Correspondence
Clinical Problem-Solving: Still Hazy after All These Years
N Engl J Med 1995; 332:332-333February 2, 1995
- Article
To the Editor:
In the medical conundrum presented by Ben-Chetrit and Putterman (Oct. 6 issue),1 despite a 21-year search for a diagnosis, the patient's illness remains hazy. The diagnosis is most obviously hereditary coproporphyria. The patient and her brother were both affected.
The patient had a 21-year history of recurrent abdominal pain, with neither clinical nor surgical peritonitis and in the absence of remarkable sequelae. There was evidence of autonomic disturbances: a rapid pulse, an episode of urinary retention, and decreased peristalsis with dilated loops on a plain film of the abdomen. There was also evidence of neuropsychiatric phenomena: anxiety, myalgia, and an episode of transient hemianopia, a form of focal seizure, and a postictal headache, which was misinterpreted as a conversion reaction. There was a history of intolerance of amitriptyline, isoniazid, and rifampin, which are considered unsafe in patients with porphyria. The coincidental findings of dry cough and splenomegaly probably amount to a red herring and did not contribute to the patient's illness.
Several quantitative tests of spot urine samples from the patient revealed a threefold to fivefold elevation in the level of porphobilinogen, and her brother had a value that was at the upper limit of the normal range. Coproporphyrin III excretion in feces and coproporphyrinogen oxidase in leukocytes and cultured skin fibroblasts were not assayed. The erythrocyte porphobilinogen deaminase activity was normal, as one would have predicted, since it is characteristically normal in patients with hereditary coproporphyria.2
2 ReferencesMarwan S. Akasheh, M.D.
P.O. Box 9668, Amman, Jordan1
Ben-Chetrit E ,Putterman C . Still hazy after all these years. N Engl J Med 1994;331:934-938
Full Text | Web of Science | Medline2
Meyer UA. Porphyrias. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison's principles of internal medicine. 11th ed. Vol. 2. New York: McGraw-Hill, 1987:1638-43.
To the Editor:
The case discussion by Ben-Chetrit and Putterman highlights the difficulties often encountered in the diagnosis of porphyria. The authors favored a diagnosis of acute intermittent porphyria even though the activity of the affected enzyme (porphobilinogen deaminase) in the patient's red cells was normal. They suggest that the patient had one of the rare variants of this disease in which the defect is not expressed in erythrocytes.
A more likely explanation, which must be considered in the differential diagnosis, is that the patient had either variegate porphyria or hereditary coproporphyria, which could easily have been identified by a fecal analysis. Both forms of porphyria often present with life-threatening acute attacks that are clinically indistinguishable from acute intermittent porphyria and are also characterized by increased porphobilinogen excretion. Photosensitivity may occur, although in approximately a third of the cases there are no dermatologic manifestations.1 Therefore, the absence of skin lesions would not rule out these two diseases.
In symptomatic patients, a fecal analysis can be used to differentiate among the three types of acute porphyria. Variegate porphyria is characterized by an elevated value for fecal protoporphyrin IX (with a smaller increase in the value for coproporphyrin III), and hereditary coproporphyria is characterized by a gross elevation in the value for fecal coproporphyrin III. Normal fecal porphyrin values during an acute attack (when the porphobilinogen value is clearly elevated) are virtually diagnostic of acute intermittent porphyria.
Since all three diseases are inherited in an autosomal dominant manner, family studies are essential to identify latent cases of porphyria so that known precipitants can be avoided, and potentially fatal acute attacks prevented. Accurate determination of the type of porphyria will dictate the most appropriate diagnostic test (or tests) for the identification of people at high risk. The hallmark of an acute porphyric attack is an elevation in the urinary excretion of porphobilinogen; during remission the excretion of porphobilinogen is often minimally elevated or even normal. The initial Watson–Schwartz test for excess porphobilinogen, performed on a urine sample obtained from this patient during one of her episodes of abdominal pain, was negative. There is now an increasing body of opinion2-4 that qualitative screening tests for porphobilinogen are insensitive and should be replaced by quantitative methods. I suggest that quantitation of porphobilinogen in this urine specimen would have resulted in an earlier diagnosis.
