Acute Intermittent Porphyria Workup

Author: Thomas G DeLoughery, MD; Chief Editor: Emmanuel C Besa, MD more...

Updated: Jan 10, 2012

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Laboratory Studies

The fundamental step in diagnosing acute intermittent porphyria (AIP) is to demonstrate increased urinary porphobilinogen secretion. If a patient has no increased secretion of porphobilinogen, acute porphyria is eliminated as a cause of the neurovisceral symptoms.^{[2, 3]}
- A common error is the failure to order urine porphyrins. Porphobilinogen, a porphyrin precursor, usually is not included in a urine porphyrin screen and must be ordered specially.
- AIP patients have elevated porphobilinogen between attacks.
- In some patients with a remote (years) history of attacks, porphobilinogen can return to the reference range.
Elevation of urine porphyrins, especially coporphobilinogen, is observed.
- This is caused by spontaneous polymerization of porphobilinogen in the urine.
- Nonspecific (1-2 times reference range) elevation of urine porphyrins, especially coproporphyrins, is common and is not indicative of porphyria.
Stool porphyrins are within the reference range or mildly elevated.
Other nonspecific signs in an attack of AIP include hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and mild leukocytosis.
Although a defective enzyme causes AIP, measuring the activity of porphobilinogen deaminase is of little value.
- Approximately 10% of AIP patients will have normal activity because a different form of the enzyme is expressed in the hematopoietic tissues.
- The vast majority of patients with the defective enzyme do not have any symptoms of the disease.

Imaging studies are not helpful.
Sometimes, abdomen films demonstrate an ileus.
Findings on cranial CT scan are normal.
Brain MRI occasionally shows signs of increased edema in patients having very severe attacks.

Other Tests

Attacks of acute porphyria are clinically indistinguishable in AIP, hereditary coproporphyria, variegate porphyria, and there are few evidence-based diagnostic strategies for these conditions. Whatley et al conducted a retrospective analysis of 467 unrelated patients to determine the diagnostic sensitivity of mutation analysis of the HMBS, CPOX, or PPOX gene.^[4]Findings included the following^[4]:

In the presence of increased porphobilinogen excretion, plasma fluorescence scanning and the coproporphyrin ratio can identify the type of acute porphyria, with rare exceptions.
In cases in which the porphobilinogen, 5-aminolevulinate, and porphyrin analyses are within reference intervals and in which the index of suspicion is high of a previous illness caused by an acute porphyria, mutation analysis of the HMBS gene followed by porphobilinogen deaminase assay is an effective strategy for diagnosis or exclusion of AIP.

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Contributor Information and Disclosures

Author

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, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Takeda Millenium Honoraria Speaking and teaching

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

Disclosure: Medscape Salary Employment

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, and Southwest Oncology Group

Disclosure: No financial interests None None

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies, 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 College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

References

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Anyaegbu E, Goodman M, Ahn SY, Thangarajh M, Wong M, Shinawi M. Acute Intermittent Porphyria: A Diagnostic Challenge. J Child Neurol. Dec 21 2011;[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].
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. Jul 2009;55(7):1406-14. [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. Apr 23 2009;epub ahead of print. [Medline].
Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. Mar 15 2005;142(6):439-50. [Medline].
Bonkovsky HL, Barnard GF. Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology. Semin Liver Dis. 1998;18(1):57-65. [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. Apr 28 2009;1-7. [Medline].
Daniell WE, Stockbridge HL, Labbe RF, et al. Environmental chemical exposures and disturbances of heme synthesis. Environ Health Perspect. Feb 1997;105 Suppl 1:37-53. [Medline].
Elder GH, Smith SG, Smyth SJ. Laboratory investigation of the porphyrias. Ann Clin Biochem. Sep 1990;27 ( Pt 5):395-412. [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. Apr 28 2009;420(1):17-25. [Medline].
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Kalman DR, Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):299-306. [Medline].
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Moore MR. The biochemistry of heme synthesis in porphyria and in the porphyrinurias. Clin Dermatol. Mar-Apr 1998;16(2):203-23. [Medline].
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Table 1. Drugs Thought Safe in Porphyria*

