellular enzyme activity, a disease manifestation cannot be attributed to porphyria unless urine or stool porphyrins are concurrently increased. From the Division of Hematology and Internal Medicine (A.T., J.P.C.), Mayo Clinic Rochester, Rochester, Minnesota; and Division of Hematology/Oncology (L.A.S.), Mayo Clinic Jacksonville, Jacksonville, Florida. Address reprint requests to Dr. Ayalew Tefferi, Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. HEME BIOSYNTHESIS The porphyrins are molecules produced along the heme biosynthetic pathway. Heme, which consists of protoporphyrin IX (the finished porphyrin product) and iron, is a functionally important component of hemoglobin, myoglobin, and heme-requiring enzymes such as the cytochrome P-450 oxidase system. Consequently, protoporphyrin biosynthesis is most pronounced in erythrocytes and hepatic cells. Protoporphyrin biosynthesis begins in the mitochondria, where glycine and succinylcoenzyme A condense to form δ- aminolevulinic acid (ALA) (catalyzed by ALA synthase). In the liver, this is the rate-limiting reaction of heme synthesis, and ALA synthase is negatively regulated by heme; in contrast, erythroid-specific ALA synthase is neither rate-limiting nor negatively regulated by heme. The subsequent steps in heme biosynthesis occur in the cytoplasm. Two ALA molecules condense to form the monopyrrole ring, porphobilinogen (PBG) (catalyzed by ALA dehydratase). Four molecules of PBG join to form an intermediary linear tetrapyrrole product called hydroxymethylbilane (catalyzed by PBG deaminase). Hydroxymethylbilane cyclizes into either uroporphyrinogen I (a spontaneous nonenzymatic reaction) or uroporphyrinogen III (catalyzed by uroporphyrinogen III synthase). Uroporphyrinogen III is converted to coproporphyrinogen III (catalyzed by uroporphyrinogen decarboxylase). Mayo Clin Proc 1994; 69:991-995 991 1994 Mayo Foundation for Medical Education and Research

992 ACUTE PORPHYRIAS Mayo Clin Proc, October 1994, Vol 69 Coproporphyrinogen III reenters the mitochondria and is converted to protoporphyrinogen IX (catalyzed by coproporphyrinogen oxidase). Protoporphyrinogen IX is then oxidized to protoporphyrin IX (catalyzed by protoporphyrinogen oxidase). The final step is the production of heme by the insertion of an iron atom in the center of the protoporphyrin IX ring (catalyzed by ferrochelatase). TYPES OF PORPHYRIAS An enzymatic defect, usually inherited, in any of the aforementioned biosynthetic steps causes excessive accumulation of the substrate porphyrin molecule and thus porphyria. An association exists between the particular disease manifestations and the type of porphyrins accumulated. In clinically overt acute porphyria, the excess is in the early precursor molecules (ALA and PBG), and affected patients will have neurologic manifestations (abdominal pain, vomiting, constipation, seizures, psychosis, peripheral neuropathy, autonomie dysfunction, retention of fluids, tachycardia, hypertension, and sweating). If the excessive porphyrins are the distal substrates (uroporphyrins, coproporphyrins, or protoporphyrins), cutaneous manifestations (such as photosensitivity, skin fragility, facial hypertrichosis, and hyperpigmentation) will be noted. With an excess of both early and distal porphyrin molecules, the manifestations will include both neurologic and cutaneous signs and symptoms. Thus, the porphyrias can be classified by their potential to involve the nervous system, the skin, or both. The cutaneous porphyrias, which produce prominent skin manifestations, are porphyria cutanea tarda, congenital erythropoietic porphyria, and erythropoietic protoporphyria. The neuroporphyrias acute intermittent porphyria (AIP) and plumboporphyria (PP) cause purely neurologic manifestations. The neurocutaneous porphyrias, in which both the skin and the nervous system may be involved, are hereditary coproporphyria (HCP) and variegate porphyria (VP). Although most porphyrias are autosomal dominant, notable exceptions are PP and congenital erythropoietic porphyria, which are autosomal recessive. In addition, homozygote variants of HCP and porphyria cutanea tarda have been described. The acute porphyrias, a group of porphyric disorders characterized by acute and recurrent neurologic attacks, include both the neuroporphyrias (AIP and PP) and the neurocutaneous porphyrias (HCP and VP). Although the pathogenesis of the associated manifestations is unknown, increased urinary excretion of ALA, PBG, or both seems to be an invariable finding. The accumulation of these early porphyrin precursors is caused by decreased activity of PBG deaminase or ALA dehydratase. In the neuroporphyrias, the decreased activity results from a hereditary enzyme deficiency. In the neurocutaneous porphyrias, the decreased PBG deaminase activity is attributable to allosteric inhibition, by excess protoporphyrinogens and coproporphyrinogens, of PBG deaminase. 