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Acute intermittent porphyria (AIP) is a genetic disorder in which patients may have life threatening attacks of neurologic dysfunction. This study examined the prognosis during the past 50 years of patients in the United States who required hospitalization for porphyric attacks. The cumulative survival was determined for 136 patients with AIP who were hospitalized for porphyric attacks between 1940 and 1988. Diagnosis was established on the basis of clinical symptoms, in combination with increased urinary excretion of porphobilinogen. The patient group had an average age of 32 years (range 9 to 75) at diagnosis and consisted of 43 males and 93 females. At follow-up, 19 males (44%) and 31 females (33%) were decreased. The standardized mortality ratio for the 136 patients, compared to an age-matched hypothetical population experiencing USA 1970 Census Death Rates was 3.2, with a 95% confidence interval of 2.4-4.0. Most deaths occurred during the initial porphyric attack (20% of deaths) or a subsequent attack (38% of deaths). Suicide was also common (five deaths). Comparison was made between 50 patients who were diagnosed before 1971, the year in which hematin therapy became available, and 86 patients who were diagnosed afterward. There was improved survival in the latter group, particularly after 10 years from the time of diagnosis, but this did not reach statistical significance. In conclusion, the proportionate increase in mortality due to symptomatic AIP was three-fold compared to the general population during the past 50 years. The major cause of the increased mortality was the porphyric attack itself.

Background: Variegate porphyria is a genetic disorder of porphyrin metabolism in which patients may have both neurologic dysfunction and photocutaneous lesions. Biochemical confirmation of the diagnosis can be difficult, particularly in patients without neurologic dysfunction at the time of testing. The demonstration of increased fecal excretion of porphyrin is frequently used for this purpose, but levels may be normal. Since elevated fecal porphyrin levels in variegate porphyria are presumably a consequence of increased biliary excretion, we evaluated whether analysis of porphyrins in bile distinguishes better between patients with variegate porphyria and controls., Methods: Bile samples were collected by duodenal aspiration from 10 patients with proved variegate porphyria who had no neurologic symptoms when they were studied and 17 control subjects. Bile and fecal porphyrin levels were measured fluorometrically., Results: The mean total porphyrin concentration in bile in the patients with variegate porphyria was significantly higher than that in the controls (67.8 vs. 0.71 mumol per liter; P less than 0.00002). There was more than a ninefold difference between the highest level in any control subject and the lowest level in any patient with variegate porphyria. The mean fecal porphyrin level in the patients with variegate porphyria also differed significantly from that in the controls (0.79 vs. 0.14 mumol per gram of dry weight; P less than 0.007), but four patients had levels within the control range., Conclusions: The concentration of porphyrin in bile is higher in patients with variegate porphyria than in controls, and the difference is greater than that for fecal porphyrin. Bile porphyrin measurements may be helpful in the evaluation of asymptomatic patients suspected of having variegate porphyria.

Blood and bile porphyrin concentrations were measured in cattle with protoporphyria and compared with those in human beings with the disease. Whereas the mean RBC porphyrin concentration in cattle was 18-fold greater than in human beings, the mean bile porphyrin concentration was only 78% greater. Sequential measurements over a 30-hour period in 1 animal with a bile fistula indicated that the ratio of total porphyrin to total bile acid in bile varied minimally. When the animal was given an IV infusion of taurocholate, the biliary excretion rate of porphyrin increased in parallel with that of bile acid, because of enhancement of bile flow. Thus, in cattle with protophorphyria, the concentration of porphyrin in bile is low compared with that of porphyrin in RBC, in contrast with findings in human beings, and adequate amounts of bile acids are secreted to maintain efficient protoporphyrin excretion. This explains, in part, why hepatobiliary disease has not been observed in cattle with protoporphyria, but has been seen in human beings with the disease.

A 38-yr-old woman with liver disease due to protoporphyria underwent orthotopic liver transplantation. The resected liver was cirrhotic and contained a massive amount of protoporphyrin, with numerous birefringent pigment deposits. Transplantation was accomplished without difficulty following blood volume exchange to reduce the blood protoporphyrin level. Sequential biopsy specimens obtained through the 13th month after transplantation showed no accumulation of protoporphyrin pigment deposits in the new liver. Portal inflammation observed in the liver biopsy specimen at 6 mo after transplantation resolved spontaneously. Erythrocyte and serum protoporphyrin levels returned to values similar to those in the pretransplantation period when the patient had normal hepatic function; the fecal level was lower. Thus orthotopic liver transplantation can be successfully done in patients with protoporphyria who have severe liver disease. Prolonged follow-up is needed to determine the ultimate outcome, however, as the new liver remains susceptible to protoporphyrin-induced damage.

An elderly woman was found to have hepatocellular carcinoma and, incidental to this, markedly elevated levels of porphobilinogen in urine and serum. The delta-aminolevulinic acid levels in urine and serum were normal, but there was a distinct increase of porphyrins in urine and feces. Neither the patient nor her family gave a history suggestive of a clinical porphyria. The patient died from the carcinoma without ever exhibiting porphyric symptoms. It is assumed that the hepatocellular carcinoma produced the excessive amounts of porphobilinogen.

We measured the activity of the enzyme porphobilinogen deaminase in red blood cells of 222 persons. Ninety-seven of 107 patients with acute intermittent porphyria had enzyme activity below the normal range, whereas 55 of 56 patients with other types of porphyria had normal activity. This underscores the utility of this test in confirming the diagnosis of acute intermittent porphyria. Measurement of enzyme activity in 41 families with acute intermittent porphyria demonstrated that deficient activity is inherited as an autosomal dominant trait. Many latent carriers of the genetic defect were identified by family studies, permitting appropriate precautions to avoid potentially lethal porphyric attacks.

The livers of patients who have protoporphyria and hepatic failure contain large amounts of pigment crystals. Two such patients underwent liver transplantation, providing the opportunity to identify the pigment crystals. Portions of liver were digested enzymically, sedimented through a sucrose gradient, treated with 1% sodium dodecylsulfate, and centrifuged to purify the crystals. Spectrophotometric and high-performance liquid chromatography analysis demonstrated them to be composed of protoporphyrin. Bile samples were obtained from the 2 patients, 4 other patients who did not have liver disease, and 10 control subjects. The porphyrin concentrations in bile from the 6 patients were significantly increased above controls (range 254-7884 micrograms/dl compared with 11-109 micrograms/dl). The ratio of protoporphyrin to bile acid in bile distinguished the 2 patients with advanced liver disease (3105 and 2756 micrograms/mmol) from the 4 patients without liver disease (range 61-926 micrograms/mmol). Thus, analysis of bile from patients with protoporphyria may help in evaluating their hepatobiliary status.