eMedicine Specialties > Hematology > Heme Synthesis and Disorders

Porphyria, Acute Intermittent

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: Aug 5, 2009

Introduction

Background

Acute intermittent porphyria (AIP) is one of the porphyrias, a group of diseases involving defects in heme metabolism and that results in excessive secretion of porphyrins and porphyrin precursors. AIP manifests itself by abdomen pain, neuropathies, and constipation, but, unlike most types of porphyria, patients with AIP do not have a rash.

Pathophysiology

AIP is an autosomal dominant disease that results from defects in the enzyme porphobilinogen-deaminase. This enzyme speeds the conversion of porphobilinogen to hydroxymethylbilane. In AIP, the porphyrin precursors, porphobilinogen and amino-levulinic acid (ALA), accumulate. The predominant problem appears to be neurologic damage that leads to peripheral and autonomic neuropathies and psychiatric manifestations.

Although patients with acute attacks always have elevations of porphobilinogen and ALA, how this leads to the symptomatic disease is still unclear because most patients with the genetic defect have excessive porphyrin secretion but no symptoms.

Frequency

United States

Estimates vary from 1-5 cases per 100,000 population.

International

Prevalence can be as high as 60-100 cases per 100,000 population in northern Sweden.

Sex

In most series, AIP affects women more than men, with a ratio of 1.5-2:1.

Age

Most patients become symptomatic at age 18-40 years. Attacks occurring before puberty or after age 40 years are unusual unless a major provocation, such as new use of phenobarbital or estrogens, had occurred.

Clinical

History

The sequence of events in attacks usually is (1) abdominal pain, (2) psychiatric symptoms, such as hysteria, and (3) peripheral neuropathies, mainly motor neuropathies.

• Most patients are completely free of symptoms between attacks. How the porphyrin precursors lead to these symptoms is unknown.
• AIP displays neurovisceral symptoms but no skin manifestations.
  • The neurovisceral symptoms consist of autonomic neuropathies (eg, constipation, colicky abdominal pain, vomiting, hypertension), peripheral neuropathy, seizures, delirium, coma, and depression.
  • The abdominal pain is severe and lasts for several days. Severe abdomen pain of short ( <1 d) duration or chronic abdominal pain is unusual.
• AIP patients may have central nervous system signs consisting of seizures, mental status changes, cortical blindness, and coma.
• Patients often experience peripheral neuropathies that are predominantly motor and can mimic Guillain-Barré syndrome. The weakness usually starts in the lower limbs and ascends, but neuropathies can be observed in any nerve distribution.
  • Diffuse pain, especially in the upper body, can be observed.
• Patients may develop autonomic neuropathies, such as hypertension and tachycardia.
• Patients may have very severe abdominal pain lasting several days.
  • Pain of short duration (minutes) or chronic abdominal pain is not observed in AIP.
  • The pain often is epigastric and colicky in nature.
  • Patients often are free of pain between attacks.
  • Constipation is common and can be very severe.
  • Frequently, nausea and vomiting are present.
• Patients can have a wide variety of psychiatric symptoms.
  • Usually, patients have concurrent neurologic or abdominal symptoms.
  • Depression is very common.

Physical

• Vital signs
  • From 30-80% of patients have tachycardia.
  • Fever can be present in some patients.
  • Hypertension is observed in half of patients and may persist between attacks.
• Neurological manifestations
  • Usually, the neuropathy is a motor neuropathy that is more predominant in the lower limbs.
  • Areflexia often is present on examination.
  • Any nerve can be involved, and cranial neuropathies also are observed.
  • Patients also may have cortical blindness.
• Abdominal examination: Despite the intense pain, the findings on abdominal examination often are nonspecific.
• Skin examination: Unlike many other porphyrias, AIP is not associated with a skin rash.

