922
decrease in ALT (85 IU/l on July 18), there were no favourable effects of IFN treatment after 6 months, when ALT was 213 IU/1, gammaglobulins 23 g/1 and liver histology showed chronic active hepatitis. At this stage, ANA (1in 40) and SMA (1in 80) first appeared in serum and IFN was withdrawn. In June, 1989, the patient was referred to us. ALT was 256 IU/1, gammaglobulins 22 g/1, SMA 1 in 40, and serum ANA, AMA, gastric parietal cell, and thyroid microsome antibodies were negative. Anti-LKMl (1 in 1280, immunofluorescence test) and anti-HCV (Ortho ELISA) antibodies were positive in serum, and hepatitis B virus markers were negative. HLA phenotype proved to be Al, B8, DR3. T-lymphocyte migration inhibitory factor assay2,3 did not show T-cell reactivity to the hepatocyte asialoglycoprotein receptor (AGPR) (migration index 0-94). Treatment with 6methylprednisolone (40 mg daily) was introduced with some benefit (ALT 110 IU/1, gammaglobulins 18 g/1, anti-LKMl1in 320), although liver histology still showed features of chronic active hepatitis. Serological investigations on stored serum revealed that anti-LKMl (1 in 640) and anti-HCV were detectable before IFN
early
treatment.
The lack of efficacy of IFN strongly suggests that, in this case, HCV replication did not contribute much to the liver cell damage. Whether HCV antibodies were merely a marker of previous infection or indicated continuing infection remains to be established by viral sequence detection analyses.’ Although studies are needed to establish whether HCV infection precedes and determines anti-LKMlantibody production and whether cellular immune reactions to liver cell surface antigen(s) are present in these patients (in our case T-cell reactivity to one such antigen, AGPR, was not seen), our observations suggest that steroids should continue to be the treatment of choice in type 2 autoimmune hepatitis. IFN therapy not only seems to be unwarranted in these patients, but also favours the development of autoantibodies5,6 (also this case) and possible serious exacerbations of liver disease.6
Infectious Diseases Unit, "A Pugliese" Hospital, 88100 Catanzaro, Italy, and Department of Infectious Diseases, "Borgo Trento" Hospital, University of Verona
SANDRO VENTO GIOVANNI DI PERRI ROBERTO LUZZATI TIZIANA GAROFANO ERCOLE CONCIA DANTE BASSETTI
1.
Homberg JC, Abuaf N, Bernard O, et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of "autoimmune" hepatitis. Hepatology 1987; 7: 1333-39. 2. Vento S, Hegarty JE, Bottazzo GF, Macchia E, Williams R, Eddleston ALWF. Antigen-specific suppressor cell function in autoimmune chronic active hepatitis. Lancet 1984; i: 1200-04. 3. Vento S, O’Brien CJ, McFarlane BM, McFarlane IG, Eddleston AWLF, Williams R. T lymphocyte sensitization to hepatocyte antigens in autoimmune chronic active hepatitis and primary biliary cirrhosis: evidence for different underlying mechanisms and different antigenic determinants as targets Gastroenterology 1986; 91: 810-17. AJ, Kuo G, Bradley DW, et al. Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet 1990; 335: 1-3. 5. Mayet WJ, Hess G, Gerken G, et al. Treatment of chronic type B hepatitis with recombinant alpha interferon induces autoantibodies not specific for autoimmune chronic hepatitis. Hepatology 1989; 10: 24-28. 6. Vento S, Di Perri G, Garofano T, et al. Hazards of interferon therapy for HBV-seronegative chronic hepatitis. Lancet 1989; ii: 926.
