The acute porphyrias, 4 inherited disorders of heme biosynthesis, cause life-threatening attacks of neurovisceral symptoms that mimic many other acute medical and psychiatric conditions. Lack of clinical recognition often delays effective treatment, and inappropriate diagnostic tests may lead to misdiagnosis and inappropriate treatment. We review the clinical manifestations, pathophysiology, and genetics of the acute porphyrias and provide recommendations for diagnosis and treatment on the basis of reviews of the literature and clinical experience. An acute porphyria should be considered in many patients with unexplained abdominal pain or other characteristic symptoms. The diagnosis can be rapidly confirmed by demonstration of a markedly increased urinary porphobilinogen level by using a single-void urine specimen. This specimen should also be saved for quantitative measurement of porphobilinogen, 5-aminolevulinic acid, and total porphyrin levels. Intravenous hemin therapy, started as soon as possible, is the most effective treatment. Intravenous glucose alone is appropriate only for mild attacks (mild pain, no paresis or hyponatremia) or until hemin is available. Precipitating factors should be eliminated, and appropriate supportive and symptomatic therapy should be initiated. Prompt diagnosis and treatment greatly improve prognosis and may prevent development of severe or chronic neuropathic symptoms. We recommend identification of at-risk relatives through enzymatic or gene studies.
Medical students have extensive exposure to pharmaceutical industry marketing during their early years of training. Given existing evidence that such exposure influences physicians' practice and prescribing patterns, the authors propose that medical school curricula include formal instruction to prepare students to critically assess these contacts.
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 deceased. 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. © 1996 Wiley‐Liss, Inc.
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.
Hepatic damage in protoporphyria appears to be caused by a toxic effect of excess protoporphyrin. Therapy which reduces the formation of excess protoporphyrin may, therefore, be helpful. We examined the effects of hematin administered i.v. to two patients with protoporphyria and decompensated cirrhosis. Neither patient had side effects from the compound or manifested signs of toxicity. The vascular disappearance of hematin in one patient was similar to that in patients with porphyria who do not have structural liver disease. In both patients, biochemical changes occurred that were compatible with a reduced rate of protoporphyrin formation. Thus, hematin administration may be useful in treating patients with protoporphyria who develop liver disease.
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 copropor hyria. 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 6-aminolevulinic acid synthetase [6-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 6-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of 6-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum 5-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement. The present preliminary report will consider briefly some basic and associated clinical aspects of the remission due to hematin, in cases of "inducible" hepatic porphyria. In a later paper this effect will be considered in greater detail (1).Those forms of hepatic porphyria in which various inducing factors are liable to precipitate a life-threatening acute neurologic relapse are appropriately grouped under the term inducible (1). This relates to 3-aminolevulinic acid synthetase [ALA-synthetase; 5-aminolevulinate synthase; succinyl-CoA: glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37], the rate-limiting enzyme of porphyrin and heme biosynthesis (2-6). The term inducible embraces the three autosomal dominant genetic errors, acute intermittent porphyria (AIP), porphyria variegata (PV), and hereditary hepatic coproporphyria (HC), but it does not include hepatic porphyria cutanea tarda, in which evidence of induction is slight or lacking (7, 8), as well as the neurologic symptoms of the acute attack in the inducible forms and the prominent excesses of porphyrin precursors, ALA and porphobilinogen (PBG) in liver, urine, and blood serum, increases of which are usually observed at least in the early symptomatic stage of the porphyric relapse. The inducible forms are characterized by derepression or impaired feedback regulation and secondary induction of hepatic ALA-synthetase (6) (see above). There is reason to believe that this is related to hepatic heme deficiency incident to the respective genetic (partial) lack of uroporphyrinogen synthetase in AIP (6), heme synthetase in PV (7), and coproporphyrinogenase in HC (9). Any one of these traits constitutes a partial block in heme synthesis, responsible, as already mentioned, for the negati...
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