Portuguese Consensus on Acute Porphyrias: Diagnosis, Treatment, Monitoring and Patient Referral
Keywords:Consensus, Porphyria, Acute Intermittent/diagnosis, Porphyria, Acute Intermittent/therapy, Porphyrias/diagnosis, Porphyrias/therapy, Portugal, Referral and Consultation
Acute porphyrias are a group of rare genetic metabolic disorders, caused by a defect in one of the enzymes involved in the heme biosynthesis, which results in an abnormally high accumulation of toxic intermediates. Acute porphyrias are characterized by potentially life-threatening attacks and, for some patients, by chronic manifestations that negatively impact daily functioning and quality of life. Clinical manifestations include a nonspecific set of gastrointestinal, neuropsychiatric, and/or cutaneous symptoms. Effective diagnostic methods are widely available, but due to their clinical heterogeneity and non-specificity, many years often elapse from symptom onset to diagnosis of acute porphyrias, delaying the treatment and increasing morbidity. Therefore, increased awareness of acute porphyrias among healthcare professionals is paramount to reducing disease burden. Treatment of acute porphyrias is centered on eliminating the potential precipitants, symptomatic treatment, and suppressing the hepatic heme pathway, through the administration of hemin or givosiran. Moreover, properly monitoring patients with acute porphyrias and their relatives is fundamental to preventing acute attacks, hospitalization, and long-term complications. Considering this, a multidisciplinary panel elaborated a consensus paper, aiming to provide guidance for an efficient and timely diagnosis of acute porphyrias, and evidence-based recommendations for treating and monitoring patients and their families in Portugal. To this end, all authors exhaustively reviewed and discussed the current scientific evidence on acute porphyrias available in the literature, between November 2022 and May 2023.
Heymans B, Meersseman W. Porphyria: awareness is the key to diagnosis! Acta Clin Belg. 2022;77:703-9.
Ma Y, Teng Q, Zhang Y, Zhang S. Acute intermittent porphyria: focus on possible mechanisms of acute and chronic manifestations. Intractable Rare Dis Res. 2020;9:187-95.
Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019;128:164-77.
Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 2019;3:193-206.
de Souza PV, Badia BM, Farias IB, Pinto W, Oliveira AS. Acute hepatic porphyria: pathophysiological basis of neuromuscular manifestations. Front Neurosci. 2021;15:715523.
Stein PE, Edel Y, Mansour R, Mustafa RA, Sandberg S, Members of the Acute Porphyria Expert P, et al. Key terms and definitions in acute porphyrias: results of an international delphi consensus led by the European Porphyria Network. J Inherit Metab Dis. 2023:46:662-74.
Schulenburg-Brand D, Stewart F, Stein P, Rees D, Badminton M. Update on the diagnosis and management of the autosomal dominant acute hepatic porphyrias. J Clin Pathol. 2022;75:537-43.
Neeleman RA, Wensink D, Wagenmakers M, Mijnhout GS, Friesema EC, Langendonk JG. Diagnostic and therapeutic strategies for porphyrias. Neth J Med. 2020;78:149-60.
Spiritos Z, Salvador S, Mosquera D, Wilder J. Acute intermittent porphyria: current perspectives and case presentation. Ther Clin Risk Manag. 2019;15:1443-51.
Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66:1314-22.
Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019;128:213-8.
Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. 2013;36:849-57.
Chen B, Solis-Villa C, Hakenberg J, Qiao W, Srinivasan RR, Yasuda M, et al. Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease. Hum Mutat. 2016;37:1215-22.
Lenglet H, Schmitt C, Grange T, Manceau H, Karboul N, Bouchet-Crivat F, et al. From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria. Hum Mol Genet. 2018;27:1164-73.
Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127:1233-41.
Edel Y, Mamet R, Cohen S, Shepshelovich D, Levi A, Sagy I. The clinical importance of early acute hepatic porphyria diagnosis: a national cohort. Intern Emerg Med. 2021;16:133-9.
Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019;128:219-27.
Kazamel M, Pischik E, Desnick RJ. Pain in acute hepatic porphyrias: updates on pathophysiology and management. Front Neurol. 2022;13:1004125.
Duque-Serrano L, Patarroyo-Rodriguez L, Gotlib D, Molano-Eslava JC. Psychiatric aspects of acute porphyria: a comprehensive review. Curr Psychiatry Rep. 2018;20:5.
Oliveira Santos M, Leal Rato M. Neurology of the acute hepatic porphyrias. J Neurol Sci. 2021;428:117605.
