Course Authors
Robert G. Lerner, M.D.
In the past three years, Dr. Lerner has served as a consultant for RPR, and has served on the Speakers' Bureau for Pharmacia & Upjohn.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the clinical manifestations of acute intermittent porphyria
List the available therapy
Find a support group for AIP patients.
Case report
A 38-year-old male nurse sought medical attention because he thought he might have porphyria. The patient had been having panic attacks, accompanied by sweating, abdominal pain and elevated blood pressure for several years. The attacks were not always debilitating, might persist with varying intensity for up to two weeks and occur about four times a year. The patient had been a heavy drinker from age 17 to 28, although he now abstained from alcohol. His alcohol use did not have a clear relationship to the attacks. About four years earlier, he sought psychiatric treatment for depression and was now being treated with Paxil®, which also did not appear to have any relationship to his attacks. The patient recalled that 20 years earlier he had an episode of dark urine and he now suspected that he might have porphyria. There was no family history of porphyria but his father died of cancer. He had a tonsillectomy at age three and a hernia repair at age 37 without complication. He reported no gastrointestinal symptoms except for vomiting with attacks.
Physical examination was entirely normal except for a hernia repair scar.
A CBC was normal, as was a chemistry panel including liver function tests and a urine analysis. Urinary d-aminolevulinic acid (ALA) was undetectable and urinary porphobilinogen (PBG) was present at 1.3 mmol/L (reference value <8.8 mmol/L). However, an assay for uroporphyrinogen synthase in erythrocytes was 5.70 nmol/sec/L (reference value>7.0).
The patient was informed that he did indeed have acute intermittent porphyria. He expressed great relief that his symptoms "were not in his head" and, after reading much of the literature about AIP, assured me that he would continue to avoid alcohol and, additionally, avoid medications thought to bring on acute attacks.
Two months later, the patient returned complaining of two days of intense anxiety, palpitations, flushing and paranoid ideation. He had been eating large amounts of pasta in an attempt to break the attack by carbohydrate loading. Treatment was begun with intravenous hemin (Panhematin®, Abbott) and his symptoms resolved in 48 hours.
Discussion
Acute intermittent porphyria is an autosomal dominant metabolic disorder characterized by a 50% defect in activity of uroporphyrinogen I synthase (also called porphobilinogen deaminase) and high levels of porphobilinogen (PBG) and d-aminolevulinic acid (ALA).
How this metabolic abnormality causes symptoms is not entirely clear, since symptoms may never appear or only appear late in life in some patients with enzymatic defects indistinguishable from symptomatic relatives. In this regard, one might postulate that the patient's father might have had a latent case of acute intermittent porphyria and gone on to develop hepatocellular carcinoma, since the intrinsic aberrations of AIP may incite carcinogenic mutations elsewhere in the genome of liver cells.(1) It has been suggested that multiple mechanisms interact, including ALA interaction with g-aminobutyric acid receptors, altered tryptophan metabolism and possibly heme depletion in nerve cells.(2)
Typical presentation
Waldenström described the first cases in 1937 in Sweden, noting the familial incidence. The prevalence is thought to be anywhere from 1.5 per 100,000 to 10 per 100,000. Family screening studies of ALA and PBG levels usually detect many asymptomatic carriers and enzyme assays even more cases. Although there is equal prevalence of the genetic defect between the sexes, about two thirds of symptomatic patients are women. Symptoms generally do not appear until after puberty and affected individuals usually have attacks lasting days to months. Most attacks begin with acute abdominal pain and may include autonomic or peripheral neurologic dysfunction and mental changes, as seen in the patient presented above. Untreated patients have gone on to death from respiratory paralysis during the acute attack.(3) However, since the introduction of intravenous hematin therapy, death from an acute attack is uncommon. Depression and suicide have been reported as well as seizures. The seizures have often been attributed to hyponatremia.
Making the Diagnosis
Routine blood counts are unrevealing and the diagnosis is usually made by finding excessive urinary PBG or ALA, especially during acute attacks. Oxidation or other chemical conversion of the PBG may cause the urine to discolor and provide a diagnostic clue. Assay of enzyme level in red blood cells provides the definitive diagnostic test.
Prevention and Treatment of Acute Attacks
An acute attack often requires narcotic analgesia. Many drugs (especially barbiturates and anticonvulsants) have been implicated as triggers for an acute attack and must be avoided. Carbohydrate loading is often prescribed based on its effect lowering ALA and PBG levels but is not always clinically effective. Intravenous hematin is now available (Panhematin®) and produces a rapid decrease in ALA and PBG levels and prompt clinical improvement if given early in an attack. After the resolution of an acute attack, the most important intervention is avoidance of fasting or exposure to drugs that may cause acute attacks.
Internet Support Groups
Although, symptomatic acute intermittent porphyria is a rare disease, support groups have sprung up on the Internet(4) and the NIH provides online information for laymen.(5) The recent popular movie, The Madness of King George, with the vivid scene of bluish purple urine (6), has heightened awareness of the disorder. Ongoing studies of heme arginate may provide safer treatment but a better understanding of the pathophysiology is sorely needed if any medical advance is to be made.