eMedicine Specialties > Hematology > Heme Synthesis and Disorders

Porphyria, Hereditary Coproporphyria

Thomas G DeLoughery, MD, Professor of Medicine and Pathology, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health Sciences University

Updated: Nov 4, 2009

Introduction

Background

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. Coproporphyria manifests with abdominal pain, neuropathies, constipation, and skin changes.

Recent research

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).¹ 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.

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.²

Frequency

United States

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

Mortality/Morbidity

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

Sex

Researchers feel that women with coproporphyria tend to be symptomatic more than men are, but the data are sparse.

Age

Most patients with porphyria become symptomatic at age 18-40 years. Attacks are rare before puberty or after age 40 years.

Clinical

History

Coproporphyria displays both neurovisceral and skin manifestations.

• Neurovisceral symptoms
  • These symptoms consist of autonomic neuropathies (constipation, colicky abdominal pain, vomiting, hypertension), peripheral neuropathy, seizures, delirium, coma, and depression.
  • The sequence of events in attacks usually is abdominal pain then psychiatric symptoms (eg, hysteria), then peripheral neuropathies.
  • 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.
  • The exact mechanism by which the porphyrin precursors lead to these symptoms is unknown.
  • Patients often are free of pain between attacks. Constipation is common and can be very severe. Nausea and vomiting frequently are present.
• Skin manifestations
  • The skin disease is similar to porphyria cutanea tarda. With long-term (not acute) sun exposure, patients can develop vesicals 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.
• Neurologic manifestations
  • Patients with coproporphyria can have central nervous system signs, including seizures, mental status changes, cortical blindness, and coma.
  • Patients often experience peripheral neuropathies that predominantly are 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.
  • Patients usually have concurrent neurologic or abdominal symptoms.

Physical

• Vital signs
  • 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
  • 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 manifestations: Despite the intense pain, the findings on abdominal examination often are nonspecific.
• Skin manifestations
  • Patients can have blisters, chronic erosion, and areas of excessive hair growth.
  • Skin damage develops in sun-exposed areas of the skin.

Causes

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. A large and detailed list, shown below, is available at Porphyria: A Patient's Guide. Fasting for several days also can trigger an attack. Many attacks will occur, however, without any obvious provocation.

Table 1. Drugs Thought Safe in Porphyria*

*Bracketed [ ] drugs are those in which experimental evidence of porphyrin genicity is conflicting.

Table 2. Drugs Thought Unsafe in Porphyria^†

*These drugs have been associated with acute attacks of porphyria.

†Bracketed [ ] drugs are those in which experimental evidence of porphyringenicity is conflicting.

Differential Diagnoses

Other Problems to Be Considered

Back pain
Diverticulosis

Workup

Laboratory Studies

• Stool coproporphyrins¹
  • Physicians establish the diagnosis of coproporphyria by demonstrating excess secretion of coproporphyrins in the stool.
  • Stool coproporphyrins are markedly elevated, usually 10-200 times greater than control samples.
• Urine coproporphyrins¹
  • Urine porphyrins vary, but usually the urine coproporphyrins also are markedly elevated, especially during acute attacks of the disease. If patients are having neurovisceral symptoms, the urine porphobilinogen is elevated.⁵ Mild elevations of urine coproporphyrins (eg, as high as 2 times the reference range) are common and nonspecific.
  • Fasting, subtle liver disease, or normal variations are the most common causes of elevated urine coproporphyrins.
  • As noted above, patients who truly have symptoms due to coproporphyria have marked elevations of urine, and especially stool, coproporphyrins.
  • As with AIP, patients who are experiencing neurovisceral symptoms due to coproporphyria have elevations in urine porphobilinogen.
  • The most common diagnostic error in proporphyria is to label patients with mild elevations of urine coproporphyrins as having porphyria.
• Other
  • Hyponatremia (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) and mild leukocytosis are other nonspecific signs during an AIP 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

• Imaging studies are not helpful.
• Abdominal films sometimes demonstrate an ileus.
• Findings on cranial CT scans are normal.
• Brain MRI scans occasionally show signs of increased edema in patients with very severe attacks.

