- Email: [email protected]
AUTOIMMUNITY IN PATIENTS WITH SPANISH TOXIC OIL SYNDROME
644
guidelines. Finally, it should be remembered that over a three-year period of placebo treatment of mild hypertension 48% of
CIRCULATING AUTOANTIBODIES AND IMMUNE COMPLEXES’ IB INDIVIDUALS WITH TOXIC OIL POISONING
individuals reduced their diastolic blood pressure below 95 mm Hg.4Surely, as suggested by Dr Miall in his letter in your Feb 26 issue, authoritative statements on the treatment of mild hypertension should await the results of the Medical Research Council’s trial of treatment in mild hypertension. Department of Medicine, Western General Hospital, PAUL L. PADFIELD
Edinburgh EH4 2XU
SIR,-It is
pity that those guidelines for the treatment of mild hypertension ignore the psychological consequences of the decision to treat. Most people with mild hypertension are symptomless and have a self-image of normality and health. The decision to treat induces a self-image diminished by chronic life-threatening disease which requires daily, and presumably life-long, therapy. The seriousness of this change is indicated by the prevalence of on adverse reactions from symptoms in placebo takers in the report the Medical Research Council trial. These included impotence in 10% of men. The MRC working party stated that: "Reported incidence figures for suspected adverse reactions are probably lower than
true
a
incidences, since
not
all reactions will have been
at follow up ..." Case finding in general practice is preferable to screening because some estimate of psychological consequences is at least possible; furthermore the psychological response to the diagnosis is a major determinant of compliance with therapeutic regimens. Being suspected of hypertension may have ill-effects, and subsequent reassurance that blood pressure is normal is not always effective. Ignoring the psychological consequences of the decision to treat tips the balance unfairly and unjustifiably towards therapeutic activism. Department of Community Health,
mentioned by patients
University of Dublin, Trinity College Medical School,
JAMES S. MCCORMICK
Dublin 2, Ireland
AUTOIMMUNITY IN PATIENTS WITH SPANISH TOXIC OIL SYNDROME
SiR,—In the so-called Spanish toxic oil syndrome caused by ingested denatured rapeseed oil respiratory distress was the major symptom at first but, after a latent period, some patients were readmitted
to
hospital
with
severe
myalgias, neurological
manifestations, pulmonary hypertension, anorexia, weight loss, sicca syndome, and skin alterations resembling those of scleroderma. The secondary manifestations were accompanied by the presence of serum autoantibodies in some patients. The role of autoimmunity in the pathogenesis of the syndrome has been much discussed by clinicians and immunologists in Spain, but the matter has not been resolved. Our autoantibody and immune complex data (table) may provide additional clues. Possession of autoantibodies (titres of 1 :80 or greater) was more common in patients with symptoms than in the symptom-free individuals who ingested the oil. However, there was no correlation with the severity of any of the clinical manifestations: some seriously affected patients had no autoantibodies. Circulating immune complex concentrations were low, and such complexes have never been found deposited on the vascular lesions in this syndrome. Moreover, on follow-up we found that antinuclear antibody (ANA) titres increased or decreased independently of clinical change. Thus, it seems unlikely that autoimmune phenomena cause the toxic oil syndrome. Nevertheless, a hypersensitive reaction to the toxin, similar to the abnormal response to certain drugs in which undefined, immunologically mediated mechanisms have been implicated, may underlie the pathogenesis of this syndrome.