Acetazolamide acetylcholine Actinomycin D Acyclovir Adenosine monophosphate Adrenaline Alclofenac Allopurinol Alpha tocopheryl Acetate Amethocaine Amiloride Aminocaproic acid Aminoglycosides Amoxicillin Amphotericin Ampicillin Ascorbic acid Aspirin Atenolol Atropine Azathioprine Beclomethasone Benzhexol HCl Beta-carotene Biguanides [Bromazepam] Bromides Buflomedil HCl Bumetanide Bupivacaine Buprenorphine Buserelin Butacaine SO₄ Canthaxanthin Carbimazole [Carpipramine HCl] Chloral hydrate [Chlormethiazole] [Chloroquine] [Chlorothiazide] Chlorpheniramine Chlorpromazine Ciprofloxacin Cisapride Cisplatin Clavulanic acid Clofibrate Clomiphene Cloxacillin Co-codamol Codeine phosphate Colchicine [Corticosteroids] Corticotrophin (adrenocorticotropic hormone [ACTH])	Coumarins Cyclizine Cyclopenthiazide Cyclopropane [Cyproterone acetate] Danthron Desferrioxamine Dexamethasone [Dextromoramide] Dextrose Diamorphine Diazoxide Dicyclomine HCl Diflunisal Digoxin Dihydrocodeine Dimercaprol Dimethicone Dinoprost Diphenoxylate HCl Dipyridamole [Disopyramide] Domperidone Doxorubicin HCl Droperidol [Estazolam] Ethacrynic acid Ethambutol [Ethinyl oestradiol] Ethoheptazine citrate Etoposide Famotidine Fenbufen [Fenofibrate] Fenoprofen Fentanyl Flucytosine Flumazenil Fluoxetine HCl Flurbiprofen Fluvoxamine Maleate Folic acid Fructose Fusidic acid Follicle-stimulating hormone Gentamicin Glafenine Glucagon Glucose Glyceryl trinitrate Goserelin Guanethidine Guanfacine HCl Haem arginate [Haloperidol] Heparin Heptaminol HCl Hexamine [Hydrocortisone] Ibuprofen Indomethacin Insulin Iron Josamycin [Ketamine]	Ketoprofen Ketotifen Labetalol Luteinizing hormone–releasing hormone Liquorice Lithium Salts lofepramine Loperamide [Lorazepam] Magnesium-sulphate [Mebendazole] Mecamylamine Meclofenoxate HCl Meclozine Mefloquine HCl [Melphalan] Meptazinol Mequitazine Metformin Methadone [Methotrimeprazine] Methylphenidate Methyluracil Metipropranolol Metopimazine Metoprolol [Metronidazole] [Midazolam] Minaprine HCl Minaxolone Morphine Nadolol Naftidrofuryl Oxalate [Naproxen sodium] Natamycin Nefopam HCl Neostigmine Netilmicin Niflumic acid Nitrous oxide Norfloxacin Ofloxacin Oxolinic acid Oxybuprocaine [Oxyphenbutazone] Oxytocin [Pancuronium bromide] Paracetamol Paraldehyde Parapenzolate Br Penicillamine Penicillin Pentolinium Pericyazine Pethidine Phenformin Phenoperidine Phentolamine mesylate Pipotiazine	Palmitate Piracetam Pirbuterol Pirenzepine Pizotifen [Prazosin] [Prednisolone] Primaquine Probucol Procainamide HCl Procaine Prochlorperazine Proguanil HCl Promazine Propantheline Br Propofol Propranolol Propylthiouracil [Proxymetacaine] Pseudoephedrine HCl Pyridoxine [Pyrimethamine] Quinidine Quinine [Ranitidine] Reserpine Resorcinol Salbutamol Senna Sodium bromide Sodium ethylenediaminetetraacetic acid Sodium fusidate Sorbitol Streptomycin Sulbutiamine Sulindac Sulfadoxine Suxamethonium Talampicillin Temazepam Tetracaine [Tetracyclines] Thiouracils Thyroxine Tiaprofenic acid Ticarcillin Tienilic acid Timolol maleate Tolazoline Tranexamic acid Triacetyloleandomycin Triamterene Triazolam [Trichlormethiazide] Trifluoperazine Trimeprazine Tartrate Trimetazidine HCl Tripelennamine Tubocurarine Vancomycin [Vincristine] Vitamins Warfarin sodium Zidovudine Zinc Preparations
*Bracketed [] drugs are those in which experimental evidence of porphyrin genicity is conflicting.

