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.
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:
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:
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]
Vital signs during attacks of acute intermittent porphyria (AIP) include the following:
Neurological manifestations are as follows:
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.
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*
View Table | See Table |
Table 2. Drugs Thought Unsafe in Porphyria†
View Table | See Table |
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, (ie, a level of 0-4 mg/L during acute symptoms), acute porphyria is eliminated as a cause of the neurovisceral symptoms.[9, 10]
A spot urine test for porphobilinogen can rapidly provide the diagnosis; these tests detect porphobilinogen at levels greater than 6 mg/L. A common error is to order a urine porphyrin screen. Porphobilinogen, a porphyrin precursor, usually is not included in a urine porphyrin screen; it must be ordered specially.
AIP patients have elevated porphobilinogen between attacks. However, in some patients with a remote (years ago) 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 specific for porphyria. Stool porphyrins are within the reference range or mildly elevated.
Other nonspecific signs in an attack of AIP include the following:
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 usually not helpful. Abdominal films will sometimes demonstrate an ileus. Findings on cranial computed tomography (CT) scan are normal.
Brain magnetic resonance imaging (MRI) scans occasionally show signs of increased edema in patients having very severe attacks. In patients with seizures, MRI may demonstrate parieto-occipital gyriform lesions on T2-weighted images that are characteristic of posterior reversible encephalopathy syndrome (PRES).[11]
Attacks of AIP are clinically indistinguishable from those of hereditary coproporphyria and 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.[12] Findings included the following[12] :
The treatment goal for acute attacks of porphyria is to decrease heme synthesis and reduce the production of porphyrin precursors. High doses of glucose can inhibit heme synthesis and are useful for treatment of mild attacks. United Kingdom guidelines recommend administering 5% glucose in 0.9% sodium chloride solution, infused intravenously at a rate of 2 L/24 h. Intravenous glucose in water solutions (eg, dextrose 5% or 10% [D5W, D10W]), should be avoided as they may aggravate hyponatremia.[13]
Patients experiencing severe attacks, especially those with severe neurologic symptoms, should be treated with hematin in a dose of 4 mg/kg/d for 4 days. Once hematin is initiated, glucose therapy no longer has a role.[13]
Pain can be remarkably severe, and pain control is best achieved with narcotics. Laxatives and stool softeners should be administered with the narcotics to avert exacerbating existing constipation.
Symptomatic treatment also includes the use of beta-blockers to control tachycardia and prevent arrhythmia; beta- blockers, clonidine, or other recommended antihypertensives can also be used to treat hypertensive crisis. Nausea and vomiting can be controlled with olanzapine, lorazepam, or prochlorperazine.[14]
Treat seizures with gabapentin. Most classic antiseizure medicines are contraindicated, as they can lead to acute porphyria attacks.
A minority of patients with acute intermittent porphyria (AIP) experience recurrent attacks. In addition to avoidance of precipitating factors, treatment options that may be considered in those cases include gonadotrophin-releasing hormone analogues (for women with attacks related to their menstrual cycles) and prophylactic hematin infusions.[13]
Rarely, liver transplantation may be indicated for patients with intractable recurrent attacks that are life-threatening or severely affect quality of life. Liver transplantation cures AIP.[13]
A comprehensive rehabilitation program, overseen by a physiatrist, can help patients regain functional independence after attacks of AIP.[15]
Gene therapy for AIP is currently under investigation. A phase I trial using intravenous delivery of normal PBGD genes to hepatocytes using an adeno-associated virus vector confirmed the safety and tolerability of this approach, but demonstrated the need for higher doses and/or more efficient vectors in order to achieve full clinical benefit.[16] In an animal model, improved vector efficiency has been accomplished by insertion into the promoter of a short enhancer element that can induce transgene expression during exposure to endogenous and exogenous stimuli that can trigger attacks.[17]
The patient should receive a high-carbohydrate diet during the attack. If the patient is unable to eat, intravenous glucose should be administered. Between attacks, eating a balanced diet is more important than eating one rich in glucose.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Intravenous hematin is the treatment of choice, both for treatment of severe acute attacks and for prevention of recurrent attacks.[8]
Clinical Context: Provides negative feedback to the heme synthetic pathway and shuts down productions of porphyrins and porphyrin precursors.
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
PipotiazinePalmitate
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.
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-trimoxazoleCyclophosphamide
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
LysurideMaleate
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.