Hereditary Coproporphyria

Practice Essentials

Hereditary coproporphyria (HCP) 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.)

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Pathophysiology

Coproporphyria is an autosomal dominant disease caused by a 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]

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Etiology

Like acute intermittent porphyria (AIP), coproporphyria is due to a combination of a genetic enzyme defect and acquired factors that results in symptomatic disease 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. However, many attacks will occur without any obvious provocation.

Haimowitz and collegues reported a case of cholestatic liver failure 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*

View Table

See Table

Table 2. Drugs Thought Unsafe in Porphyria^†

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See Table

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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 population.^[7]  Researchers feel that symptomatic coproporphyria tends to occur more often in women than in men, 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. 

Chronic and long-term complications of acute hepatic porphyrias can include neuropathy, chronic kidney disease, and hepatocellular carcinoma.^[8]  However, a matched cohort study that compared complication risks against a matched reference population found no increased risk for hypertension, neuropathy, psychiatric disorders, or mortality among 56 patients with coproporphyria.^[9]

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Patient Education

See the list below:

• Teach patients the importance of avoiding unsafe drugs and fasting.
• Make patients aware of the possible chronic and long-term complications and the need for long-term monitoring.^[8]
• The American Porphyria Foundation recommends that people with coproporphyria wear a medical alert bracelet and/or carry a medical alert card.^[10]

Patient education information on hereditary coproporphyria is available on the American Porphyria Foundation Web site.

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History

Coproporphyria has neurovisceral, psychiatric, neurologic, and skin manifestations. The usual sequence of events in acute attacks is abdominal pain, then psychiatric symptoms, 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.^[11]

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 agitation, confusion, hallucinations, anxiety, and psychosis have been reported.^[12]  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, vesicles and bullae may develop. 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.

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Physical Examination

Vital signs during attacks are as follows:

• Tachycardia develops in 30-80% of patients
• Fever can sometimes be present
• 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; 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

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Approach Considerations

The diagnosis of hereditary coproporphyria is established by demonstrating excess secretion of coproporphyrins in the stool.^[13] 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).^{[15, 16]} After symptom resolution, urinary porphobilinogen levels may return to normal relatively quickly.^[16]

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.^[16] 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 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 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.^[17]

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Approach Considerations

The goals in managing an acute attack of porphyria are to decrease heme synthesis and to reduce the production of porphyrin precursors.^{[18, 19]} For mild attacks (ie, mild pain and no vomiting, paralysis, or hyponatremia), guidelines from the British and Irish Porphyria Network 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.^[16]

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.^[16]

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.^[16]

Treatment options for other manifestations are as follows^[16] :

• 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.

Givosiran

In 2019, givosiran (Givlaari) was approved by the US Food and Drug Administration (FDA) for adults with acute hepatic porphyrias (ie, acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, ALA dehydratase deficiency porphyria), in which attacks are caused by induction of the enzyme 5-aminolevulinic acid synthase 1 (ALAS1). The recommended givosiran dose is 2.5 mg/kg once monthly by subcutaneous injection.^[20]

Givosiran is a small-interfering RNA that causes degradation of ALAS1 messenger RNA (mRNA) in hepatocytes, reducing the elevated levels of ALAS1 mRNA in the liver. The ENVISION study demonstrated that long-term givosiran has an acceptable safety profile and significantly reduces the frequency of attacks, hemin use, and pain severity.^{[21, 22]}  

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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.

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Prevention

Avoid medicines that can provoke an attack. The presumptive list of medications to avoid is long (see Overview/Etiology); 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 long-term hematin infusion. For example, women with severe symptoms at the time of their menses can have a single dose of 4 mg/kg before the onset of their period.

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Long-Term Monitoring

All patients should be monitored annually for liver disease.  Regardless of the severity of symptoms, surveillance for hepatocellular carcinoma (HCC) with liver ultrasound every 6 months should begin at age 50. Patients receiving treatment should undergo surveillance for chronic kidney disease, with annual measurement of serum creatinine and estimated glomerular filtration rate.^[8]

Patients should be counseled on the chronic and long-term complications of acute hepatic porphyrias, including neuropathy, chronic kidney disease, hypertension, and HCC, and the consequent need for long-term monitoring.

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Guidelines Summary

In 2023, the American Gastroenterological Association (AGA) offered the following best practice advice for the diagnosis and management of acute hepatic porphyrias (AHPs)^[8] :

• Screen for AHPs in women aged 15–50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup 
• Initial diagnosis is based on biochemical testing, with measurement of amino-levulinic acid (ALA), porphobilinogen (PBG), porphyrins, and creatinine in a random urine sample.
• Diagnosis is confirmed by genetic testing in patients with positive biochemical testing.
• Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein.
• Additional management of acute attacks includes pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia and hypomagnesemia, as needed.
• Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks (eg, alcohol and medications).
• Outpatient prophylactic heme therapy or givosiran should be considered in patients with recurrent attacks (≥4 per year).
• Liver transplantation may be indicated for patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy.
• All patients should be monitored annually for liver disease. 
• Regardless of the severity of symptoms, surveillance for hepatocellular carcinoma (HCC) with liver ultrasound every 6 months should begin at age 50.
• Patients receiving treatment for AHP should undergo surveillance for chronic kidney disease (CKD) annually with serum creatinine and estimated glomerular filtration rate.
• Patients should be counseled on the chronic and long-term complications including neuropathy, CKD, hypertension, and HCC, and need for long-term monitoring.

The British Inherited Metabolic Disease Group published guidelines in 2021 on the emergency management of acute porphyria in adults.^[23] Recommended initial investigations included the following:

• A complete blood cell count, blood urea nitrogen, and electrolytes; serum sodium should be monitoried at least every 12-24 hours, as serum hyponatremia can evolve rapidly and lead to seizures
• Urine PBG
• Other tests as indicated by clinical findings (eg, C-reactive protein, infection screen)

Recommended treatment measures included the following:

• Analgesia – Opiates are almost always indicated and should be administered regularly, by subcutaneous or oral routes when possible; consider patient-controlled analgesia with morphine if pain is severe
• Maintain fluid and calorie intake – If the patient tolerates oral intake, encourage carbohydrates; if not, start intravenous 0.9% sodium chloride, with or without 5% glucose; avoid dextrose in water (D5W, D10W), which can precipitate or exacerbate hyponatremia
• Treat symptoms as indicated

Recommended symptomatic treatments include the following:

• Vomiting – Ondansetron, cyclizine, prochlorperazine
• Agitation – Chlorpromazine
• Seizures – Diazepam, clonazepam, magnesium sulfate
• Hypertension/tachycardia – Propranolol, labetalol
• Constipation – Bulk laxatives, senna

The guidelines recommend considering treatment with haem arginate in select patients. Indications for haem arginate include the following:

• Severe persistent pain
• Persistent vomiting
• Neuropathy
• Seizures
• Hyponatremia
• Psychosis
• Severe hypertension and tachycardia

However, the guidelines caution that haem arginate carries a risk of significant extravasation injury with thrombophlebitis, and offer measures for reducing the risk of these complications.

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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.

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Panhematin (Hemin)

Clinical Context:  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.

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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.

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Gabapentin (Gralise, Neurontin)

• Dosing, Interactions, etc.

Clinical Context:  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.

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