4 ReferencesA.C. Deacon, Ph.D.
Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, United Kingdom1
Eales L ,Linder GC . Porphyria -- the acute attack: an analysis of 80 cases. S Afr Med J 1962;36:284-292
Medline2
Deacon AC . Performance of screening tests for porphyria. Ann Clin Biochem 1988;25:392-397
Web of Science | Medline3
Schreiber WE ,Jamani A ,Pudek MR . Screening tests for porphobilinogen are insensitive: the problem and its solution. Am J Clin Pathol 1989;92:644-649
Web of Science | Medline4
Buttery JE ,Carrera AM ,Pannall PR . Analytical sensitivity and specificity of two screening methods for urinary porphobilinogen. Ann Clin Biochem 1990;27:165-166
Web of Science | Medline
To the Editor:
Although acute porphyria was considered in the differential diagnosis early in the workup, it appears that it was discarded as a diagnostic possibility on the basis of a single negative Watson–Schwartz test. Unfortunately, acute porphyrias cannot be ruled out by a single negative Watson–Schwartz test, because the sensitivity of this test in acute porphyria is only about 40 to 60 percent (28 to 53 percent when the color of the urine is normal).1 On the other hand, a quantitatively determined increase in porphobilinogen has a specificity approaching 100 percent for the acute porphyrias (acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria) during the acute phase of illness.1 There is disagreement in the literature about whether the sensitivity of the test for porphobilinogen is also close to 100 percent. This appears to be the sensitivity when the test is performed in patients with acute symptoms, but the test probably has some false negative results in patients who are in full clinical remission.
Similarly, the sensitivity and specificity of the test for porphobilinogen deaminase activity are 90 and 98 percent, respectively, for acute intermittent porphyria.1 The normal result of this test in the patient (and in her brother, who had similar symptoms, pointing to an autosomal dominant type of hereditary disorder) may have been a false negative result, or the patient may have had other types of acute porphyria, which were not discussed by the authors.
1 ReferencesBenjamin Djulbegovic, M.D.
University of Louisville, Louisville, KY 40292To the Editor:
The most likely diagnosis in the case described in the Clinical Problem-Solving article jumps off the page: migraine. It is unfortunate that the patient's transient hemianopia followed by severe headache was thought to be a conversion reaction, since in retrospect it was undoubtedly migraine. That this episode accompanied her abdominal pain on at least one reported occasion supports the diagnosis of migraine, as does the improvement with dietary manipulation and the history of similar problems in her brother.
Although head pain is the most common manifestation of migraine, it may be overshadowed by other symptoms or absent altogether, which was probably the case with this patient. People with features of migraine other than pain, such as visual, somatosensory, or vegetative symptoms (including abdominal pain), may minimize or ignore headache, and physicians are apt to do the same.
Migraine is an important yet frequently overlooked consideration in the differential diagnosis of visual, sensory, motor, or vegetative symptoms in a young patient, especially a woman, that are unexplained, paroxysmal, and self-limited. The appropriate diagnosis can be made only by recognizing the varied manifestations of migraine, taking a careful history, and disavowing the incorrect assumption that in most cases head pain is psychogenic. In retrospect, maybe this case was not as “hazy” as it seemed.
Stephen G. Reich, M.D.
Johns Hopkins Hospital, Baltimore, MD 21287-0857Author/Editor Response
The authors reply:
To the Editor: We agree with Drs. Akasheh, Deacon, and Djulbegovic that variegate porphyria and hereditary coproporphyria are important diagnostic considerations in the case of our patient. An accurate analysis of fecal porphyrins is the key to establishing the correct diagnosis, but the interpretation of such an analysis can be difficult.1 Dietary constituents and bacterial metabolism may affect fecal porphyrin excretion and blur the border between a normal and an abnormal result. Furthermore, there is a substantial enterohepatic circulation of porphyrins secreted into the bile, which can also affect fecal measurements. These problems can be overcome by analyzing biliary rather than fecal porphyrins.2
In the patient we described, the urinary level of porphobilinogen was not elevated in many of her acute attacks. In several stool samples, the porphyrin levels were variable and inconclusive. Clinically, the patient could have had any of the acute porphyrias, but none of the tests were diagnostic.
The fact that Dr. Reich bases the diagnosis of migraine on the same clinical data that are consistent with the acute porphyrias only emphasizes our point that the diagnosis of this patient's disorder is not obvious and indeed is still hazy after all these years.
2 ReferencesEldad Ben-Chetrit, M.D.
Hadassah University Hospital, Jerusalem 91120, IsraelChaim Putterman, M.D.
Albert Einstein College of Medicine, Bronx, NY 104611
Kushner JP . Laboratory diagnosis of the porphyrias. N Engl J Med 1991;324:1432-1434
Full Text | Web of Science | Medline2
Logan GM ,Weimer MK ,Ellefson M ,Pierach CA ,Bloomer JR . Bile porphyrin analysis in the evaluation of variegate porphyria. N Engl J Med 1991;324:1408-1411
Full Text | Web of Science | Medline
