AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Diverticulosis
Manic-depressive illness

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Blood products

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• 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].
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• Kalman DR, Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):299-306. [Medline].
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• Moore MR. The biochemistry of heme synthesis in porphyria and in the porphyrinurias. Clin Dermatol. Mar-Apr 1998;16(2):203-23. [Medline].
• Murphy GM. The cutaneous porphyrias: a review. The British Photodermatology Group. Br J Dermatol. Apr 1999;140(4):573-81. [Medline].
• Peters TJ, Sarkany R. Porphyria for the general physician. Clin Med. May-Jun 2005;5(3):275-81. [Medline].
• Poh-Fitzpatrick MB. Clinical features of the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):251-64. [Medline].
• Tefferi A, Colgan JP, Solberg LA Jr. Acute porphyrias: diagnosis and management. Mayo Clin Proc. Oct 1994;69(10):991-5. [Medline].
• Zaider E, Bickers DR. Clinical laboratory methods for diagnosis of the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):277-93. [Medline].

Article Last Updated: Jun 30, 2006