Diagnosis of Porphyria
NB The diagnostic algorithms recommended in the pages are designed for patients in the South African context. Approaches will differ for patients in other settings.
The principles underlying the diagnosis of porphyria are outlined here, whereas specific step-by-step instructions for diagnosis in a South African setting will be found by selecting the remaining links under Diagnosis in the menu.
Making a Clinical Diagnosis of Porphyria
One should never accept a diagnosis of porphyria based on clinical symptoms alone. Skin symptoms suggestive of photosensitivity are indeed sufficient reason to have a patient tested for porphyria, as are are symptoms suggestive of the acute attack. Bear in mind however that appropriate diagnostic laboratory tests must be regarded as more sensitive and specificthan the clinical history alone. In particular, to have any relevance, the skin symptoms and possible acute symptoms must be consistent with these diagnoses. Bear in mind that the symptoms of both are quite specific:
- Disease limited to sun-exposed areas, with complaints of increased skin fragility accompanied by blisters, erosions and scarring
- Severe abdominal pain present in discreet episodes lasting at least several days at a time, accompanied by severe ill health, darkening of the urine and nausea (possibly proceeding to paralysis). A chronic history of intermittent low-grade abdominal pain waxing and waning during the course of the day and present for weeks and months is not suggestive of porphyria.
Note that we have never yet confirmed a diagnosis of porphyria in a patient whose primary complaint was psychiatric, e.g. stress, anxiety, aggression or depression.
It is best to exercise caution in interpreting a family history of porphyria. Prior to the current generation of diagnostic tests, a low threshold for diagnosing variegate porphyria on stool porphyrin analysis and on the basis of clinical symptoms led to many people in South Africa being incorrectly diagnosed as having variegate porphyria when they were in fact normal.
Laboratory Diagnosis of Porphyria
In dealing with any patient with suspected porphyria, it is therefore essential to have the appropriate diagnostic tests performed in a competent laboratory. A point often not appreciated by both patients and doctors is that an accurate set of diagnostic results will provide more information than merely confirming that porphyria is present. In order to manage the patient appropriately, we require the following information from our diagnostic testing:
- A definitive diagnosis of the type of porphyria.
- An estimation of the biochemical activity of the porphyria. (In general there is a relationship between the the degree of elevation of urine ALA, PBG and porphyrins and the likelihood that acute symptoms are due to porphyria.)
- Identification of the mutation responsible for the porphyria in the patient (which is of great value in subsequent screening of the family).
Recommended Approach to the Diagnosis of Porphyria in South Africa
Initial samples required are blood and urine.
Positive test suggests erythropoietic protoporphyria or congenital erythropoietic porphyria. One must then proceed to erythrocyte and plasma porphyrin chromatographic quantitation.
In variegate porphyria, an accumulation of a particular mixture of porphyrins bound to albumin in the plasma gives rise to a characteristic peak in porphyrin fluorescence at 625 nm. This ishighly specific for variegate porphyria. The test is more sensitive than stool porphyrin analysis, which it has replaced in our laboratory. Plasma scanning will detect approximately 80% of adults with variegate porphyria (including all those with symptoms).
In other forms of porphyria, particularly acute intermittent porphyria and porphyria cutanea tarda, the accumulation of uroporphyrin in the plasma leads to a characteristic peak in porphyrin fluorescence at 619 nm.
Urine porphyrin and precursor analysis
An initial quantitative screening test for both porphobilinogen (the Watson-Schwartz reaction) and urine porphyrins (Dean's method) should be performed on a urine sample. If tests are positive, or where there is strong clinical evidence for any form of porphyria, or a positive plasma scan, one should proceed to a chromatographic quantitation of ALA, and PBG and porphyrins. This may confirm a diagnosis of acute intermittent porphyria or porphyria cutanea tarda, and is the most appropriate way to assess the biochemical activity of variegate porphyria.
if the plasma scan is suggestive of variegate porphyria, or if there is a family history of VP, one should perform a DNA test for the common South African (R59W) mutation. In the rare patient with variegate porphyria who is R59W-negative, one can then screen the protoporphyrinogen oxidase gene for other known and unknown mutations.
Stool porphyrin analysis
We no longer perform this as an initial test for the diagnosis of variegate porphyria in view of the greater simplicity, sensitivity and specificity of the plasma porphyrin scan. We will perform stool porphyrin analysis for specific indications, including the diagnosis of hereditary coproporphyria.
Pitfalls in Diagnosis
A common problem is the patient who has had an incomplete sets of tests performed. Typically this comprises a DNA test for the common South African mutation without appropriate biochemical urine and plasma porphyrin analysis. Such a test will not detect forms of porphyria other than R59W-positive VP, and provides no information on biochemical activity.