4. Weiner
"Natural"
benzodiazepines
in
man
SIR,-Professor Dencker and Dr Johansson (Feb 17, p 413) report that benzodiazepine-like substances could be detected in mothers’ milk by a radioreceptor technique. The milk concentrations (expressed as equivalents of lorazepam) of the benzodiazepine-like agents varied between 4 and 8 ng/ml. Since the radioreceptor technique is unspecific cross-reacting material might also account for these levels. The stated concentrations would be high enough to be measurable by gas chromatographic and mass spectrometry
analysis. We have used such specific and sensitive techniques (applying the stable isotope dilution technique for exact quantification) to detect "natural" benzodiazepines in the brain of various animals
and in plants.1 When we examined stored brain samples from patients who had died before the clinical introduction of benzodiazepines (to exclude any effects due to unknown ingestion of such drugs) we found low concentrations of diazepam (02-03 ng/g wet weight)? Therefore it is likely that low concentrations of benzodiazepines are also present in other tissues (including breast), but which are probably too low to exert direct pharmacological
effects. Since various benzodiazepines have been found in many plants,1,3,4 the "endogenous" benzodiazepines found in human brain or milk might arise from this food source. Dr Margarete Fischer-Bosch-Institut fur Klinische Pharmakologie, 7000 Stuttgart 50, West Germany 1. Unseld
ULRICH KLOTZ
E, Krishna DR, Fischer C, Klotz U. Detection of desmethyldiazepam and m brain of different species and plants. Biochem Pharmacol 1989; 38:
diazepam
2473-78. E, Fischer C, Rothemund E, Klotz U. Occurrence of ’natural’ diazepam in human brain. Biochem Pharmacol 1990; 39: 210-12. 3. Wildmann J, Mohler H, Vetter W, Ranadaler U, Schmidt K, Maurer R. Diazepam and N-desmethyldiazepam are found in rat brain and adrenals and may be of plant origin.J Neural Transm 1987; 70: 383-89. 4. Wildmann J, Vetter W, Ranadaler UB, Schmidt K, Maurer R, Mohler H. Occurrence of pharmacologically active BZD in trace amounts in wheat and potato. Biochem Pharmacol 1988; 37: 3549-59. 2. Unseld
Thiazides with loop diuretics for severe congestive heart failure SiR,—Dr Kiyingi and colleagues (Jan 6, p 29) report the use of metolazone in severe refractory congestive cardiac failure. Metolazone has been used in this context for nearly 20 years.! However, its impressive effect is not unique; we report the combined use of bendrofluazide with frusemide. Ten patients (table) admitted with severe refractory heart failure were investigated. All failed to respond to frusemide given orally and intravenously, and body weight was unchanged or increased. Bendrofluazide 10 mg (5 mg in 1 patient) orally was added to their treatment, diuresis was established within 24 h, and weight loss was progressive. When diuresis started, bendrofluazide was withdrawn in 6 patients and weight loss continued with frusemide treatment alone, the dose being progressively reduced in 4 patients. In 1 other patient the frusemide was also reduced but bendrofluazide was continued. Only 3 patients were discharged on both frusemide and bendrofluazide. 2 patients who were hyponatraemic on frusemide therapy before the introduction of bendrofluazide remained so; no other patient had hyponatraemia. 9 patients were normokalaemic on frusemide therapy and 1 was hyperkalaemic, but mild hypokalaemia developed in only 2 (both 29 mmol/1). In 6 the serum creatinine/ urea fell and in 3 small increases occurred which reversed after the drug was stopped. In 1 patient, with evidence of at least moderate renal impairment, there was a more pronounced increase in creatinine to 310 umol/1. In all patients fluid retention resolved with PATIENT DETAILS IN RELATION TO BENDROFLUAZIDE TREATMENT
decrease in ALT (85 IU/l on July 18), there were no favourable effects of IFN treatment after 6 months, when ALT was 213 IU/1, gammaglobulins 23 g/1 and liver histology showed chronic active hepatitis. At this stage, ANA (1in 40) and SMA (1in 80) first appeared in serum and IFN was withdrawn. In June, 1989, the patient was referred to us. ALT was 256 IU/1, gammaglobulins 22 g/1, SMA 1 in 40, and serum ANA, AMA, gastric parietal cell, and thyroid microsome antibodies were negative. Anti-LKMl (1 in 1280, immunofluorescence test) and anti-HCV (Ortho ELISA) antibodies were positive in serum, and hepatitis B virus markers were negative. HLA phenotype proved to be Al, B8, DR3. T-lymphocyte migration inhibitory factor assay2,3 did not show T-cell reactivity to the hepatocyte asialoglycoprotein receptor (AGPR) (migration index 0-94). Treatment with 6methylprednisolone (40 mg daily) was introduced with some benefit (ALT 110 IU/1, gammaglobulins 18 g/1, anti-LKMl1in 320), although liver histology still showed features of chronic active hepatitis. Serological investigations on stored serum revealed that anti-LKMl (1 in 640) and anti-HCV were detectable before IFN
early
treatment.