Table 2. Drugs Thought Unsafe in Porphyria^†

Alcuronium Alphaxalone Alphadolone Alprazolam Aluminium Preparations Amidopyrine Aminoglutethimide Aminophylline Amiodarone Amitriptyline [Amphetamines] Amylobarbitone Antipyrine Auranofin Aurothiomalate Azapropazone Baclofen Barbiturates Bemegride Bendrofluazide Benoxaprofen Benzbromarone [Benzylthiouracil] [Bepridil] Bromocriptine Busulphan Butylscopolamine Captopril Carbamazepine Carbromal Carisoprodol [Cefuroxime] [Cephalexin] [Cephalosporins] [Cephradine] [Chlorambucil] Chloramphenicol Chlordiazepoxide Chlormezanone Chloroform Chlorpropamide Cinnarizine Clemastine [Clobazam] [Clomipramine HCl] [Clonazepam] Clonidine HCl Clorazepate Cocaine [Colistin] Co-trimoxazole	Cyclophosphamide Cycloserine Cyclosporin Danazol Dapsone Dexfenfluramine Dextropropoxyphene Diazepam Dichloralphenazone Diclofenac Na Dienoestrol Diethylpropion Dihydralazine Dihydroergotamine Diltiazem Dimenhydrinate Diphenhydramine [Dothiepin HCl] Doxycycline Dydrogesterone Econazole NO₃ Enalapril Enflurane Ergot compounds Ergometrine maleate Ergotamine tartrate Erythromycin Estramustine Ethamsylate Ethanol Ethionamide Ethosuximide Ethotoin Etidocaine Etomidate Fenfluramine Flucloxacillin Flufenamic acid Flunitrazepam Flupenthixol Flurazepam Frusemide Glibenclamide Glutethimide Glipizide Gramicidin Griseofulvin [Haloperidol] Halothane Hydantoins Hydralazine Hydrochlorothiazide Hydroxyzine Hyoscine Imipramine Iproniazid Isometheptene mucate [Isoniazid] Kebuzone Ketoconazole Levonorgestrel Lignocaine Lisinopril Loprazolam Loxapine *Lynestrenol Lysuride	Maleate Maprotiline HCl Mebeverine HCl Mecillinam Medroxyprogesterone [Mefenamic acid] Megestrol acetate Mephenytoin Mepivacaine Meprobamate Mercaptopurine Mercury compounds Mestranol [Metapramine HCl] Methamphetamine Methohexitone Methotrexate Methoxyflurane Methsuximide Methyldopa Methylsulphonal Methyprylone Methysergide Metoclopramide Metyrapone Mianserin HCl Miconazole [Mifepristone] Minoxidil Nandrolone Nalidixic acid Natamycin Nandrolone [Nicergoline] Nifedipine Nikethamide Nitrazepam Nitrofurantoin Nordazepam Norethynodrel Norethisterone [Nortriptyline] Novobiocin Oral contraceptives Orphenadrine Oxanamide [Oxazepam] Oxybutynin HCl Oxycodone Oxymetazoline Oxyphenbutazone Oxytetracycline Paramethadione Pargyline Pentazocine Perhexiline Phenacetin Phenelzine Phenobarbitone Phenoxybenzamine Phensuximide Phenylbutazone Phenylhydrazine Phenytoin Pipebuzone Pipemidic Acid Piritramide *Piroxicam	Pivampicillin Pivmecillinam Prazepam Prenylamine Prilocaine Primidone [Probenecid] Progesterone Progabide Promethazine [Propanidid] Pyrazinamide Pyrrocaine Quinalbarbitone Rifampicin Simvastatin Sodium aurothiomalate Sodium oxybate [Sodium valproate] Spironolactone Stanozolol Succinimides Sulfacetamide Sulfadiazine Sulfadimidine Sulfadoxine Sulfamethoxazole Sulfasalazine Sulfonylureas Sulfinpyrazone Sulpiride Sulthiame Sultopride Tamoxifen Terfenadine Tetrazepam Theophylline Thiopentone Na Thioridazine Tilidate Tinidazole Tolazamide Tolbutamide Tranylcypromine Trazodone HCl Trimethoprim [Trimipramine] Troxidone Valproate Valpromide Veralipride Verapamil Vibramycin Viloxazine HCl [Vinblastine] [Vincristine] Zuclopenthixol
*These drugs have been associated with acute attacks of porphyria. †Bracketed [] drugs are those in which experimental evidence of porphyringenicity is conflicting.

