Pathogenesis, clinical manifestations, and diagnosis of acute intermittent porphyria
- Gagan K Sood, MD
Gagan K Sood, MD
- Associate Professor, Department of Surgery and Medicine
- Baylor College of Medicine
- Karl E Anderson, MD, FACP
Karl E Anderson, MD, FACP
- The University of Texas Medical Branch
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Donald H Mahoney, Jr, MD
Donald H Mahoney, Jr, MD
- Section Editor — Pediatric Hematology
- Professor of Pediatrics
- Baylor College of Medicine
Acute intermittent porphyria (AIP; also called Swedish porphyria, pyrroloporphyria, intermittent acute porphyria) is an acute neurovisceral porphyria resulting from a partial deficiency of the heme biosynthetic enzyme porphobilinogen deaminase (PBGD). It is an autosomal dominant disorder with low penetrance; development of symptoms is affected by a variety of exacerbating factors.
Despite its well characterized molecular genetics, the diagnosis of AIP is challenging. Symptoms are often vague and nonspecific; the other possible causes of neurologic findings and abdominal pain are numerous; and acute porphyria is often not considered because it is rare. Clues from the family history may be absent, because penetrance of AIP is low and symptoms may not manifest in the majority of family members with a disease-causing mutation. Even if acute porphyria is considered, many clinicians are unfamiliar with typical findings of the disease, appropriate testing, and interpretation of test results. As a consequence, diagnosis and life-saving treatment are often delayed.
The pathogenesis, clinical manifestations, and diagnosis of AIP will be reviewed here. Management of AIP and a general overview of the porphyrias are presented separately. (See "Management and prognosis of acute intermittent porphyria" and "Porphyrias: An overview".)
Porphyrias are caused by alterations in the enzymes of heme biosynthesis. Heme is essential in the function of hemoglobin and many other hemoproteins, including hepatic enzymes such as cytochrome P450 enzymes. The liver is the major source of overproduction of heme pathway intermediates in patients with hepatic porphyrias such as AIP; and the central, peripheral, autonomic, and enteric nervous systems are affected when levels of these intermediates are elevated in the circulation, suggesting neurotoxic effects of one or more intermediates. Some neurological manifestations may result from heme depletion in neuronal cells, although this remains unproven. (See 'Neurological dysfunction' below.)
Gene mutation — AIP is caused by heterozygosity for a mutation in the gene encoding porphobilinogen deaminase (PBGD), also called hydroxymethylbilane synthase (HMBS) and previously referred to as uroporphyrinogen I synthase. Inheritance is autosomal dominant with low penetrance. More than 300 PBGD gene mutations have been recognized in AIP, all of which lead to severe loss of PBGD enzymatic activity from the mutant allele. Virtually all remaining PBGD activity is due to expression from the unaffected allele.
Subscribers log in hereLiterature review current through: Sep 2017. | This topic last updated: May 31, 2016.References
- Grandchamp B, Beaumont C, de Verneuil H, et al. Genetic expression of porphobilinogen deaminase and urod during the erythroid differentiation of mouse erythroleukemic cells. In: Porphyrins and porphyrias, Nordmann Y (Ed), John Libbey & Company, London 1986. p.35.
- Grandchamp B, De Verneuil H, Beaumont C, et al. Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. Eur J Biochem 1987; 162:105.
- Mignotte V, Eleouet JF, Raich N, Romeo PH. Cis- and trans-acting elements involved in the regulation of the erythroid promoter of the human porphobilinogen deaminase gene. Proc Natl Acad Sci U S A 1989; 86:6548.
- Grandchamp B, Picat C, Kauppinen R, et al. Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase. Eur J Clin Invest 1989; 19:415.
- Chretien S, Dubart A, Beaupain D, et al. Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression. Proc Natl Acad Sci U S A 1988; 85:6.
- Wang AL, Arredondo-Vega FX, Giampietro PF, et al. Regional gene assignment of human porphobilinogen deaminase and esterase A4 to chromosome 11q23 leads to 11qter. Proc Natl Acad Sci U S A 1981; 78:5734.
- Dowman JK, Gunson BK, Bramhall S, et al. Liver transplantation from donors with acute intermittent porphyria. Ann Intern Med 2011; 154:571.
- Podvinec M, Handschin C, Looser R, Meyer UA. Identification of the xenosensors regulating human 5-aminolevulinate synthase. Proc Natl Acad Sci U S A 2004; 101:9127.
- Peyer AK, Jung D, Beer M, et al. Regulation of human liver delta-aminolevulinic acid synthase by bile acids. Hepatology 2007; 46:1960.
- Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: The Metabolic and Molecular Basis of Inherited Disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, et al. (Eds), McGraw-Hill, New York 2001. p.2991.
- Jordan PM. The biosynthesis of 5-aminolevulinic acid and its transformation into coproporphyrinogen in animals and bacteria. In: Biosynthesis of heme and chlorophylls, Dailey HA (Ed), McGraw-Hill, New York 1990. p.55.
- Minder EI. Coproporphyrin isomers in acute-intermittent porphyria. Scand J Clin Lab Invest 1993; 53:87.
