Acute Intermittent Porphyria Clinical Presentation

Updated: Dec 22, 2018
  • Author: Thomas G DeLoughery, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Presentation

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:

  1. Abdominal pain
  2. Psychiatric symptoms
  3. 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:

  • Seizures
  • Delirium
  • Cortical blindness
  • 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]

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Physical

Vital signs during attacks of acute intermittent porphyria (AIP) include the following:

  • From 30-80% of patients have tachycardia
  • Fever can be present in some patients
  • Hypertension is observed in half of patients and may persist between attacks

Neurological manifestations are as follows:

  • Usually, the neuropathy is a motor neuropathy that is more predominant in the lower limbs
  • Areflexia often is present on examination
  • Any nerve can be involved, and cranial neuropathies also are observed
  • 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.

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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.

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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