Acute Intermittent Porphyria

Updated: Jan 13, 2023
  • Author: Thomas G DeLoughery, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

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. Unlike some other acute porphyrias, AIP does not manifest as sun sensitivity and skin rashes.

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).

Treatment options in AIP are as follows:

  • Avoidance of precipitating factors (eg, fasting, unsafe drugs; see Etiology)
  • High doses of glucose for mild attacks
  • Hematin for severe attacks, especially those with severe neurologic symptoms
  • During attacks, which generally last for several days, symptomatic treatment for pain and other manifestations (eg, tachycardia, nausea and vomiting, seizures)
  • Gonadotropin-releasing hormone analogues for women with attacks related to their menstrual cycles
  • Prophylactic hematin infusions
  • Givosiran, in patients with acute hepatic porphyria, to decrease the rate of acute attacks [2]  
  • Liver transplantation, as a last resort for patients with intractable recurrent attacks that are life-threatening or severely affect quality of life

See Treatment and Medication.

For more information on the porphyrias, see Porphyria Overview.

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Pathophysiology

AIP is an autosomal dominant disease that, like all forms of porphyria, is due to disruption of the pathway for the synthesis of heme. Specifically, AIP results from defects in the enzyme porphobilinogen deaminase (PBGD; also known as hydroxymethylbilane synthase [HMBS]), which catalyzes the conversion of porphobilinogen to hydroxymethylbilane. Impaired function of PBGD leads to the accumulation of the porphyrin precursors porphobilinogen and amino-levulinic acid (ALA). The predominant clinical problem appears to be neurologic damage that leads to peripheral and autonomic neuropathies and psychiatric manifestations. [3]

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. [4]

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Etiology

Acute intermittent porphyria (AIP) is due to a combination of a genetic defect—mutations in the HMBS (hydroxymethylbilane synthase) gene that encodes the enzyme porphobilinogen deaminase [5] —and acquired factors. In patients with AIP, the function of porphobilinogen deaminase is only 40-60% of normal. With the advent of molecular technique, it has become clear that carriage of the genetic defect is much more common than symptomatic AIP. On average, out of 100 patients with the genetic defect, perhaps 10-20 secrete excess porphyrin precursors and only 1-2 have symptoms.

The classic inducers of porphyria attacks are chemicals or situations that boost heme synthesis. This includes fasting and many medications. Although very large lists of "safe" and "unsafe" drugs exist, many of these are based on anecdotes or laboratory evidence and do not meet strict criteria. In general, drugs that lead to increased activity of the hepatic P450 system, such as phenobarbital, sulfonamides, estrogens, and alcohol, are associated with porphyria. See the tables below. A large and detailed list is available on the University of Queensland, Department of Medicine Web site. However, many attacks occur without any obvious provocation.

Table 1. Drugs Thought Unsafe in Porphyria (Open Table in a new window)

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] [6]

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

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.

Table 2. Drugs Thought Safe in Porphyria* (Open Table in a new window)

Acetazolamide acetylcholine

Actinomycin D [6]

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.

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Epidemiology

Frequency

Estimates of the prevalence of AIP in the United States vary from 1-5 cases per 100,000 population. European studies indicate that the prevalence of AlP is approximately five per 100,000 population. [7] The prevalence can be as high as 60-100 cases per 100,000 population in northern Sweden. [8] In Japan, the prevalence of acute hepatic porphyria (most of which is AIP) is estimated to be 1.18 cases per 100 000 population. [9]

Sex- and Age-related Demographics

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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Prognosis

Untreated AIP is associated with significant morbidity and can lead to pareses and death. Long-term complications include chronic hypertension, chronic neuropathy, chronic kidney disease, and hepatocellular carcinoma. [10, 11]  

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