*Circulating, IgG and/or IgM. Positivity is defined as a figure exceeding the mean +2 SD for 50 blood donors (50 I-’g/ml for IgG and 70 pg/m1 for IgM). Autoantibodies were tested by Immunofluorescence and immune complexes by polyethyleneglycol precipitation
Increased IgE levels, intense eosinophilia, lack of dose relationship, predominance in females, circulating autoantibodies which persist for at least a year after the intoxication, mononuclear cell infiltrations, and the finding (unpublished) of specific IgE to oleyl anilide strongly support this hypothesis. In addition, the frequency of DR3 and DR4 in female chronic patients has been reported to be 1 significantly higher than that in controls. CARMEN GUTIERREZ Departments of Immunology, LUISA GASPAR and Internal Medicine, RICARDO MURO Universidad Autónoma, Clinica Puerta de Hierro,
Madrid-35, Spain
MIGUEL KREISLER PEDRO FERRIZ
FATE OF FATTY ACID ANILIDES IN THE RAT
SIR,-Dr Rodrigo and colleagues have described neurotoxic effects of fatty acid anilides in the New Zealand rabbit (Feb 19, p 414), findings that contrast with studies in rats.2,3 Our results throw some light on the failure to find toxic effects in the rat. We gave oleylanilide, labelled with 3H in the acyl group and/or with 14C in the aromatic group to male Porton Wistar rats as a single intragastric dose in rape oil at 0’ 5 ml or 2 - 0 ml of a 1 % w/v solution per rat. Over 3 days about 60% of the dose was recovered as unchanged anilide in the faeces. About 90% of the remainder of the aromatic label was recovered in urine as hydrophilic metabolites, the major component being conjugates ofp-hydroxyacetanilide, the principal metabolite of aniline, indicating extensive hydrolysis of the absorbed anilide. The site of such hydrolysis was investigated in rats fitted with a cannula in the abdominal part of the thoracic lymph duct. Administration of double-labelled anilide to such rats resulted in a disproportionately large recovery of the acyl group label in the triglyceride component of the lymph chylomicra. This indicates hydrolysis of the anilide before or during absorption from the gut with subsequent re-esterification of released fatty acid. Less than 6% of the dose of anilide administered was recovered in the lymph, as confirmed by capillary gas chromatography. The distribution of label in the other tissues indicated negligible absorption of intact anilides via other routes. We have so far been unable to detect anilides in rat tissues following intragastric administration, suggesting that a potential for rapid hydrolysis subsequent to absorption via the lymph may also be present.
2
JL, Serrano-Rios M, San Andres F, Arnaiz-Villena A. HLA-DR3, DR4 in chronic stage of Spanish oil disease Lancet 1982; i: 98-99 Aldridge WN, Connors TA Toxic oil syndrome in Spain Fd Chem Toxic 1982; 20:
3
Beauberpand C, Spencer PS, Koppel C, Altenkirch H. "Spanish oil" not neurotoxic in
1. Vicario
Study Management Committee. therapeutic trial in mild hypertension Lancet 1980; i 1261-67
4. Australian National Blood Pressure
The Australian
1 Medical Research Council Working Party on Mild to Moderate Hypertension reactions to
Lancet
ii
539
989-92
Adverse
bendrofluazide and propranolol for the treatment of mild hypertension.
1981;
increase
rats
Lancet
1982; ii: 1278-79.
guidelines. Finally, it should be remembered that over a three-year period of placebo treatment of mild hypertension 48% of
CIRCULATING AUTOANTIBODIES AND IMMUNE COMPLEXES’ IB INDIVIDUALS WITH TOXIC OIL POISONING
individuals reduced their diastolic blood pressure below 95 mm Hg.4Surely, as suggested by Dr Miall in his letter in your Feb 26 issue, authoritative statements on the treatment of mild hypertension should await the results of the Medical Research Council’s trial of treatment in mild hypertension. Department of Medicine, Western General Hospital, PAUL L. PADFIELD
Edinburgh EH4 2XU
SIR,-It is
pity that those guidelines for the treatment of mild hypertension ignore the psychological consequences of the decision to treat. Most people with mild hypertension are symptomless and have a self-image of normality and health. The decision to treat induces a self-image diminished by chronic life-threatening disease which requires daily, and presumably life-long, therapy. The seriousness of this change is indicated by the prevalence of on adverse reactions from symptoms in placebo takers in the report the Medical Research Council trial. These included impotence in 10% of men. The MRC working party stated that: "Reported incidence figures for suspected adverse reactions are probably lower than
true
a
incidences, since
not
all reactions will have been
at follow up ..." Case finding in general practice is preferable to screening because some estimate of psychological consequences is at least possible; furthermore the psychological response to the diagnosis is a major determinant of compliance with therapeutic regimens. Being suspected of hypertension may have ill-effects, and subsequent reassurance that blood pressure is normal is not always effective. Ignoring the psychological consequences of the decision to treat tips the balance unfairly and unjustifiably towards therapeutic activism. Department of Community Health,
mentioned by patients
University of Dublin, Trinity College Medical School,
JAMES S. MCCORMICK
Dublin 2, Ireland
AUTOIMMUNITY IN PATIENTS WITH SPANISH TOXIC OIL SYNDROME
SiR,—In the so-called Spanish toxic oil syndrome caused by ingested denatured rapeseed oil respiratory distress was the major symptom at first but, after a latent period, some patients were readmitted
to
hospital
with
severe
myalgias, neurological
manifestations, pulmonary hypertension, anorexia, weight loss, sicca syndome, and skin alterations resembling those of scleroderma. The secondary manifestations were accompanied by the presence of serum autoantibodies in some patients. The role of autoimmunity in the pathogenesis of the syndrome has been much discussed by clinicians and immunologists in Spain, but the matter has not been resolved. Our autoantibody and immune complex data (table) may provide additional clues. Possession of autoantibodies (titres of 1 :80 or greater) was more common in patients with symptoms than in the symptom-free individuals who ingested the oil. However, there was no correlation with the severity of any of the clinical manifestations: some seriously affected patients had no autoantibodies. Circulating immune complex concentrations were low, and such complexes have never been found deposited on the vascular lesions in this syndrome. Moreover, on follow-up we found that antinuclear antibody (ANA) titres increased or decreased independently of clinical change. Thus, it seems unlikely that autoimmune phenomena cause the toxic oil syndrome. Nevertheless, a hypersensitive reaction to the toxin, similar to the abnormal response to certain drugs in which undefined, immunologically mediated mechanisms have been implicated, may underlie the pathogenesis of this syndrome.
