Practice Essentials
Hereditary coproporphyria is one of the porphyrias, a group of diseases that involves defects in heme metabolism and that results in excessive secretion of porphyrins and porphyrin precursors. Inheritance is autosomal (usually autosomal dominant, but sometimes autosomal recessive). [1]
Many persons with the disorder remain asymptomatic. Attacks may be triggered by chemicals (including many medications) or situations (eg, fasting) that boost heme synthesis. Coproporphyria manifests with signs and symptoms that include abdominal pain, neuropathies, constipation, and skin changes. (See Presentation.)
The diagnosis of hereditary coproporphyria is established by demonstrating excess secretion of coproporphyrins in the stool. Gene studies confirm the diagnosis and allow family studies. During attacks, serum sodium levels should be measured, as hyponatremia is common. (See Workup.)
Glucose and supportive care are used to treat mild attacks. Patients with severe attacks require hospitalization; along with supportive care for specific manifestations, treatment is with hematin, narcotics for pain control, and gabapentin for seizures. (See Treatment and Medication.)
Pathophysiology
Coproporphyria is an autosomal dominant disease caused by a genetic mutation of the CPOX gene that results in defects in the enzyme coproporphyrinogen oxidase. [2] This enzyme speeds the conversion of coproporphyrinogen to protoporphyrinogen. In coproporphyria, the porphyrin precursors porphobilinogen and amino-levulinic acid (ALA) accumulate, as well as the formed porphyrin coproporphyrin. The predominant problem is neurologic damage that leads to peripheral and autonomic neuropathies and psychiatric manifestations. In coproporphyria, skin disease also is present but not as commonly as the neurovisceral symptoms.
The etiology of the skin disease may be the deposition of formed porphyrins in the skin that react with sunlight and lead to skin damage. Although patients with acute neurovisceral attacks always have elevations of porphobilinogen and ALA, researchers still are unclear about how this leads to the symptomatic disease, because most patients with the genetic defect have excessive porphyrin secretion but no symptoms. [3]
Etiology
Like acute intermittent porphyria (AIP), coproporphyria is due to a combination of a genetic enzyme defect and acquired causes that become symptomatic in rare cases. [4] In patients with coproporphyria, the function of coproporphyrinogen oxidase is only 40-60% of normal. [5] Also, like AIP, most patients with defects in coproporphyrinogen oxidase never have any symptoms. The classic inducers of porphyria are chemicals or situations that boost heme synthesis. This includes fasting and many medications.
Although extensive lists of safe and unsafe drugs exist, many of these are based on anecdotes or laboratory evidence rather than meeting strict criteria. In general, drugs that lead to increased activity of the hepatic P450 system (eg, phenobarbital, sulfonamides, estrogens, alcohol) are associated with porphyria attacks. A large and detailed list, shown below, is available through the European Porphyria Network. Fasting for several days also can trigger an attack. Many attacks will occur, however, without any obvious provocation.
Haimowitz and collegues reported a case of cholestatic liver failure due in a patient with undiagnosed hereditary coproporphyria after the use of an over-the-counter supplement containing Camellia sinensis and hydroxycitric acid. This case is an example of how environmental exposures can incite disease in a patient with genetic susceptibility to it. [6]
Table 1. Drugs Thought Safe in Porphyria* (Open Table in a new window)
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. |
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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 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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Epidemiology
A 3‐year prospective study of newly diagnosed symptomatic patients with inherited porphyrias in 11 European countries reported an annual incidence for symptomatic hereditary coproporphyria of 0.02 per million. [7] Researchers feel that women with coproporphyria tend to be symptomatic more than men are, but the data are sparse. Most patients with porphyria become symptomatic at age 18-40 years. Attacks are rare before puberty or after age 40 years.
Prognosis
Most patients (60-80%) who have an acute attack of porphyria never have another. Avoiding precipitating factors also helps prevent attacks. Researchers feel that coproporphyria is a less severe disease than AIP, but deaths have been reported in improperly treated cases.
Patient Education
Teach patients the importance of avoiding unsafe drugs and fasting.
The American Porphyria Foundation recommends patients wear medical alert bracelets and/or carry medical alert cards. [8]
Patient education information on hereditary coproporphyria is available on the American Porphyria Foundation Web site.
Tables
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. |
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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. |
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