Suh Y, Gandhi J, Seyam O, Jiang W, Joshi G, Smith NL, et al. Neurological and neuropsychiatric manifestations of porphyria. Int J Neurosci. 2019;129:1226-33.
Santosh PJ, Malhotra S. Varied psychiatric manifestations of acute intermittent porphyria. Biol Psychiatry. 1994;36:744-7.
Gerischer LM, Scheibe F, Numann A, Kohnlein M, Stolzel U, Meisel A. Acute porphyrias - a neurological perspective. Brain Behav. 2021;11:e2389.
Solares I, Tejedor M, Jerico D, Morales-Conejo M, Enriquez de Salamanca R, Fontanellas A, et al. Management of hyponatremia associated with acute porphyria-proposal for the use of tolvaptan. Ann Transl Med. 2020;8:1098.
Dos Santos AR, De Albuquerque RR, Doriqui MJ, Costa GC, Dos Santos AP. Biochemical and hematological analysis in acute intermittent porphyria (AIP): a case report. An Acad Bras Cienc. 2013;85:1207-14.
Norton J, Hymers C, Stein P, Jenkins JM, Bew D. Acute porphyria presenting as major trauma: case report and literature review. J Emerg Med. 2016;51:e115-22.
Bylesjo I, Forsgren L, Lithner F, Boman K. Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria. Epilepsia. 1996;37:230-5.
Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL. Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab. 2019;128:242-53.
Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stolzel U, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020;71:1546-58.
Kakoullis L, Louppides S, Papachristodoulou E, Panos G. Porphyrias and photosensitivity: pathophysiology for the clinician. Postgrad Med. 2018;130:673-86.
Dawe R. An overview of the cutaneous porphyrias. F1000Res. 2017;6:1906.
Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39:412-25.
Cassiman D, Kauppinen R, Monroy S, Lee MJ, Bonkovsky HL, Thapar M, et al. EXPLORE B: A prospective, long-term natural history study of patients with acute hepatic porphyria with chronic symptoms. J Inherit Metab Dis. 2022;45:1163-74.
Buendia-Martinez J, Barreda-Sanchez M, Rodriguez-Pena L, Ballesta-Martinez MJ, Lopez-Gonzalez V, Sanchez-Soler MJ, et al. Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients. Orphanet J Rare Dis. 2021;16:106.
Simon A, Pompilus F, Querbes W, Wei A, Strzok S, Penz C, et al. Patient perspective on acute intermittent porphyria with frequent attacks: a disease with intermittent and chronic manifestations. Patient. 2018;11:527-37.
Wheeden K, Lyon Howe D, Burrell S, Gill L, Chamberlayne J, Williams ER, et al. Patient perspective on acute hepatic porphyria with sporadic attacks: a chronic disease with substantial health-related quality of life impacts. Adv Ther. 2022;39:4330-45.
Ramai D, Deliwala SS, Chandan S, Lester J, Singh J, Samanta J, et al. Risk of hepatocellular carcinoma in patients with porphyria: a systematic review. Cancers. 2022;14:2947.
Saberi B, Naik H, Overbey JR, Erwin AL, Anderson KE, Bissell DM, et al. Hepatocellular carcinoma in acute hepatic porphyrias: results from the longitudinal study of the U.S. Porphyrias Consortium. Hepatology. 2021;73:1736-46.
Pallet N, Mami I, Schmitt C, Karim Z, Francois A, Rabant M, et al. High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria. Kidney Int. 2015;88:386-95.
Lissing M, Vassiliou D, Floderus Y, Harper P, Yan J, Hagstrom H, et al. Risk for incident comorbidities, non-hepatic cancer and mortality in acute hepatic porphyria: a matched cohort study in 1,244 individuals. J Inherit Metab Dis. 2023;46:286-99.
Ricci A, Guida CC, Manzini P, Cuoghi C, Ventura P. Kidney involvement in acute hepatic porphyrias: pathophysiology and diagnostic implications. Diagnostics. 2021;11:2324.
Pallet N, Karras A, Thervet E, Gouya L, Karim Z, Puy H. Porphyria and kidney diseases. Clin Kidney J. 2018;11:191-7.
Neeleman RA, Wagenmakers M, Koole-Lesuis RH, Mijnhout GS, Wilson JHP, Friesema ECH, et al. Medical and financial burden of acute intermittent porphyria. J Inherit Metab Dis. 2018;41:809-17.
