Acute Intermittent Porphyria

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Acute intermittent porphyria (AIP) is one of the porphyrias, a group of hereditary diseases that involve defects in heme metabolism and result in excessive secretion of porphyrins and porphyrin precursors. ^[1] AIP manifests as episodes of abdominal pain, neuropathies, and constipation, but, unlike most types of porphyria, patients with AIP do not have a rash.

The diagnosis of AIP can be confirmed by finding an elevated level of porphobilinogen (>6 mg/L) on a spot urine test during an acute attack (see Workup). High doses of glucose can inhibit heme synthesis and are useful for treatment of mild attacks. Patients experiencing severe attacks, especially those with severe neurologic symptoms, should be treated with hematin. During attacks, which generally last for several days, patients require symptomatic treatment for pain and other manifestations. (See Treatment and Medication.)

For more information on the porphyrias, see Porphyria Overview.

AIP is an autosomal dominant disease that results from defects in the enzyme porphobilinogen-deaminase. This enzyme speeds the conversion of porphobilinogen to hydroxymethylbilane. In AIP, the porphyrin precursors, porphobilinogen and amino-levulinic acid (ALA), accumulate. The predominant problem appears to be neurologic damage that leads to peripheral and autonomic neuropathies and psychiatric manifestations. ^[2]

Although levels of porphobilinogen and ALA are always elevated during acute attacks, how this leads to the symptomatic disease is still unclear because most patients with the genetic defect have excessive porphyrin secretion but no symptoms.

A case-control study in 50 patients by Storjord et al found evidence that AIP is associated with systemic inflammation. Levels of prealbumin, C-peptide, and insulin, along with measures of kidney function, were all decreased in symptomatic patients, but not in asymptomatic ones. The decrease in C-peptide levels in symptomatic AIP cases indicates that reduced insulin release is associated with enhanced disease activity and reduction in kidney function. ^[3]

United States

Estimates vary from 1-5 cases per 100,000 population.

International

European studies indicate that the prevalence of AlP is approximately five per 100,000 population. ^[4]   The prevalence can be as high as 60-100 cases per 100,000 population in northern Sweden.

In most series, AIP affects women more than men, with a ratio of 1.5-2:1.

Most patients become symptomatic at age 18-40 years. Attacks occurring before puberty or after age 40 years are unusual unless a major provocation, such as new use of phenobarbital or estrogens, had occurred.

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Kuo HC, Huang CC, Chu CC, Lee MJ, Chuang WL, Wu CL, et al. Neurological complications of acute intermittent porphyria. Eur Neurol. 2011. 66(5):247-52. [Medline].

Storjord E, Dahl JA, Landsem A, Fure H, Ludviksen JK, Goldbeck-Wood S, et al. Systemic inflammation in acute intermittent porphyria: a case-control study. Clin Exp Immunol. 2017 Mar. 187 (3):466-479. [Medline].

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Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, et al. Acute Porphyrias in the USA: Features of 108 Subjects from Porphyria Consortium. Am J Med. 2014 Jul 9. [Medline].

Anyaegbu E, Goodman M, Ahn SY, Thangarajh M, Wong M, Shinawi M. Acute Intermittent Porphyria: A Diagnostic Challenge. J Child Neurol. 2011 Dec 21. [Medline].

Menegueti MG, Gil Cezar AT, Casarini KA, Muniz Cordeiro KS, Basile-Filho A, Martins-Filho OA, et al. Acute intermittent porphyria associated with respiratory failure: a multidisciplinary approach. Crit Care Res Pract. 2011. 2011:283690. [Medline]. [Full Text].

Zheng X, Liu X, Wang Y, Zhao R, Qu L, Pei H, et al. Acute intermittent porphyria presenting with seizures and posterior reversible encephalopathy syndrome: Two case reports and a literature review. Medicine (Baltimore). 2018 Sep. 97 (36):e11665. [Medline]. [Full Text].

Whatley SD, Mason NG, Woolf JR, et al. 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 Jul. 55(7):1406-14. [Medline].

[Guideline] Stein P, Badminton M, Barth J, Rees D, Stewart MF, British and Irish Porphyria Network. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013 May. 50 (Pt 3):217-23. [Medline]. [Full Text].

Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015. 8:201-14. [Medline]. [Full Text].

Bonnefoy Mirralles AM, Torres-Castro R, Ovalle Guzman C. A Comprehensive Rehabilitation Program and Follow-up Assessment for Acute Intermittent Porphyria. Am J Phys Med Rehabil. 2017 May. 96 (5):e85-e88. [Medline].

D’Avola D, López-Franco E, Sangro B, Pañeda A, Grossios N, Gil-Farina I, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016 Oct. 65 (4):776-83. [Medline]. [Full Text].

Serrano I, Sampedro A, Alegre M, Enriquez de Salamanca R, Berraondo P, Fontanellas A. An inducible promoter responsive to different porphyrinogenic stimuli improves gene therapy vectors for acute intermittent porphyria. Hum Gene Ther. 2017 Oct 7. [Medline].

Willandt B, Langendonk JG, Biermann K, Meersseman W, D’Heygere F, George C, et al. Liver Fibrosis Associated with Iron Accumulation Due to Long-Term Heme-Arginate Treatment in Acute Intermittent Porphyria: A Case Series. JIMD Rep. 2015 Jun 21. 50 (Pt 3):217-23. [Medline].

Delaby C, To-Figueras J, Deybach JC, et al. Role of two nutritional hepatic markers (insulin-like growth factor 1 and transthyretin) in the clinical assessment and follow-up of acute intermittent porphyria patients. J Intern Med. 2009 Apr 23. epub ahead of print. [Medline].

Syal K, Bhatt R, Singh S, Ohri A. Acute intermittent porphyria. J Anaesthesiol Clin Pharmacol. 2015 Apr-Jun. 31 (2):261-3. [Medline]. [Full Text].

Zaider E, Bickers DR. Clinical laboratory methods for diagnosis of the porphyrias. Clin Dermatol. 1998 Mar-Apr. 16(2):277-93. [Medline].

Bylesjo I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: A population-based study. Scand J Clin Lab Invest. 2009 Apr 28. 1-7. [Medline].

Daniell WE, Stockbridge HL, Labbe RF, et al. Environmental chemical exposures and disturbances of heme synthesis. Environ Health Perspect. 1997 Feb. 105 Suppl 1:37-53. [Medline].

Gill R, Kolstoe SE, Mohammed F, et al. Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria. Biochem J. 2009 Apr 28. 420(1):17-25. [Medline].

Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). 1992 Jan. 71(1):1-13. [Medline].

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†Bracketed [] drugs are those in which experimental evidence of porphyringenicity is conflicting.

Thomas G DeLoughery, MD Professor of Medicine, Pathology, and Pediatrics, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health and Science University School of Medicine

Thomas G DeLoughery, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American College of Physicians, American Society of Hematology, International Society on Thrombosis and Haemostasis, Wilderness Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Clarence Sarkodee Adoo, MD, FACP Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Clarence Sarkodee Adoo, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

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