Hereditary Coproporphyria

Updated: Dec 27, 2020
  • Author: Thomas G DeLoughery, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

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).

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.

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Pathophysiology

Coproporphyria is an autosomal dominant disease caused by a genetic mutation of the CPOX gene that results from defects in the enzyme coproporphyrinogen oxidase. [1] 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 the 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. [2]

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Etiology

Like AIP, coproporphyria is due to a combination of a genetic enzyme defect and acquired causes that become symptomatic in rare cases. [3]  In patients with coproporphyria, the function of coproporphyrinogen oxidase is only 40-60% of normal. [4]  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 HCP after the use of Hydroxycut™, an over-the-counter supplement containing Camellia sinensis and hydroxycitric acid. This case highlights the genetic susceptibility of the disease that can be incited by environmental exposures. [5]

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.

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 HCP of 0.02 per million. [6]  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.

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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. 

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Patient Education

Teach patients the importance of avoiding unsafe drugs and fasting.

For patient education information, see the Digestive Disorders Center, as well as Abdominal Pain in AdultsConstipation in Adults, and Chronic Pain.

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