Jeans JB, Savik K, Gross CR, Weimer MK, Bossenmaier IC, Pierach CA, et al. Mortality in patients with acute intermittent porphyria requiring hospitalization: a United States case series. Am J Med Genet. 1996;65:269-73.
Baravelli CM, Aarsand AK, Sandberg S, Tollanes MC. Sick leave, disability, and mortality in acute hepatic porphyria: a nationwide cohort study. Orphanet J Rare Dis. 2020;15:56.
Di Pierro E, De Canio M, Mercadante R, Savino M, Granata F, Tavazzi D, et al. Laboratory diagnosis of porphyria. Diagnostics. 2021;11:1343.
Anderson KE, Lobo R, Salazar D, Schloetter M, Spitzer G, White AL, et al. Biochemical diagnosis of acute hepatic porphyria: updated expert recommendations for primary care physicians. Am J Med Sci. 2021;362:113-21.
Agarwal S, Habtemarium B, Xu Y, Simon AR, Kim JB, Robbie GJ. Normal reference ranges for urinary delta-aminolevulinic acid and porphobilinogen levels. JIMD Rep. 2021;57:85-93.
Whatley SD, Mason NG, Woolf JR, Newcombe RG, Elder GH, Badminton MN. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem. 2009;55:1406-14.
Whatley SD, Badminton MN. Role of genetic testing in the management of patients with inherited porphyria and their families. Ann Clin Biochem. 2013;50:204-16.
Ventura P, Cappellini MD, Biolcati G, Guida CC, Rocchi E, Gruppo Italiano P. A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias. Eur J Intern Med. 2014;25:497-505.
Schanbacher CF, Vanness ER, Daoud MS, Tefferi A, Su WP. Pseudoporphyria: a clinical and biochemical study of 20 patients. Mayo Clin Proc. 2001;76:488-92.
Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380:549-58.
Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematol. 2017;176:527-38.
Linenberger M, Fertrin KY. Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP. Hematology Am Soc Hematol Educ Program. 2020;2020:400-10.
Akshatha LN, Rukmini MS, Mamatha TS, Sadashiva RP, Prashanth, B. Lead poisoning mimicking acute porphyria! J Clin Diagn Res. 2014;8:CD01-2.
Sassa S, Kappas A. Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone. J Clin Invest. 1983;71:625-34.
Wang B. The acute hepatic porphyrias. Transl Gastroenterol Hepatol. 2021;6:24.
NAPOS-database. The drug database for acute porphyria of the Norwegian Porphyria Centre (NAPOS). 2023. [cited 2023 Jan 06]. Available from: http://www.drugs-porphyria.org.
Marcacci M, Ricci A, Cuoghi C, Marchini S, Pietrangelo A, Ventura P. Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives. Orphanet J Rare Dis. 2022;17:160.
Zhao L, Wang X, Zhang X, Liu X, Ma N, Zhang Y, et al. Therapeutic strategies for acute intermittent porphyria. Intractable Rare Dis Res. 2020;9:205-16.
Gilles A, Vermeersch S, Vermeersch P, Wolff F, Cotton F, Tilleux S, et al. Expert consensus statement on acute hepatic porphyria in Belgium. Acta Clin Belg. 2022;77:735-41.
Jerico D, Cordoba KM, Sampedro A, Jiang L, Joucla G, Cabanne C, et al. Recent insights into the pathogenesis of acute porphyria attacks and increasing hepatic PBGD as an etiological treatment. Life. 2022;12:1858.
Rigor J, Pinto SA, Martins-Mendes D. Porphyrias: a clinically based approach. Eur J Intern Med. 2019;67:24-9.
Wang B. Novel treatment options for acute hepatic porphyrias. Curr Opin Gastroenterol. 2021b;37:194-9.
Petrides PE. Therapy follows diagnosis: old and new approaches for the treatment of acute porphyrias, what we know and what we should know. Diagnostics. 2022;12:1618.
Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170:G1-47.
Mrozek S, Rousset D, Geeraerts T. Pharmacotherapy of sodium disorders in neurocritical care. Curr Opin Crit Care. 2019;25:132-7.
Jain G, Bennett JI, Resch DS, Godwin JE. Schizoaffective disorder with missed diagnosis of acute porphyria: a case report and overview. Prim Care Companion CNS Disord. 2011;13:PCC.11br01234.
Majeed CN, Ma CD, Xiao T, Rudnick S, Bonkovsky HL. Spotlight on givosiran as a treatment option for adults with acute hepatic porphyria: design, development, and place in therapy. Drug Des Devel Ther. 2022;16:1827-45.
