History
The onset of attacks in individuals with acute intermittent porphyria (AIP) typically occurs at age 18-40 years. Attacks before puberty or after age 40 years may be triggered by a major provocation, such as new use of phenobarbital or estrogens. Attacks generally last for 3 to 7 days.
The usual sequence of events in attacks of AIP is as follows:
- Abdominal pain
- Psychiatric symptoms
- Peripheral neuropathies
The abdominal pain often is epigastric and colicky in nature; it is severe and lasts for several days. Constipation or vomiting may also occur. Severe abdominal pain of short (< 1 d) duration or chronic abdominal pain is unusual. Diffuse pain, especially in the upper body, may also be observed.
Patients can have a wide variety of psychiatric symptoms. Depression is very common. Usually, patients have concurrent neurologic or abdominal symptoms. A Swedish study documented a fourfold increased risk of schizophrenia or bipolar disorder in patients with AIP. The risk in relatives of individuals with AIP was increased twofold, suggesting common genetic influences with these diseases. [5]
Peripheral neuropathies tend to be predominantly motor and can mimic Guillain-Barré syndrome. The weakness usually starts in the lower limbs and ascends, but neuropathies can be observed in any nerve distribution. Autonomic neuropathies that produce hypertension and tachycardia may also occur.
Central nervous system signs may include the following:
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Seizures
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Delirium
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Cortical blindness
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Coma
Skin manifestations are not a feature of AIP attacks, as they are of other forms of porphyria (eg, porphyria cutanea tarda).
Between attacks, patients may be completely free of symptoms. However, emerging evidence points to chronic manifestations as a feature in 20-64% of patients with AIP. In a study of patients with frequent attacks of AIP, 18 of the 19 patients interviewed also described chronic symptoms, which were often disabling. Key chronic symptoms consisted of pain, nausea, fatigue, and features of neuropathy (eg, tingling and numbness). [6]
Physical
Vital signs during attacks of acute intermittent porphyria (AIP) include the following:
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From 30-80% of patients have tachycardia
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Fever can be present in some patients
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Hypertension is observed in half of patients and may persist between attacks
Neurological manifestations are as follows:
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Usually, the neuropathy is a motor neuropathy that is more predominant in the lower limbs
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Areflexia often is present on examination
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Any nerve can be involved, and cranial neuropathies also are observed
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Patients also may have cortical blindness
Despite the intense pain, the findings on abdominal examination often are nonspecific. Skin examination is noncontributory; unlike many other porphyrias, AIP is not associated with a skin rash.
Causes
Acute intermittent porphyria (AIP) is due to a combination of a genetic enzyme defect and acquired causes that become symptomatic only in some patients. 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 the genetic defect is 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 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.
A large and detailed list is available on the University of Queensland, Department of Medicine Web site.
Fasting for several days also can trigger an attack. However, many attacks occur without any obvious provocation.
Table 1. Drugs Thought Safe in Porphyria* (Open Table in a new window)
Acetazolamide acetylcholine Actinomycin D [7] 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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Table 2. 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] [7] 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. |
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Tables
Acetazolamide acetylcholine Actinomycin D [7] 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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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] [7] 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. |
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