HEREDITARY COPROPORPHYRIA

SUMMARY Hereditary coproporphyria is a rarely diagnosed disease and is one of the acute porphyrias. The classic mental, neurological and abdominal symptoms are often observed, but there appear to be atypical clinical features and laboratory findings that may lead to underdiagnosis. In an oral stomatology practice, a group of patients having oral conditions with unknown pathophysiology and multiple systemic complaints were evaluated for porphyrin abnormalities. Blood enzymes, urine and stool porphyrin panels were usually run. A large number of the patients had the clinical symptomatology and porphyrin abnormalities classically found in hereditary coproporphyria.

T he porphyrias are a family of metabolic diseases involving the heme pathway. They are generally subdivided into the acute and non-acute porphyrias.
Hereditary coproporphyria is considered to be the least common of the acute porphyrias. 1 • 3 The major clinical · symptoms for this and other acute porphyrias include mental abnormalities, gastrointestinal abnormalities with pain, and neurologic dysfunction. 3 Those with coproporphyria will also often complain of sun intolerance. 1 The trait is passed on by an autosomal-dominant pattern. There appears to be high penetrance but variable expressivity, as only a small number of patients seem ever to experience an acute attack.
The acute porphyrias often occur following the use of porphyrogenic drugs; however, hormones, stress and infection have been known to trigger the condition.
1 · 3 In many cases no inducer can be identified. Recently, a case of acute porphyria was reported to be induced by copperpalladium dental prostheses. 4 This article is a compilation of findings in a group of patients with oral problems, multiple systemic symptoms, and blood, stool and urine tests for porphyrin abnormalities.

METHODS AND RESULTS
The patients were seen in an oral stomatology practice for a wide variety of oral symptoms, which included: xerostomia, atypical facial pain, temporomandibular joint pai~, metallic taste, allergy supposedly related to dental matenals, and burning mouth. A thorough medical history was taken, and those who had evidence of two of the three major symptom complexes for porphyria were recommended for further testing. Some family members with no oral complaints were also later tested. Table I lists their  major symptomatology and concurrent medical diagnoses,  if any. Panels were often run on the various enzymes available for routine testing; these included: aminolevulinic acid dehydrase (ALA-d), uroporphyrinogen-1-synthase (uro-1 ), uroporphyrinogen decarboxylase ( uro-d) and coproporphyrinogen oxidase (copro). 1\venty-four-hour stool samples checked levels of coproporphyrins, uroporphyrins and protoporphyrins. 1\venty-four-hour urine samples checked levels of uroporphyrins, coproporphyrins, hepta-, hexaand pentacarboxyporphyrins and porphobilinogen. These results are presented in Table 2.
All the tests were not run on each person for various reasons, including: possible 'silent' carriers among asymptomatic family members; MA, after the initial tests, showed abnormalities and elected to have his health maintenance organisation perform further tests; inexperience of the examiner.
All tests were performed at a specialty laboratory (Mayo Medical Laboratory, Rochester, Minnesota, USA). In most instances one laboratory's results are not directly comparable with another laboratory's reporting.

DISCUSSION
The clinical symptomatology appears to be explained by the consistency of results from laboratory testing. Could this mean that coproporphyria is more prevalent than previously thought? It is interestingly to review some previously recorded information that has played a role in the identification and testing of this group of patients.
Doss identified a substantial group of patients with seemingly divergent medical problems who had elevated levels of coproporphyrins in their urine that apparently subsided as the disease process abated or therapy was instigated. 5 No stool or enzyme studies were described. Unless complete testing as well as evaluation of family members were performed, the possibility of coproporphyria was not excluded. An article of equal importance by Day et al demonstrated that porphyrin precursors are made in the kidney, and concluded that all cells probably have a · heme pathway and thus are susceptible to disordered porphyrin metabolism. 6 DeMatteis et al showed that heme can be formed in the brain; thus, excess heptic precursors do not necessarily cause the neurologic symptoms of porphyria. 7 Downey discussed how disordered heme metabolism and different tissue sensitivity may lead to atypical clinical presentations and thus to many cases going unrecognised or perhaps being defined as another entity. 8 Hudson et al discussed fibromyalgia and its co-morbidity with other medical and psychiatric disorders, again suggesting a common metabolic link. 9 Two patients in this report (JA and PV) have a diagnosis of fibromyalgia made by board-certified rheumatologists. Some time ago Goldberg et al suggested that coproporphyria could have a more atypical presentation when they identified a group of patients with mental derangements but no other symptomatology. 10 An area of possible concern is that many of my group of patients had only minimally elevated or normal levels of precursors in the urine. As the number of known cases of coproporphyria is currently low, this may ultimately be found to be more common than was previously thought. Almost all of these patients have been ill for an extended period of time, but none were known to have had an acute attack. Moore describes the urine findings as variable if the patient is not in an attack. 1 Bissell agrees, saying that heme precursors vary widely in carriers. 3 Wintrob states that urine coproporphyrin excretion may be profoundly increased during symptomatic periods but is usually normal during remissions. 11 Stool porphyrins are most critical in identifying coproporphyria, according to Berger 12 and Cripps. 13 Even in acute intermittent porphyria, where it is thought that urine porphyrins are always elevated, Tishler et al found 18 patients in a mental hospital with diminished uroporphyrinogen-1-synthase levels, while only 8 had elevated levels of porphobilinogen in the urine. 14 Based on the results from Table 2, 17 of 19 patients had abnormal enzyme activity. Three had two abnormal enzyme results. This has previously been noted by Moore. 1 All patients with abnormal enzyme activity when tested had elevated urine and/or stool precursors. The two patients with normal enzyme activities both had urine abnormalities. They could be followed and retested if they ever had an acute illness. Further evaluation could include testing of other tissue (ie liver biopsy) and expanded testing of other family members.
In hereditary porphyrias, testing of family members is extremely important. 1 If asymptomatic patients are identified and avoid inducers that may trigger the disease, they may never have an acute attack. It is thought that some asymptomatic carriers will be missed if only tests for heme precursors are used; enzyme studies are critical in identifying these patients.

FOR DISCUSSION
Our testing of family members identified a number of latent cases whose future medical and dental management should be that of a porphyric. In one family, the testing of the patient's sister showed an enzyme level slightly higher than twice that of the patient's levels (PH). Her sister is not included in this report, but it is confirmatory evidence that the patient has diminished levels of coproporphyrinogen oxidase. 11 As more is learned, dentistry may join medicine as an inadvertent inducer of acute attacks in unknown porphyries. It has been recommended that these patients avoid aluminium and mercury compounds, 15 which are major components in many dental restorations. 16 The recent report of copper-palladium dental prostheses inducing an acute attack of porphyria suggests there may be other such cases that have gone unrecognised. This possible connection should be investigated in greater depth in both the fields of medicine and dentistry.