- Anderson KE, Drummond GS, Freddara U, et al. Porphyrogenic effects and induction of heme oxygenase in vivo by delta-aminolevulinic acid. Biochim Biophys Acta 1981; 676:289.
- Soonawalla ZF, Orug T, Badminton MN, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet 2004; 363:705.
- Seth AK, Badminton MN, Mirza D, et al. Liver transplantation for porphyria: who, when, and how? Liver Transpl 2007; 13:1219.
- Brennan MJ, Cantrill RC. Delta-aminolaevulinic acid is a potent agonist for GABA autoreceptors. Nature 1979; 280:514.
- Müller WE, Snyder SH. delta-Aminolevulinic acid: influences on synaptic GABA receptor binding may explain CNS symptoms of porphyria. Ann Neurol 1977; 2:340.
- Mustajoki P, Timonen K, Gorchein A, et al. Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer: no porphyric symptoms. Eur J Clin Invest 1992; 22:407.
- Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol 2011; 122:2336.
- Sze G. Cortical brain lesions in acute intermittent porphyria. Ann Intern Med 1996; 125:422.
- Lithner F. Could attacks of abdominal pain in cases of acute intermittent porphyria be due to intestinal angina? J Intern Med 2000; 247:407.
- Litman DA, Correia MA. Elevated brain tryptophan and enhanced 5-hydroxytryptamine turnover in acute hepatic heme deficiency: clinical implications. J Pharmacol Exp Ther 1985; 232:337.
- Lindberg RL, Porcher C, Grandchamp B, et al. Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria. Nat Genet 1996; 12:195.
- Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 1998; 18:43.
- Lindberg RL, Martini R, Baumgartner M, et al. Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria. J Clin Invest 1999; 103:1127.
- Mustajoki P, Heinonen J. General anesthesia in "inducible" porphyrias. Anesthesiology 1980; 53:15.
- Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005; 142:439.
- Louis CA, Sinclair JF, Wood SG, et al. Synergistic induction of cytochrome P450 by ethanol and isopentanol in cultures of chick embryo and rat hepatocytes. Toxicol Appl Pharmacol 1993; 118:169.
- Thunell S, Floderus Y, Henrichson A, et al. Alcoholic beverages in acute porphyria. J Stud Alcohol 1992; 53:272.
- Lip GY, McColl KE, Goldberg A, Moore MR. Smoking and recurrent attacks of acute intermittent porphyria. BMJ 1991; 302:507.
- Bylesjö I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand J Clin Lab Invest 2009; 69:612.
- Anderson KE, Spitz IM, Bardin CW, Kappas A. A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch Intern Med 1990; 150:1469.
- Anderson KE, Freddara U, Kappas A. Induction of hepatic cytochrome P-450 by natural steroids: relationship to the induction of delta-aminolevulinate synthase and porphyrin accumulation in the avian embryo. Arch Biochem Biophys 1982; 217:597.
- Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 1992; 71:1.
- Milo R, Neuman M, Klein C, et al. Acute intermittent porphyria in pregnancy. Obstet Gynecol 1989; 73:450.
- Shenhav S, Gemer O, Sassoon E, Segal S. Acute intermittent porphyria precipitated by hyperemesis and metoclopramide treatment in pregnancy. Acta Obstet Gynecol Scand 1997; 76:484.
- Handschin C, Lin J, Rhee J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell 2005; 122:505.
- Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98:115.
- Scassa ME, Guberman AS, Ceruti JM, Cánepa ET. Hepatic nuclear factor 3 and nuclear factor 1 regulate 5-aminolevulinate synthase gene expression and are involved in insulin repression. J Biol Chem 2004; 279:28082.
- Scassa ME, Guberman AS, Varone CL, Cánepa ET. Phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase signaling pathways are required for the regulation of 5-aminolevulinate synthase gene expression by insulin. Exp Cell Res 2001; 271:201.
- Thaler MM, Dawber NH. Stimulation of bilirubin formation in liver of newborn rats by fasting and glucagon. Gastroenterology 1977; 72:312.
- Welland FH, Hellman ES, Gaddis EM, et al. Factors affecting the excretion of porphyrin precursors by patients with acute intermittent porphyria. I. The effect of diet. Metabolism 1964; 13:232.
- Phillips JD, Kushner JP. Fast track to the porphyrias. Nat Med 2005; 11:1049.
- Andersson C, Bylesjö I, Lithner F. Effects of diabetes mellitus on patients with acute intermittent porphyria. J Intern Med 1999; 245:193.
- Hultdin J, Schmauch A, Wikberg A, et al. Acute intermittent porphyria in childhood: a population-based study. Acta Paediatr 2003; 92:562.
- Sardh E, Andersson DE, Henrichson A, Harper P. Porphyrin precursors and porphyrins in three patients with acute intermittent porphyria and end-stage renal disease under different therapy regimes. Cell Mol Biol (Noisy-le-grand) 2009; 55:66.