2 Neuroporphyrias. In patients with AIP, the partially defective enzyme is PBG deaminase, and the substrate molecule (PBG) and its immediate precursor (ALA) accumulate. Exogenous (alcohol, drugs, and hormones) or endogenous (infection and starvation) stimuli that induce ALA synthase and result in overproduction of ALA can precipitate acute attacks, whereas glucose prevents induction of the enzyme and may ameliorate symptoms ("glucose effect") The urinary excretion of these precursors is always very high during attacks and lower but not normal between attacks. 3 4 Of importance, in most patients with such a defective gene, the disease does not manifest (that is, they have latent porphyria). 1 5 These patients do have biochemical evidence of disease (decreased PBG deaminase activity and normal or increased urinary porphyrins or porphyrin precursors). When clinical disease is present, the manifestations include recurrent autonomie dysfunction, which is expressed as abdominal pain, nausea or vomiting, constipation, tachycardia, and hypertension. Unusual manifestations include the syndrome of inappropriate production of antidiuretic hormone, fever, leukocytosis, paresis of the extremities, and peripheral edema. The diagnosis of the second type of neuroporphyria PP (ALA dehydratase deficiency) is suggested by a pronounced increase in urinary ALA and decreased erythrocyte ALA dehydratase activity. This disorder is rare (only four cases have been reported thus far), 6 and the biochemical manifestations are similar to those attributable to lead intoxication (lead inhibits ALA dehydratase) or hereditary tyrosinemia (succinylacetone excess inhibits ALA dehydratase). Neurocutaneous Porphyrias. Two types of porphyria HCP and VP demonstrate both cutaneous and neurologic manifestations. In both these disorders, the terminal inadequacy of heme synthesis deprives the negative feedback with ALA synthase and results in overproduction of precursors; thus, neurologic symptoms and laboratory findings consistent with AIP eventuate. Unlike patients with AIP, however, those with clinically manifested HCP or VP may have normal urinary PBG and ALA levels during asymptomatic periods. In these patients, stool porphyrins are almost always increased. In VP, a deficiency of proto-oxidase activity leads to accumulation of protoporphyrinogen and protoporphyrin (produced by nonenzymatic oxidation of protoporphyrinogen) in bile and feces. VP can coexist with porphyria cutanea tarda (dual porphyria) or AIP (ehester porphyria). The diagnosis is suggested by persistent increases in fecal

Mayo Clin Proc, October 1994, Vol 69 ACUTE PORPHYRIAS 993 protoporphyrins and coproporphyrins and increases in urinary ALA and PBG during acute attacks. In HCP, the defective enzyme is copro-oxidase, and coproporphyrin accumulates primarily in the stool but also in the urine. Copro-oxidase levels are typically 50% of normal and may be as low as 2% in the rare homozygous condition. A variant of homozygous HCP (harderoporphyria) is characterized by increased excretion of harderoporphyrins in the stool. DIAGNOSIS Clinical In patients with unexplained recurrent abdominal pain or recurrent sensorimotor neuropathy with or without associated psychiatric or other neurologic manifestations, the diagnosis of neuroporphyria (AIP or PP) or of neurocutaneous porphyria (HCP or VP) should be considered. The acute attacks are transient but can persist for several days. Therefore, brief episodes (with a duration of less than 1 day) or prolonged and nontransient symptoms are unlikely to be porphyria. Neurologic manifestations can sometimes mimic Guillain-Barré syndrome. Results of analysis of cerebrospinal fluid, however, are usually normal. Useful historical facts include family history, relationship of symptoms to intake of alcohol or drugs, history of photosensitivity, and age at occurrence of initial manifestations. The dominantly inherited variants usually manifest after puberty and earlier in female than male patients. 4 A history of discoloration of the urine is also useful information. Urine that contains large amounts of PBG will darken on standing because of the auto-oxidative conversion of PBG into porphobilin. In contrast, the presence of excessive porphyrins causes red discoloration of the urine. Although skin involvement- is suggestive of the diagnosis of neurocutaneous porphyria, this finding is not always present. 