*Circulating, IgG and/or IgM. Positivity is defined as a figure exceeding the mean +2 SD for 50 blood donors (50 I-’g/ml for IgG and 70 pg/m1 for IgM). Autoantibodies were tested by Immunofluorescence and immune complexes by polyethyleneglycol precipitation
Increased IgE levels, intense eosinophilia, lack of dose relationship, predominance in females, circulating autoantibodies which persist for at least a year after the intoxication, mononuclear cell infiltrations, and the finding (unpublished) of specific IgE to oleyl anilide strongly support this hypothesis. In addition, the frequency of DR3 and DR4 in female chronic patients has been reported to be 1 significantly higher than that in controls. CARMEN GUTIERREZ Departments of Immunology, LUISA GASPAR and Internal Medicine, RICARDO MURO Universidad Autónoma, Clinica Puerta de Hierro,
Madrid-35, Spain
MIGUEL KREISLER PEDRO FERRIZ
FATE OF FATTY ACID ANILIDES IN THE RAT
SIR,-Dr Rodrigo and colleagues have described neurotoxic effects of fatty acid anilides in the New Zealand rabbit (Feb 19, p 414), findings that contrast with studies in rats.2,3 Our results throw some light on the failure to find toxic effects in the rat. We gave oleylanilide, labelled with 3H in the acyl group and/or with 14C in the aromatic group to male Porton Wistar rats as a single intragastric dose in rape oil at 0’ 5 ml or 2 - 0 ml of a 1 % w/v solution per rat. Over 3 days about 60% of the dose was recovered as unchanged anilide in the faeces. About 90% of the remainder of the aromatic label was recovered in urine as hydrophilic metabolites, the major component being conjugates ofp-hydroxyacetanilide, the principal metabolite of aniline, indicating extensive hydrolysis of the absorbed anilide. The site of such hydrolysis was investigated in rats fitted with a cannula in the abdominal part of the thoracic lymph duct. Administration of double-labelled anilide to such rats resulted in a disproportionately large recovery of the acyl group label in the triglyceride component of the lymph chylomicra. This indicates hydrolysis of the anilide before or during absorption from the gut with subsequent re-esterification of released fatty acid. Less than 6% of the dose of anilide administered was recovered in the lymph, as confirmed by capillary gas chromatography. The distribution of label in the other tissues indicated negligible absorption of intact anilides via other routes. We have so far been unable to detect anilides in rat tissues following intragastric administration, suggesting that a potential for rapid hydrolysis subsequent to absorption via the lymph may also be present.
2
JL, Serrano-Rios M, San Andres F, Arnaiz-Villena A. HLA-DR3, DR4 in chronic stage of Spanish oil disease Lancet 1982; i: 98-99 Aldridge WN, Connors TA Toxic oil syndrome in Spain Fd Chem Toxic 1982; 20:
3
Beauberpand C, Spencer PS, Koppel C, Altenkirch H. "Spanish oil" not neurotoxic in
1. Vicario
Study Management Committee. therapeutic trial in mild hypertension Lancet 1980; i 1261-67
4. Australian National Blood Pressure
The Australian
1 Medical Research Council Working Party on Mild to Moderate Hypertension reactions to
Lancet
ii
539
989-92
Adverse
bendrofluazide and propranolol for the treatment of mild hypertension.
1981;
increase
rats
Lancet
1982; ii: 1278-79.