Hereditary Coproporphyria 

Updated: Dec 27, 2017
Author: Thomas G DeLoughery, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Background

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.

Pathophysiology

Coproporphyria is an autosomal dominant disease that results from defects in the enzyme coproporphyrinogen oxidase. 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.[1]

Epidemiology

Frequency

United States

Coproporphyria is 20 times less common (ie, 1-4 cases per 1,000,000 people) than acute intermittent porphyria (AIP).

Mortality/Morbidity

Researchers feel that coproporphyria is a less severe disease than AIP, but deaths have been reported in improperly treated cases.

Sex- and Age-based Demographics

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.

 

Presentation

History

Coproporphyria has neurovisceral, psychiatric, neurologic, and skin manifestations. The usual sequence of events in acute attacks is abdominal pain, then psychiatric symptoms (eg, hysteria), then peripheral neuropathies. The exact mechanism by which the porphyrin precursors lead to these symptoms is unknown.

Neurovisceral manifestations

Neurovisceral signs and symptoms consist of autonomic neuropathies such as constipation, abdominal pain, and vomiting. Patients can have very severe abdominal pain that lasts for several days. Pain of short duration (minutes) or chronic abdominal pain does not develop in coproporphyria. The pain often is epigastric and is colicky in nature.

Patients often are free of pain between attacks. Constipation is common and can be very severe. Nausea and vomiting frequently are present.

Neurologic manifestations

Patients with coproporphyria can have both central nervous system (CNS) and peripheral nervous system manifestations. CNS manifestations include seizures, mental status changes, cortical blindness, and coma. Peripheral neuropathies are predominantly motor neuropathies and can mimic Guillain-Barré syndrome. The weakness usually starts in the lower limbs and ascends, but neuropathies occur in any nerve distribution.

Diffuse pain, especially in the upper body, can be observed. Patients also can develop autonomic neuropathies, including hypertension and tachycardia.

Psychiatric manifestations

Patients can have a wide variety of psychiatric symptoms. Depression is common. Patients with psychiatric manifestations usually have concurrent neurologic or abdominal symptoms.

Skin manifestations

The skin disease is similar to porphyria cutanea tarda. With long-term (not acute) sun exposure, patients can develop vesicles and bullae. If patients are symptomatic with coproporphyria, they tend to have neurovisceral symptoms rather than skin symptoms. Blisters form in sun-exposed areas and can evolve into chronic scarred areas of fragile skin. Patients also may develop excessive hair growth in sun-exposed areas.

Causes

Like AIP, coproporphyria is due to a combination of a genetic enzyme defect and acquired causes that become symptomatic in rare cases.[2] In patients with coproporphyria, the function of coproporphyrinogen oxidase is only 40-60% of normal.[3] 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.[4]

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.

Physical Examination

Vital signs are as follows:

  • Tachycardia develops in 30-80% of patients

  • Fever can be present in some patients

  • Hypertension develops in 50% of cases and may persist between attacks

Neurologic manifestations are as follows:

  • Typically, the neuropathy is a motor neuropathy that is more predominant in the lower limbs

  • Areflexia is observed during the examination; however, any nerve can be involved. Cranial neuropathies also are observed, and the patient may have cortical blindness

Abdominal examination: Despite the intense pain that may accompany a severe attack, the findings on abdominal examination often are nonspecific.

Skin manifestations are as follows:

  • Patients can have blisters, chronic erosion, and areas of excessive hair growth

  • Skin damage develops in sun-exposed areas of the skin

 

DDx

Diagnostic Considerations

In a retrospective analysis of 467 patients, Whatley et al examined the diagnostic accuracy of plasma fluorescence scanning, fecal porphyrin analysis, and porphobilinogen deaminase (PBGD) assay in differentiating between coproporphyria, acute intermittent porphyria (AIP), and variegate porphyria (VP).[5, 6] The authors determined that the specificity and sensitivity of the fecal coproporphyrin isomer ratio and of the fluorescence emission peak's wavelength were great enough to differentiate between the 3 conditions. They also found that in mutation-negative patients, the accuracy of deoxyribonucleic acid (DNA) analysis followed by PBGD assay was greater than that for either test individually, in the diagnosis or exclusion of AIP.

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of hereditary coproporphyria is established by demonstrating excess secretion of coproporphyrins in the stool.[5] Levels of stool coproporphyrins, especially coproporphyrin type III, are markedly elevated, usually 10-200 times greater than in controls.

Levels of urine porphyrins vary, but urine coproporphyrin levels usually are also markedly elevated, especially during acute attacks of the disease. Elevated porphobilinogen levels in the presence of appropriate clinical symptoms is diagnostic of porphyria; this is true of both hereditary coproporphyria and acute intermittent porphyria (AIP).[7, 8] After symptom resolution, urinary porphobilinogen levels may return to normal relatively quickly.[8]

Mild elevations of urine coproporphyrins (eg, as high as two times the reference range) are common and nonspecific. Fasting, subtle liver disease, or normal variations are the most common causes of elevated urine coproporphyrins. In such cases, patients may be incorrectly labeled as having porphyria.