7 8 Laboratory. The laboratory diagnosis of the porphyrias depends primarily on the measurement of porphyrins or their precursors in urine or stool specimens. Remembering that porphyrin intermediates in the first half of the heme biosynthetic pathway (PBG, ALA, and uroporphyrin) are water soluble and fat insoluble is useful. Thus, excessive excretions should be sought in the urine and not in the stool. In contrast, the porphyrin intermediates in the terminal half of the biosynthetic pathway (coproporphyrin and protoporphyrin) are fat soluble and are excreted, through the bile, in the stool. Because coproporphyrin retains some water solubility, it is also excreted in the urine. The second-line test in the evaluation of porphyrias is the measurement of enzyme activity in erythrocytes (when the enzymes involved are cytoplasmic) or nucleated cells such as lymphocytes (when the enzymes involved are in the mitochondria). As previously mentioned, the demonstration of decreased cellular enzyme activity proves the presence of the genetic defect but does not necessarily indicate that the symptoms and signs in a specific patient are attributable to porphyria. For implication of porphyria as the cause of observed neurologic symptoms, urinary ALA or PBG (or both) must be concurrently increased. The enzyme assays are best used for identifying asymptomatic family members whose quantitative porphyrin excretions may be normal. Because acute attacks of porphyria are always associated with substantial increases in ALA, PBG, or both, the essential diagnostic finding is values for these porphyrin intermediates during acute attacks that are more than twice the normal levels. Otherwise, the patient's symptoms cannot be attributed to neuroporphyria or neurocutaneous porphyria. Between attacks, the levels remain abnormal in neuroporphyria but may decline to the normal range in neurocutaneous porphyria. 3 4 7-8 For detection of increased levels of PBG, two qualitative screening tests are available the Watson-Schwartz test and the Hoesch test. These studies are based on formation of red pigment when PBG in the urine reacts with Ehrlich's reagent in an acidified solution. These tests, however, are not totally specific, and because of their dependence on high PBG concentrations, they usually yield negative results between attacks. 7 Therefore, quantitative tests should always be done. Methods used to distinguish and quantify urinary and stool porphyrins include high-performance liquid chromatography, solvent extraction, and thin-layer chromatography. Quantitative measurements of PBG are based on ionexchange chromatography. Prominently increased ALA suggests PP, and the diagnosis is supported by the demonstration of decreased ALA dehydratase activity in erythrocytes. This neuroporphyria is also associated with increased urinary coproporphyrin. In AIP, urinary PBG (and occasionally ALA) is increased; the demonstration of diminished erythrocyte PBG deaminase activity strengthens the diagnosis. Because the enzymatic defect may affect only hepatic cells, the finding of normal erythrocyte PBG deaminase activity does not exclude AIP. 1 9 In both neuroporphyrias (AIP and PP), the stool porphyrins are normal. In contrast, stool porphyrins are always increased in neurocutaneous porphyria (both during and between attacks). 7 8 In VP, the preponderant stool porphyrin is protoporphyrin, but coproporphyrin is also increased. 7 HCP is characterized by massive fecal excretion of coproporphyrin and only traces of protoporphyrin. 8 The urinary porphyrin profile (excluding porphyrin precursors) is seldom useful for either diagnosis of or distinction among the acute porphyrias. In AIP, uroporphyrin may be increased because of nonenzymatic polymerization of

994 ACUTE PORPHYRIAS Mayo Clin Proc, October 1994, Vol 69 PBG into uroporphyrin. Although substantial coproporphyrinuria is consistent with HCP, this finding lacks specificity, and levels may be normal between attacks. In VP, porphyrin excretion is variable and, similar to HCP, may not be increased during remission. Increases in urinary porphyrins have been noted in several nonporphyric disorders, including lead poisoning (coproporphyrinuria and ALA excretion), liver disease (coproporphyrinuria and uroporphyrinuria), and chronic renal failure during hemodialysis (uroporphyrinuria). In these disorders, stool porphyrins are usually normal. MANAGEMENT The first step for managing the acute porphyrias is confirming the diagnosis. In all affected patients, 24-hour measurements of urinary and stool porphyrins should be done during acute attacks. Between attacks, evaluation should always include measurement of stool porphyrins. As emphasized earlier, the demonstration of decreased cellular enzyme activity, by itself, is insufficient evidence for implication of porphyria as the cause of symptoms. Once the diagnosis has been confirmed, the next step is to ensure appropriate family screening and family counseling. Family members who have no biochemical and enzymatic evidence of disease should be reassured that both they and their offspring have a minimal risk for development of the disease. In contrast, in family members with either latent or overt disease, a 50% possibility exists for occurrence of the genetic defect in their offspring. The risk of subsequent occurrence of acute attacks in patients with latent porphyria is low (less than 10%). 