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Alcuronium Alphaxalone Alphadolone Alprazolam Aluminium Preparations Amidopyrine Aminoglutethimide Aminophylline Amiodarone Amitriptyline [Amphetamines] Amylobarbitone Antipyrine Auranofin Aurothiomalate Azapropazone Baclofen Barbiturates Bemegride Bendrofluazide Benoxaprofen Benzbromarone [Benzylthiouracil] [Bepridil] Bromocriptine Busulphan Butylscopolamine Captopril Carbamazepine Carbromal Carisoprodol [Cefuroxime] [Cephalexin] [Cephalosporins] [Cephradine] [Chlorambucil] Chloramphenicol Chlordiazepoxide Chlormezanone Chloroform Chlorpropamide Cinnarizine Clemastine [Clobazam] [Clomipramine HCl] [Clonazepam] Clonidine HCl Clorazepate Cocaine [Colistin] Co-trimoxazole	Cyclophosphamide Cycloserine Cyclosporin Danazol Dapsone Dexfenfluramine Dextropropoxyphene Diazepam Dichloralphenazone Diclofenac Na Dienoestrol Diethylpropion Dihydralazine Dihydroergotamine Diltiazem Dimenhydrinate Diphenhydramine [Dothiepin HCl] Doxycycline Dydrogesterone Econazole NO₃ Enalapril Enflurane Ergot compounds Ergometrine maleate Ergotamine tartrate Erythromycin Estramustine Ethamsylate Ethanol Ethionamide Ethosuximide Ethotoin Etidocaine Etomidate Fenfluramine Flucloxacillin Flufenamic acid Flunitrazepam Flupenthixol Flurazepam Frusemide Glibenclamide Glutethimide Glipizide Gramicidin Griseofulvin [Haloperidol] Halothane Hydantoins Hydralazine Hydrochlorothiazide Hydroxyzine Hyoscine Imipramine Iproniazid Isometheptene mucate [Isoniazid] Kebuzone Ketoconazole Levonorgestrel Lignocaine Lisinopril Loprazolam Loxapine *Lynestrenol Lysuride	Maleate Maprotiline HCl Mebeverine HCl Mecillinam Medroxyprogesterone [Mefenamic acid] Megestrol acetate Mephenytoin Mepivacaine Meprobamate Mercaptopurine Mercury compounds Mestranol [Metapramine HCl] Methamphetamine Methohexitone Methotrexate Methoxyflurane Methsuximide Methyldopa Methylsulphonal Methyprylone Methysergide Metoclopramide Metyrapone Mianserin HCl Miconazole [Mifepristone] Minoxidil Nandrolone Nalidixic acid Natamycin Nandrolone [Nicergoline] Nifedipine Nikethamide Nitrazepam Nitrofurantoin Nordazepam Norethynodrel Norethisterone [Nortriptyline] Novobiocin Oral contraceptives Orphenadrine Oxanamide [Oxazepam] Oxybutynin HCl Oxycodone Oxymetazoline Oxyphenbutazone Oxytetracycline Paramethadione Pargyline Pentazocine Perhexiline Phenacetin Phenelzine Phenobarbitone Phenoxybenzamine Phensuximide Phenylbutazone Phenylhydrazine Phenytoin Pipebuzone Pipemidic Acid Piritramide *Piroxicam	Pivampicillin Pivmecillinam Prazepam Prenylamine Prilocaine Primidone [Probenecid] Progesterone Progabide Promethazine [Propanidid] Pyrazinamide Pyrrocaine Quinalbarbitone Rifampicin Simvastatin Sodium aurothiomalate Sodium oxybate [Sodium valproate] Spironolactone Stanozolol Succinimides Sulfacetamide Sulfadiazine Sulfadimidine Sulfadoxine Sulfamethoxazole Sulfasalazine Sulfonylureas Sulfinpyrazone Sulpiride Sulthiame Sultopride Tamoxifen Terfenadine Tetrazepam Theophylline Thiopentone Na Thioridazine Tilidate Tinidazole Tolazamide Tolbutamide Tranylcypromine Trazodone HCl Trimethoprim [Trimipramine] Troxidone Valproate Valpromide Veralipride Verapamil Vibramycin Viloxazine HCl [Vinblastine] [Vincristine] Zuclopenthixol
*These drugs have been associated with acute attacks of porphyria. †Bracketed [] drugs are those in which experimental evidence of porphyringenicity is conflicting.

Acute Intermittent Porphyria Workup

Laboratory Studies

Imaging Studies

Other Tests