Hereditary Coproporphyria

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]

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)

Table 2. Drugs Thought Unsafe in Porphyria^† (Open Table in a new window)

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.

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. 

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.

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. Posterior reversible encephalopathy has been reported.[9]

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

A wide variety of psychiatric symptoms including aggitation, confusion, hallucinations, anxiety and psychosis have been reported.[10]  Depression is common. Patients with psychiatric manifestations usually have concurrent neurologic or abdominal symptoms.

Skin manifestations

Hereditary coproporphyria rarely (5%) involves skin photosensitivity.[2] 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. Excessive hair growth may also develop in sun-exposed areas.

Vital signs during attacks 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
• Dark reddish urine may be present ^[1]

Neurologic manifestations of attacks 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:

• Blisters, chronic erosion, and areas of excessive hair growth may be present
• Skin damage develops in sun-exposed areas of the skin

The diagnosis of hereditary coproporphyria is established by demonstrating excess secretion of coproporphyrins in the stool.[11] 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).[13, 14] After symptom resolution, urinary porphobilinogen levels may return to normal relatively quickly.[14]

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.[14] 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.[15]

The goals in managing an acute attack of porphyria are to decrease heme synthesis and to reduce the production of porphyrin precursors.[16, 17] 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.[14]

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.[14]

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.[14]

Treatment options for other manifestations are as follows[14] :

• 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.

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.

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.

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.

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.

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.

Gabapentin (Gralise, Neurontin)

GABA analogue that is structurally related to neurotransmitter GABA, but has no effect on GABA binding, uptake, or degradation; presence of gabapentin binding sites throughout the brain reported; mechanism for analgesic and anticonvulsant activity unknown. Indicated for adjunctive therapy for partial seizures with or without secondary generalization.