- Ridley A. Porphyric neuropathy. In: Peripheral neuropathy, Dyck PJ, Thomas PK, Lambert EH, Bunge R (Eds), WB Saunders Co, Philadelphia 1984. p.1704.
- Wikberg A, Andersson C, Lithner F. Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria. J Intern Med 2000; 248:27.
- Beal MF, Atuk NO, Westfall TC, Turner SM. Catecholamine uptake, accumulation, and release in acute porphyria. J Clin Invest 1977; 60:1141.
- Tschudy DP, Valsamis M, Magnussen CR. Acute intermittent porphyria: clinical and selected research aspects. Ann Intern Med 1975; 83:851.
- Kuo HC, Huang CC, Chu CC, et al. Neurological complications of acute intermittent porphyria. Eur Neurol 2011; 66:247.
- Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine (Baltimore) 1970; 49:1.
- Jeans JB, Savik K, Gross CR, et al. Mortality in patients with acute intermittent porphyria requiring hospitalization: a United States case series. Am J Med Genet 1996; 65:269.
- Ostrowski J, Kostrzewska E, Michalak T, et al. Abnormalities in liver function and morphology and impaired aminopyrine metabolism in hereditary hepatic porphyrias. Gastroenterology 1983; 85:1131.
- Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors. J Hepatol 2000; 32:933.
- Andant C, Puy H, Faivre J, Deybach JC. Acute hepatic porphyrias and primary liver cancer. N Engl J Med 1998; 338:1853.
- Andersson C, Bjersing L, Lithner F. The epidemiology of hepatocellular carcinoma in patients with acute intermittent porphyria. J Intern Med 1996; 240:195.
- Bengtsson NO, Hardell L. Porphyrias, porphyrins and hepatocellular cancer. Br J Cancer 1986; 54:115.
- Gubler JG, Bargetzi MJ, Meyer UA. Primary liver carcinoma in two sisters with acute intermittent porphyria. Am J Med 1990; 89:540.
- Hardell L, Bengtsson NO, Jonsson U, et al. Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria--an epidemiological investigation. Br J Cancer 1984; 50:389.
- Kauppinen R, Mustajoki P. Acute hepatic porphyria and hepatocellular carcinoma. Br J Cancer 1988; 57:117.
- Linet MS, Gridley G, Nyrén O, et al. Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 1999; 149:1010.
- Lithner F, Wetterberg L. Hepatocellular carcinoma in patients with acute intermittent porphyria. Acta Med Scand 1984; 215:271.
- Church SE, McColl KE, Moore MR, Youngs GR. Hypertension and renal impairment as complications of acute porphyria. Nephrol Dial Transplant 1992; 7:986.
- Andersson C, Wikberg A, Stegmayr B, Lithner F. Renal symptomatology in patients with acute intermittent porphyria. A population-based study. J Intern Med 2000; 248:319.
- Marsden JT, Chowdhury P, Wang J, et al. Acute intermittent porphyria and chronic renal failure. Clin Nephrol 2008; 69:339.
- Barone GW, Gurley BJ, Anderson KE, et al. The tolerability of newer immunosuppressive medications in a patient with acute intermittent porphyria. J Clin Pharmacol 2001; 41:113.
- http://www.thermoscientific.com/en/product/porphobilinogen-pbg-kit.html (Accessed on May 13, 2014).
- Deacon AC, Peters TJ. Identification of acute porphyria: evaluation of a commercial screening test for urinary porphobilinogen. Ann Clin Biochem 1998; 35 ( Pt 6):726.
- Anderson KE, Sassa S, Peterson CM, Kappas A. Increased erythrocyte uroporphyrinogen-l-synthetase, delta-aminolevulinic acid dehydratase and protoporphyrin in hemolytic anemias. Am J Med 1977; 63:359.
- Blum M, Koehl C, Abecassis J. Variations in erythrocyte uroporphyrinogen I synthetase activity in non porphyrias. Clin Chim Acta 1978; 87:119.
- Kostrzewska E, Gregor A. Increased activity of porphobilinogen deaminase in erythrocytes during attacks of acute intermittent porphyria. Ann Clin Res 1986; 18:195.
- Kauppinen R, von und zu Fraunberg M. Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families. Clin Chem 2002; 48:1891.
- Gene mutation
- Enzymatic defect
- Neurological dysfunction
- EXACERBATING FACTORS
- Ethanol and smoking
- Sex hormones
- Nutrition, glucose metabolism, and stress
- CLINICAL MANIFESTATIONS
- Acute attacks
- - Abdominal pain
- - Peripheral neuropathy
- - Autonomic, enteric, and central nervous system involvement
- - Bladder dysfunction/red urine
- - Laboratory and imaging findings
- Chronic manifestations
- DIAGNOSTIC EVALUATION
- Overview of the evaluation
- Symptomatic patients
- - Test urinary PBG and initiate treatment if positive
- - Obtain plasma and stool samples during the acute attack
- Asymptomatic patients
- Confirmatory testing
- - PBGD activity (erythrocytes)
- - DNA testing
- Diagnostic criteria
- DIFFERENTIAL DIAGNOSIS
- SUMMARY AND RECOMMENDATIONS