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.
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]
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.
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]
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
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]
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.
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.
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.
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.
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.
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.
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.
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.
Thomas G DeLoughery, MD, Professor of Medicine, Pathology, and Pediatrics, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health and Science University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine
Disclosure: Partner received none from No financial interests for none.
Chief Editor
Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Nothing to disclose.
Additional Contributors
Clarence Sarkodee Adoo, MD, FACP, Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program
Bissell DM, Wang B, Lai J. Hereditary Coproporphyria. Bissell DM, Wang B, Lai J, Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K. GeneReviews®. [internet]. Seattle, WA: University of Washington, Seattle; 1993-2016.
Bickers DR, Pathak MA, Lim HW. The Porphyrias. In: Fitzpatrick B, et al, eds. Dermatology in General Medicine. New York, NY:. McGraw-Hill, Inc. 1993:1854-1893.