Causes

Acute intermittent porphyria (AIP) is due to a combination of a genetic enzyme defect and acquired causes that become symptomatic only in some patients. In patients with AIP, the function of porphobilinogen-deaminase is only 40-60% of normal. With the advent of molecular technique, the genetic defect clearly is more common than symptomatic AIP. On average, out of 100 patients with the genetic defect, perhaps 10-20 secrete excess porphyrin precursors and only 1-2 have symptoms.

The classic inducers of porphyria are chemicals or situations that boost heme synthesis. This includes fasting and many medications. Although very large lists of "safe" and "unsafe" drugs exist, many of these are based on anecdotes or laboratory evidence and do not meet strict criteria. In general, drugs that lead to increased activity of the hepatic P450 system, such as phenobarbital, sulfonamides, estrogens, and alcohol, are associated with porphyria.

A large and detailed list is available on the University of Queensland, Department of Medicine Web site.

Fasting for several days also can trigger an attack. However, many attacks occur 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

Diverticulosis
Manic-depressive illness

Workup

Laboratory Studies

• The fundamental step in diagnosing acute intermittent porphyria (AIP) is to demonstrate increased urinary porphobilinogen secretion. If a patient has no increased secretion of porphobilinogen, acute porphyria is eliminated as a cause of the neurovisceral symptoms.
  • A common error is the failure to order urine porphyrins. Porphobilinogen, a porphyrin precursor, usually is not included in a urine porphyrin screen and must be ordered specially.
  • AIP patients have elevated porphobilinogen between attacks.
  • In some patients with a remote (years) history of attacks, porphobilinogen can return to the reference range.
• Elevation of urine porphyrins, especially coporphobilinogen, is observed.
  • This is caused by spontaneous polymerization of porphobilinogen in the urine.
  • Nonspecific (1-2 times reference range) elevation of urine porphyrins, especially coproporphyrins, is common and is not indicative of porphyria.
• Stool porphyrins are within the reference range or mildly elevated.
• Other nonspecific signs in an attack of AIP include hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and mild leukocytosis.
• Although a defective enzyme causes AIP, measuring the activity of porphobilinogen deaminase is of little value.
  • Approximately 10% of AIP patients will have normal activity because a different form of the enzyme is expressed in the hematopoietic tissues.
  • The vast majority of patients with the defective enzyme do not have any symptoms of the disease.

Imaging Studies

• Imaging studies are not helpful.
• Sometimes, abdomen films demonstrate an ileus.
• Findings on cranial CT scan are normal.
• Brain MRI occasionally shows signs of increased edema in patients having very severe attacks.

Other Tests

• In the presence of increased porphobilinogen excretion, plasma fluorescence scanning and the coproporphyrin ratio can identify the type of acute porphyria, with rare exceptions.
• In cases in which the porphobilinogen, 5-aminolevulinate, and porphyrin analyses are within reference intervals and in which the index of suspicion is high of a previous illness caused by an acute porphyria, mutation analysis of the HMBS gene followed by porphobilinogen deaminase assay is an effective strategy for diagnosis or exclusion of AIP.

Treatment

Medical Care

• The treatment goal for acute attacks of porphyria is to decrease heme synthesis and reduce the production of porphyrin precursors.
  • High doses of glucose (400 g/d) can inhibit heme synthesis and are useful for treatment of mild attacks.
  • People experiencing severe attacks, especially those with severe neurologic symptoms, should be treated with hematin in a dose of 4 mg/kg/d for 4 days.
• Pain control is best achieved with narcotics. Laxatives and stool softeners should be administered with the narcotics to avert exacerbating existing constipation.
• Treat seizures with Neurontin. Most classic antiseizure medicines can lead to acute porphyria attacks.

Diet

• The patient should receive a high-carbohydrate diet during the attack. If the patient is unable to eat, intravenous glucose should be administered.
• Between attacks, eating a balanced diet is more important than eating one rich in glucose.

Medication

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

Blood products

The key step in treatment of porphyria is to stop heme synthesis.

Hemin (Panhematin)

Provides negative feedback to the heme synthetic pathway and shuts down productions of porphyrins and porphyrin precursors.

