Mortality in patients with acute intermittent porphyria requiring hospitalization: a United States case series.

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.

Liver transplantation in a patient with protoporphyria.

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.

Red blood cell porphobilinogen deaminase in the evaluation of acute intermittent porphyria.

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.

Pseudo-porphyria in a patient with hepatocellular carcinoma.

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.

Hematin therapy in porphyric attacks.

We report our experience with hematin in the treatment of 57 patients in porphyric attacks. The ratio of acute intermittent porphyria: variegate porphyria: hereditary coproporphyria was 43:11:3. More than 90% of the patients showed not only a decline in their porphyrin precursors, but also a favor able clinical response. Hematin was well tolerated and should be considered the treatment of choice in porphyric relapse.

Transitory renal failure following rapid administration of a relatively large amount of hematin in a patient with acute intermittent porphyria in clinical remission.

Transitory renal failure occurred in a patient with acute intermittent porphyria in clinical remission following i.v. administration of 1 000 mg hematin. The clinical and biochemical picture suggested "acute tubular necrosis", which was followed by a prompt and complete return of renal function without any late sequelae. The renal failure is thought to have resulted from the presence of circulating free hematin, formed as a result of rapid administration of such a relatively large amount. Such a complication has not occurred in patients given hematin for acute porphyric relapse, in whom much smaller amounts have been infused.

Effect of hematin in porphyric neuropathy.

Early, intravenous administration of hematin in a patient with acute intermittent porphyria and severe quadriparesis may have produced partial but remarkable improvement of neuropathy, and resulted in simultaneous decline of porphyrin precursors in the blood. Intermittent, biweekly hematin infusions given 1 month after the onset of the porphyric relapse had no effect on recovery of the residual neuropathy. We believe hematin may be effective in the treatment of porphyric neuropathy, if administered before irreversible neuronal damage has occured.

Comparison of the Hoesch and the Watson-Schwartz tests for urinary porphobilinogen.

A comparison of the Hoesch and the Watson-Schwartz tests shows that the latter, although slightly more complicated, generally yields more concise results and is superior in sensitivity and specificity for porphobilinogen. The recommendation of the Hoesch test for use as a "bedside screening" method seems unrealistic. Before the diagnosis of an "inducible" porphyria is made, a positive Hoesch test requires that indoles, indoleacetic acid, methyldopa, end-stage alcoholic malnutrition, and phenazopyridine HCl be excluded, to avoid misinterpretation.

Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.

There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of delta-aminolevulinic acid synthetase [delta-aminolevulinate synthase; succinyl--CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of delta-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of delta-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum delta-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement.

Porphyria variegata and porphyria cutanea tarda in siblings: chemical and genetic aspects (addendum).

A porphyria kindred in which the index case has porphyria variegata had also been shown to include a case of porphyria cutanea tarda, typical both from chemical and clinical features. The possibility that this was purely acquired rather than genetic seemed unlikely, but could not be wholly excluded. Recently, a niece of both of these cases, although asymptomatic, has been found to conform chemically with porphyria cutanea tarda, including the excretion of the isocoproporphyrin series, and thus represents the second case of this form of porphyria in this family. This strengthens the concept of genetic heterogeneity in this kindred and supports the suggestion of a double heterozygosity, as proposed in the primary paper [Watson, C.J. et al. (1975) Proc. Nat. Acad. Sci. USA 72, 5126-5129].

Hematin treatment of acute porphyria. Early remission of an almost fatal relapse.

Intravenous infusions of hematin in a young woman with acute porphyria in profound relapse was followed within 48 hours by remission of symptoms and rapid recovery. From a state of severe central and peripheral nervous-system involvement, the patient recovered so completely that she was able to leave the hospital in less than a month, with only a residual weakness of her arms. Serial studies of serum and urinary levles of porphyrin precursors and serum level of hematin provided highly important information about the effect of hematin on acute porphyria.

The activities of uroporphyrinogen synthetase and cosynthetase in congenital erythropoietic porphyria (CEP).

Normal or increased amounts of series III porphyrins with greater amounts of series I were observed on incubation of PBG in hemolysates of congenital erythropoietic porphyria vs. normal erythrocytes, human or bovine. Correlation with reticulocyte percentage was poor, in the aggregate a general trend toward increased values of both isomers I and III was noted with increasing reticulocytes. When the percent of type III was low the net amount was increased as compared with normal. Hemolysates of non-porphyric, reticulocyte-rich red cells (hemolytic or posthemorrhagic anemia) formed only minute amounts of type I porphyrin but at the same time no more, or even less type III than the porphyric hemolysates, although representing red cells of greater reticulocyte content. No evidence of deficient heme synthesis was observed in porphyric hemolysates incubayed with [14C]-porphobilinogen or 59Fe. Other studies of porphyric hemolysates incubated with and without added mouse spleen synthetase failed to reveal evidence of an absolute UPG-III cosynthetase (Co-S) deficiency. The large increases of type I porphyrin with normal or increased formation of type III, both in the disease and in the hemolysates, are believed due to a primary increase of ALA-S or UPG-S activity rather than a decrease of Co-S. Possible mutations which might be responsible for this increase are considered.

Porphyria variegata and porphyria cutanea tarda in siblings: chemical and genetic aspects.

A woman aged 54 was studied because of a severe acute porphyric (neurologic) relapse with clinical and chemical findings characteristic of porphyria variegata. During a family survey, her brother, aged 59, was found to have chemical abnormalities typical of porphyria cutanea tarda, without suggestion of neurologic manifestations. He had mild skin changes compatible with either of these forms of porphyria. The sister exhibited the protocoproporphyria of porphyria variegata, together with a large amount of fecal "x" porphyrin fraction, without demonstrable isocoproporphyrins. The brother had a uro-isocopro-type of porphyria in accord with the diagnosis of porphyria cutanea tarda, and quite at variance with the sister's findings. This occurrence of porphyria variegata and porphyria cutanea tarda in siblings is thus far unique. Certain hypotheses are considered in respect to genetic aspects of the differing prophyrias in this sibling pair.

Effects of hematin in hepatic porphyria. Further studies.

The present study was carried out in five cases of hepatic porphyria, including three of acute intermittent porphyria, one of variegate porphyria, and one of porphyria cutanea tarda in clinical remission. In two cases of acute intermittent porphyria (in relapse), a marked lowering effect on serum and urine porphobilinogen and delta-aminolevulinic acic was observed, together with prompt and gratifying clinical improvement. In a third case, in chemical remission but with longstanding psychoneurosis, no significant effects were noted, nor were any observed in the case of porphyria cutanea tarda. Although clinical improvements occurred in the case of variegate porphyria, the results were inconclusive for reasons given. Hematin was generally well tolerated. Preliminary reference is made to a transitory renal injury, without sequelae, where an excess of hematin was given in relation to time. Limits of tolerance are proposed. In the light of these observations the basic mechanism of the acute attack is diccussed.