3 Therefore, we do not recommend overzealous restriction of possible "porphyrogenic factors" in family members with latent porphyria. Prevention. The management of specific patients with clinically overt porphyria should begin with a discussion of preventive measures. The patient should wear a warning bracelet and carry a list of medications considered safe and unsafe in porphyria. Precipitation of acute attacks has been associated with starvation, dehydration, infection, menstrual cycles, consumption of alcohol, and administration of several medications. 3 4 Therefore, maintenance of adequate intake of carbohydrates and fluids and avoidance of porphyrogenic drugs are advisable. Most drugs considered unsafe, however, have been implicated on the basis of theoretical risks because of their potential to induce ALA synthase or the cytochrome P-450 system. Few systematic clinical studies have evaluated the actual risks associated with porphyrogenic drugs. 3 4 10 The evidence incriminating barbiturates, sulfonamides, and excessive use of alcohol is sufficiently strong to recommend strict avoidance of these factors. 3 410 The overall clinical risk associated with other drugs is not well established; the best approach might be careful individualized assessment rather than indiscriminate restrictions. 3 In general, pregnancy does not seem to impose a major risk of precipitating acute attacks and should not be contraindicated in patients with acute porphyria. 3 4 Similarly, despite the high frequency of cyclic symptoms in menstruating women, the use of oral contraceptive pills or other sex hormone preparations is seldom associated with symptoms of porphyria and may be allowed under supervision. 3 Likewise, surgical procedures with use of local or general anesthesia are uncommonly associated with symptoms of porphyria. 3 Treatment of Acute Attacks. During acute attacks of porphyria, the initial step is to identify and address the possible precipitating factor, including review of medications, treatment of active infections, and maintenance of adequate intake of carbohydrates (more than 400 g/day either orally or intravenously as a 10% dextrose solution) and fluids (more than 2 L/day). During fluid resuscitation, the serum sodium level should be monitored to guard against the presence of the syndrome of inappropriate production of antidiuretic hormone, an uncommon complication of acute porphyria. After implementation of the foregoing supportive measures, the second step is to manage particular symptoms and signs of the disease. Pain may be controlled adequately by the use of opiates (morphine, 5 to 10 mg administered intravenously or intramuscularly every 4 hours, or immediaterelease morphine tablets, 10 to 30 mg given orally every 4 hours). Anxiety, agitation, and psychotic symptoms may be managed by the use of phenothiazines (chlorpromazine hydrochloride, 25 to 50 mg administered orally or intramuscularly four times a day). If hypertension and tachycardia need to be treated, ß-blocker therapy (orally administered propranolol, 20 to 40 mg four times a day) may be used. Diazepam (5 to 10 mg intravenously) has been used safely and effectively in patients with seizures. During initiation of therapy with all the aforementioned drugs, the blood pressure and pulse should be monitored closely. Specific intravenous therapy with hematin (Panhematin, 4 mg/kg given every 12 hours for 3 days) has produced biochemical remissions. 11 12 Randomized studies, however, have not shown clinical benefits. 11 12 Similarly, the use of tin protoporphyrin (an inhibitor of heme oxygenase) in combination with hematin has prolonged the biochemical remission induced by hematin, but the clinical course was unaffected. 12 Side effects of hematin include venous irritation and coagulopathy. Biochemical and possibly clinical remission with cimetidine (800 mg/day) has been reported in a patient with AIP. 13 Finally, analogues of luteinizing hormone releasing hormone 14 or oral contraceptives 3 may benefit patients with symptoms related to the menstrual cycle.