Traber GM, Yu AM. RNAi-Based therapeutics and novel RNA bioengineering technologies. J Pharmacol Exp Ther. 2023;384:133-54.
SmPC-Givlaari®. Product information of Givlaari® 189 mg/mL solution for injection. 2022. [cited 2023 January 06]. Available from: https://www.ema.europa.eu/en/documents/product-information/givlaari-eparproduct-information_en.pdf.
Balwani M, Sardh E, Ventura P, Peiro PA, Rees DC, Stolzel U, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382:2289-301.
Ventura P, Bonkovsky HL, Gouya L, Aguilera-Peiro P, Montgomery Bissell D, Stein PE, et al. Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int. 2022;42:161-72.
Wang B, Ventura P, Takase KI, Thapar M, Cassiman D, Kubisch I, et al. Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study. Orphanet J Rare Dis. 2022;17:327.
Sardh E, Harper P. RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria. J Intern Med. 2022;291:593-610.
Poli A, Schmitt C, Moulouel B, Mirmiran A, Talbi N, Riviere S, et al. Givosiran in acute intermittent porphyria: a personalized medicine approach. Mol Genet Metab. 2022;135:206-14.
Lazareth H, Poli A, Bignon Y, Mirmiran A, Rabant M, Cohen R, et al. Renal function decline with small interfering RNA silencing aminolevulinic acid synthase 1 (ALAS1). Kidney Int Rep. 2021;6:1904-11.
Ventura P, Sardh E, Longo N, Balwani M, Plutzky J, Gouya L, et al. Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran. Expert Rev Gastroenterol Hepatol. 2022;16:879-94.
Kuo HC, Lin CN, Tang YF. Prophylactic heme arginate infusion for acute intermittent porphyria. Front Pharmacol. 2021;12:712305.
Yarra P, Faust D, Bennett M, Rudnick S, Bonkovsky HL. Benefits of prophylactic heme therapy in severe acute intermittent porphyria. Mol Genet Metab Rep. 2019;19:100450.
Schulenburg-Brand D, Gardiner T, Guppy S, Rees DC, Stein P, Barth J, et al. An audit of the use of gonadorelin analogues to prevent recurrent acute symptoms in patients with acute porphyria in the United Kingdom. JIMD Rep. 2017;36:99-107.
Singal AK, Anderson KE. Variegate porphyria. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews. Seattle: University of Washington, Seattle. [cited 2023 Jan 05]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121283/.
Wang BB, Bissell DM. Hereditary coproporphyria. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews. Seattle: University of Washington, Seattle. [cited 2023 Jan 05]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114807/.
Ferrer MD, Tauler P, Sureda A, Palacin C, Tur JA, Pons A. Variegate porphyria induces plasma and neutrophil oxidative stress: effects of dietary supplementation with vitamins E and C. Br J Nutr. 2010;103:69-76.
Lissing M, Nowak G, Adam R, Karam V, Boyd A, Gouya L, et al. Liver transplantation for acute intermittent porphyria. Liver Transpl. 2021;27:491-501.
Vassiliou D, Sardh E. Acute hepatic porphyria and maternal health: clinical and biochemical follow-up of 44 pregnancies. J Intern Med. 2022;291:81-94.
Sociedade Portuguesa de Doenças Metabólicas (SPDM). Lista de centros de referência de doenças hereditárias do metabolismo. 2023. [cited 2023 Sep 06]. Available from: https://www.spdm.org.pt/crefer%C3%AAncia/centros-de-refer%C3%AAncias-doen%C3%A7asheredit%C3%A1rias-do-metabolismo-dhm/.
How to Cite
Copyright (c) 2023 Acta Médica Portuguesa
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All the articles published in the AMP are open access and comply with the requirements of funding agencies or academic institutions. The AMP is governed by the terms of the Creative Commons ‘Attribution – Non-Commercial Use - (CC-BY-NC)’ license, regarding the use by third parties.
It is the author’s responsibility to obtain approval for the reproduction of figures, tables, etc. from other publications.
Upon acceptance of an article for publication, the authors will be asked to complete the ICMJE “Copyright Liability and Copyright Sharing Statement “(http://www.actamedicaportuguesa.com/info/AMP-NormasPublicacao.pdf) and the “Declaration of Potential Conflicts of Interest” (http:// www.icmje.org/conflicts-of-interest). An e-mail will be sent to the corresponding author to acknowledge receipt of the manuscript.
After publication, the authors are authorised to make their articles available in repositories of their institutions of origin, as long as they always mention where they were published and according to the Creative Commons license.