Dosing

Adult

4 mg/kg/d IV for 4 d
For severe attacks: 4 mg/kg IV q12h until symptoms abate

Pediatric

Not established

Interactions

May further increase effects of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

Can lead to intense thrombophlebitis; should be administered through central catheter or PICC line; 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

[#hepmkrs]Due to the fact that clinical manifestations of acute intermittent porphyria (AIP) include abdominal pain, neurovisceral symptoms, and overproduction of long-lasting heme-precursors in the liver, Delaby et al assessed the possible role of hepatic protein changes with AIP.² The investigators found most of the analyzed serum hepatic proteins known to be affected by conditions such as malnutrition, inflammation, or liver disease were within reference ranges; however, insulin-like growth factor 1 (IGF-1) was decreased in 53.8% of AIP patients and transthyretin (prealbumin) was found significantly decreased in 38.5% of patients.² In addition, the coincident decrease of both IGF-1 and transthyretin was associated with a worsening clinical condition.

Thus, Delaby et al suggest that clinical expression of AIP is associated with a state of malnutrition and/or with hepatic inflammation and propose the use of IGF-1 and transthyretin for clinical assessment and follow-up of AIP patients.²

• Patients with severe attacks should be admitted for close monitoring.
• Patients with paralysis should be monitored 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 a dose of 4 mg/kg before the onset of their period.

Deterrence/Prevention

• Avoid medicines that can provoke an attack. Lists of medicines to avoid are available, although only a few of these have been clearly implicated in porphyria.
• Avoid excessive alcohol consumption.
• Avoid fasting.

Prognosis

• Most patients (60-80%) who have an acute attack of porphyria never have another one.
• Avoidance of precipitating factors helps prevent attacks.

Patient Education

• Emphasize 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

• Failure to order urine porphyrins is a common error in diagnosing AIP. Porphobilinogen, a porphyrin precursor, usually is not included in a urine porphyrin screen and must be ordered specially.

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. Delaby C, To-Figueras J, Deybach JC, et al. Role of two nutritional hepatic markers (insulin-like growth factor 1 and transthyretin) in the clinical assessment and follow-up of acute intermittent porphyria patients. J Intern Med. Apr 23 2009;epub ahead of print. [Medline].

3. 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].

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5. Bylesjo I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: A population-based study. Scand J Clin Lab Invest. Apr 28 2009;1-7. [Medline].

6. 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].

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

8. Gill R, Kolstoe SE, Mohammed F, et al. Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria. Biochem J. Apr 28 2009;420(1):17-25. [Medline].

9. Gorchein A. Drug treatment in acute porphyria. Br J Clin Pharmacol. Nov 1997;44(5):427-34. [Medline].

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

12. 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].

13. Laiwah AC, McColl KE. Management of attacks of acute porphyria. Drugs. Nov 1987;34(5):604-16. [Medline].

14. Massey EW. Neuropsychiatric manifestations of porphyria. J Clin Psychiatry. Jun 1980;41(6):208-13. [Medline].

15. Mattern SE, Tefferi A. Acute porphyria: the cost of suspicion. Am J Med. Dec 1999;107(6):621-3. [Medline].

16. Moore MR. The biochemistry of heme synthesis in porphyria and in the porphyrinurias. Clin Dermatol. Mar-Apr 1998;16(2):203-23. [Medline].

17. Murphy GM. The cutaneous porphyrias: a review. The British Photodermatology Group. Br J Dermatol. Apr 1999;140(4):573-81. [Medline].

18. Peters TJ, Sarkany R. Porphyria for the general physician. Clin Med. May-Jun 2005;5(3):275-81. [Medline].

19. Poh-Fitzpatrick MB. Clinical features of the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):251-64. [Medline].

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Keywords

acute intermittent porphyria, AIP, defects in heme metabolism, increased secretion of porphobilinogen, abdominal pain, psychiatric problems, hysteria, peripheral neuropathies, abdominal pain, neuropathy, constipation

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
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