Serum sodium levels should be measured in patients experiencing attacks, as hyponatremia is common; this has been attributed to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but renal and/or gastrointestinal sodium loss may also be involved.[8] Mild leukocytosis is another nonspecific finding during an attack.

Although coproporphyria is caused by a defective enzyme, there is little use in measuring the activity of coproporphyrinogen oxidase. The vast majority of patients who have the defective enzyme do not have any symptoms of the disease. Furthermore, the only available clinical assay has been withdrawn due to problems with high rates of false-positive results. The diagnosis of a porphyria attack rests on demonstration of excessive excretion of porphyrins and porphyrin precursors.

Imaging studies are not helpful. Abdominal films sometimes demonstrate an ileus. Findings on cranial computed tomography scans are normal. Brain magnetic resonance imaging scans occasionally show signs of increased edema in patients with very severe attacks.

Identification of a heterozygous pathogenic variant in CPOX (encoding the enzyme coproporphyrinogen-III oxidase) confirms the diagnosis and enables family studies.[9]

 

Treatment

Approach Considerations

The goals in managing an acute attack of porphyria are to decrease heme synthesis and to reduce the production of porphyrin precursors.[10, 11] For mild attacks (ie, mild pain and no vomiting, paralysis, or hyponatremia), guidelines from the advise that a high-carbohydrate diet (eg, with glucose-containing drinks and high-energy foods) and supportive measures may be used for up to 48 hours.[8]

High oral doses of glucose (400 g/d) can inhibit heme synthesis and are useful for the treatment of mild attacks. Intravenous glucose solutions (eg, 5% or 10% dextrose in water) can be used in patients who cannot eat, but may aggravate hyponatremia.

Treat severe attacks, especially those involving severe neurologic symptoms, with hematin at a dose of 4 mg/kg/d for 4 days. Patients with severe attacks should be hospitalized for symptom control and monitoring of fluid and electrolyte balance, as well as cardiovascular, respiratory, and neurologic function.[8]

Pain control is best achieved with narcotics; high doses are typically required. Administer laxatives and stool softeners with the narcotics to avert exacerbating the patient's constipation.

For seizure control, administer gabapentin. Most of the classic antiseizure medications are contraindicated in acute attacks of porphyria. However, the British and Irish Porphyria Network, while acknowledging that the safety of intravenous diazepam is controversial in porphyria attacks, concludes that benefit outweighs risk in this acute situation.[8]

Treatment options for other manifestations are as follows[8] :

  • Nausea and vomiting - Prochloperazine, promazine, or ondansetron.

  • Severe agitation and anxiety - Chlorpromazine

  • Hypertension and tachycardia - Atenolol, propranolol or labetalol (but use with caution and monitor for hypotension and bradycardia)

Unlike porphyria cutanea tarda, the skin disease in coproporphyria does not respond to phlebotomy or antimalarial drugs.

Diet

Patients should receive a high-carbohydrate diet during the attack. Administer intravenous glucose if patients cannot eat. Between attacks, patients should eat a constant balanced diet rather than one that is extremely rich in glucose.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Panhematin is the drug of choice for severe attacks and may be used long-term for patients with recurrent attacks. Narcotics are used to control pain, and gabapentin is used to control seizures.

Blood products

Class Summary

The key treatment of porphyria is stopping heme synthesis. Hematin provides negative feedback to the heme synthetic pathway and shuts down productions of porphyrins and porphyrin precursors.

Panhematin (Hemin)

DOC for severe porphyria attacks. Enzyme inhibitor derived from processed red blood cells and an iron-containing metalloporphyrin. Was previously known as hematin, a term used to describe the chemical reaction product of hemin and sodium carbonate solution.

 

Follow-up

Further Outpatient Care

Patients with recurrent attacks may benefit from a program of chronic hematin infusion. For example, women with severe symptoms at the time of their menses can have 1 dose of 4 mg/kg before the onset of their period.

Deterrence/Prevention

Avoid medicines that can provoke an attack. The list of medications to avoid is long (see Causes); however, only a few have been implicated clearly in porphyria. Patients also should avoid overconsumption of alcohol and avoid fasting.

Prognosis

See the list below:

  • Most patients (60-80%) who have an acute attack of porphyria never have another. Avoiding precipitating factors also helps prevent attacks. Researchers consider coproporphyria a less severe disease than AIP.

Patient Education

See the list below:

  • 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 Adults, Constipation in Adults, and Chronic Pain.