Treatment

Medical Care

The goals in managing an acute attack of porphyria are to decrease heme synthesis and to reduce the production of porphyrin precursors.⁶

• Glucose
  • High doses of glucose (400 g/d) can inhibit heme synthesis and are useful for the treatment of mild attacks.
  • Treat severe attacks, especially those with severe neurologic symptoms, with hematin at a dose of 4 mg/kg/d for 4 days.
• Pain control: This is best achieved with narcotics. Administer laxatives and stool softeners with the narcotics to avert exacerbating the patient's constipation.
• Seizure control: Treat with Neurontin; most of the classic antiseizure medications are contraindicated in acute attacks of porphyria.
• Other: 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

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Blood products

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.

Dosing

Adult

4 mg/kg/d IV for 4 d; for severe attacks can administer 4 mg/kg q12h until symptoms abate; 1-4 mg/kg/d IV over 10-15 min for 3-14 d, based on clinical signs; in severe cases, may repeat no earlier than q12h; not to exceed 6 mg/kg/24h

Pediatric

Not established

Interactions

May further increase effect of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Attacks of porphyria may progress to irreversible neuronal damage; may prevent an attack from causing neuronal degeneration; not effective in repairing neuronal damage; asymptomatic and reversible renal shutdown, oliguria, and increased nitrogen retention have occurred; no worsening of renal function has been observed with recommended dosages

Follow-up

Further Inpatient Care

• Admit patients with severe attacks for close monitoring.
• Monitor patients with paralysis for signs of respiratory compromise.

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; however, only a few have been implicated clearly in porphyria. Patients also should avoid overconsumption of alcohol and avoid fasting.

Prognosis

• 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

• Teach patients the importance of avoiding unsafe drugs and fasting.
• For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center and Muscle Disorders Center. Also, see eMedicine's patient education articles Abdominal Pain in Adults, Constipation in Adults, and Chronic Pain.

Miscellaneous

Medicolegal Pitfalls

• The most common diagnostic error in proporphyria is to label patients with mild elevations of urine coproporphyrins as having porphyria.

References

1. Whatley SD, Mason NG, Woolf JR, et al. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem. Jul 2009;55(7):1406-14. [Medline].

2. Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine. Intern Emerg Med. Aug 2009;4(4):297-308. [Medline].

3. Billoo AG, Lone SW. A family with acute intermittent porphyria. J Coll Physicians Surg Pak. May 2008;18(5):316-8. [Medline].

4. Corrigall AV, Campbell JA, Siziba K, Kirsch RE, Meissner PN. The expression of protoporphyrinogen oxidase in human tissues. Cell Mol Biol (Noisy-le-grand). Jul 1 2009;55(2):89-95. [Medline].

5. Roshal M, Turgeon J, Rainey PM. Rapid quantitative method using spin columns to measure porphobilinogen in urine. Clin Chem. Feb 2008;54(2):429-31. [Medline].

6. Harper P, Wahlin S. Treatment options in acute porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria. Curr Treat Options Gastroenterol. Dec 2007;10(6):444-55. [Medline].

7. Anderson KE. The Porphyrias. In: Zakim D, Boyer TD, eds. Hepatology: A Textbook of Liver Disease. Philadelphia, Pa:. WB Saunders;1996:417-463.

8. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. Mar 15 2005;142(6):439-50. [Medline].

9. 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.

10. Bonkovsky HL, Barnard GF. Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology. Semin Liver Dis. 1998;18(1):57-65. [Medline].

11. Daniell WE, Stockbridge HL, Labbe RF, et al. Environmental chemical exposures and disturbances of heme synthesis. Environ Health Perspect. Feb 1997;105 Suppl 1:37-53. [Medline].

12. Elder GH, Smith SG, Smyth SJ. Laboratory investigation of the porphyrias. Ann Clin Biochem. Sep 1990;27 ( Pt 5):395-412. [Medline].

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15. Kalman DR, Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):299-306. [Medline].

16. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). Jan 1992;71(1):1-13. [Medline].

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Keywords

hereditary coproporphyria, porphyria, heme, porphyrin, acute porphyria, porphyrias, acute intermittent porphyria, cutaneous porphyria, porphyria tarda

Contributor Information and Disclosures

Author

Thomas G DeLoughery, MD, Professor of Medicine and Pathology, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health Sciences University
Thomas G DeLoughery, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American College of Physicians, American Society of Hematology, International Society on Thrombosis and Haemostasis, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Clarence Sarkodee-Adoo, MD, Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

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