Mayo Clin Proc, October 1994, Vol 69 ACUTE PORPHYRIAS 995 REFERENCES 1. Pierach CA, Weimer MK, Cardinal RA, Bossenmaier IC, Bloomer JR. Red blood cell porphobilinogen deaminase in the evaluation of acute intermittent porphyria. JAMA 1987; 257:60-61 2. Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen: a possible mechanism for the acute attack of variegate porphyria. J Clin Invest 1993;91:1436-1444 3. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine 1992;71:1-13 4. Stein JA, Tschudy DP. Acute intermittent porphyria: a clinical and biochemical study of 46 patients. Medicine 1970;49:1-16 5. Lamon JM, Frykholm BC, Tschudy DP. Family evaluations in acute intermittent porphyria using red cell uroporphyrinogen I synthetase. J Med Genet 1979; 16:134-139 6. Hassoun A, Verstraeten L, Mercelis R, Martin JJ. Biochemical diagnosis of an hereditary aminolaevulinate dehydratase deficiency in a 63-year-old man. J Clin Chem Clin Biochem 1989; 27:781-786 7. Eales L, Levey MJ, Sweeney GD. The place of screening tests and quantitative investigations in the diagnosis of the porphyrias, with particular reference to variegate and symptomatic porphyria. SAfrMedJ 1966;40:63-71 8. With TK. Hereditary coproporphyria and variegate porphyria in Denmark. Dan Med Bull 1983;30:106-112 9. Mustajoki P, Tenhunen R. Variant of acute intermittent porphyria with normal erythrocyte uroporphyrinogen- I-synthase activity. Eur J Clin Invest 1985; 15:281-284 10. Saksena HC, Panwar RB, Rajvanshi P, Sabir M, Suri M. Alcohol and Indian porphyries. Postgrad Med J 1991; 67:823-824 11. Herrick AL, McColl KE, Moore ME, Cook A, Goldberg A. Controlled trial of haem arginate in acute hepatic porphyria. Lancet 1989; 1:1295-1297 12. Dover SB, Moore MR, Fitzsimmons EJ, Graham A, McColl KE. Tin protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria. Gastroenterology 1993; 105:500-506 13. Baccino E, Lan Cheong Wah LS, Bressollette L, Mottier D. Cimetidine in the treatment of acute intermittent porphyria [letter]. JAMA 1989; 262:3000 14. Anderson KE, Spitz IM, Sassa S, Bardin CW, Kappas A. Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormonereleasing hormone. N Engl J Med 1984; 311:643-645 Questions About Acute Porphyrias (See article, pages 991 to 995) Note: One or more answers may be correct. 1. Abdominal pain or neurologic symptoms can be attributed to acute porphyria only if: a. A family history of porphyria is present b. Stool porphyrins are increased c. Porphyrin precursors in the urine are increased d. Enzyme activity in erythrocytes is decreased e. Uroporphyrin or coproporphyrin in the urine is increased 2. Increased protoporphyrin in the stool is consistent with: a. Acute intermittent porphyria b. Hereditary coproporphyria c. Liver disease d. Variegate porphyria e. Lead intoxication 3. Which of the following is not strongly associated with precipitation of attacks of acute porphyria: a. Excessive use of alcohol b. Pregnancy c. Starvation d. Barbiturates e. Sulfonamides 4. The presence of decreased porphobilinogen deaminase activity in erythrocytes suggests: a. Overt acute porphyria b. Plumboporphyria c. Latent acute intermittent porphyria d. Hereditary coproporphyria e. Lead intoxication 5. Which of the following is controversial in the management of acute porphyria: a. The use of hematin b. Appropriate hydration and nutrition c. Infusion of glucose d. Avoidance of porphyrinogenic medications e. Avoidance of excessive use of alcohol Correct answers: νς Ό-ρ 'q- 'fi 'D\