The lack of efficacy of IFN strongly suggests that, in this case, HCV replication did not contribute much to the liver cell damage. Whether HCV antibodies were merely a marker of previous infection or indicated continuing infection remains to be established by viral sequence detection analyses.’ Although studies are needed to establish whether HCV infection precedes and determines anti-LKMlantibody production and whether cellular immune reactions to liver cell surface antigen(s) are present in these patients (in our case T-cell reactivity to one such antigen, AGPR, was not seen), our observations suggest that steroids should continue to be the treatment of choice in type 2 autoimmune hepatitis. IFN therapy not only seems to be unwarranted in these patients, but also favours the development of autoantibodies5,6 (also this case) and possible serious exacerbations of liver disease.6
Infectious Diseases Unit, "A Pugliese" Hospital, 88100 Catanzaro, Italy, and Department of Infectious Diseases, "Borgo Trento" Hospital, University of Verona
SANDRO VENTO GIOVANNI DI PERRI ROBERTO LUZZATI TIZIANA GAROFANO ERCOLE CONCIA DANTE BASSETTI
1.
Homberg JC, Abuaf N, Bernard O, et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of "autoimmune" hepatitis. Hepatology 1987; 7: 1333-39. 2. Vento S, Hegarty JE, Bottazzo GF, Macchia E, Williams R, Eddleston ALWF. Antigen-specific suppressor cell function in autoimmune chronic active hepatitis. Lancet 1984; i: 1200-04. 3. Vento S, O’Brien CJ, McFarlane BM, McFarlane IG, Eddleston AWLF, Williams R. T lymphocyte sensitization to hepatocyte antigens in autoimmune chronic active hepatitis and primary biliary cirrhosis: evidence for different underlying mechanisms and different antigenic determinants as targets Gastroenterology 1986; 91: 810-17. AJ, Kuo G, Bradley DW, et al. Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet 1990; 335: 1-3. 5. Mayet WJ, Hess G, Gerken G, et al. Treatment of chronic type B hepatitis with recombinant alpha interferon induces autoantibodies not specific for autoimmune chronic hepatitis. Hepatology 1989; 10: 24-28. 6. Vento S, Di Perri G, Garofano T, et al. Hazards of interferon therapy for HBV-seronegative chronic hepatitis. Lancet 1989; ii: 926.
4. Weiner
"Natural"
benzodiazepines
in
man
SIR,-Professor Dencker and Dr Johansson (Feb 17, p 413) report that benzodiazepine-like substances could be detected in mothers’ milk by a radioreceptor technique. The milk concentrations (expressed as equivalents of lorazepam) of the benzodiazepine-like agents varied between 4 and 8 ng/ml. Since the radioreceptor technique is unspecific cross-reacting material might also account for these levels. The stated concentrations would be high enough to be measurable by gas chromatographic and mass spectrometry
analysis. We have used such specific and sensitive techniques (applying the stable isotope dilution technique for exact quantification) to detect "natural" benzodiazepines in the brain of various animals
and in plants.1 When we examined stored brain samples from patients who had died before the clinical introduction of benzodiazepines (to exclude any effects due to unknown ingestion of such drugs) we found low concentrations of diazepam (02-03 ng/g wet weight)? Therefore it is likely that low concentrations of benzodiazepines are also present in other tissues (including breast), but which are probably too low to exert direct pharmacological
effects. Since various benzodiazepines have been found in many plants,1,3,4 the "endogenous" benzodiazepines found in human brain or milk might arise from this food source. Dr Margarete Fischer-Bosch-Institut fur Klinische Pharmakologie, 7000 Stuttgart 50, West Germany 1. Unseld
ULRICH KLOTZ
E, Krishna DR, Fischer C, Klotz U. Detection of desmethyldiazepam and m brain of different species and plants. Biochem Pharmacol 1989; 38:
diazepam
2473-78. E, Fischer C, Rothemund E, Klotz U. Occurrence of ’natural’ diazepam in human brain. Biochem Pharmacol 1990; 39: 210-12. 3. Wildmann J, Mohler H, Vetter W, Ranadaler U, Schmidt K, Maurer R. Diazepam and N-desmethyldiazepam are found in rat brain and adrenals and may be of plant origin.J Neural Transm 1987; 70: 383-89. 4. Wildmann J, Vetter W, Ranadaler UB, Schmidt K, Maurer R, Mohler H. Occurrence of pharmacologically active BZD in trace amounts in wheat and potato. Biochem Pharmacol 1988; 37: 3549-59. 2. Unseld
Thiazides with loop diuretics for severe congestive heart failure SiR,—Dr Kiyingi and colleagues (Jan 6, p 29) report the use of metolazone in severe refractory congestive cardiac failure. Metolazone has been used in this context for nearly 20 years.! However, its impressive effect is not unique; we report the combined use of bendrofluazide with frusemide. Ten patients (table) admitted with severe refractory heart failure were investigated. All failed to respond to frusemide given orally and intravenously, and body weight was unchanged or increased. Bendrofluazide 10 mg (5 mg in 1 patient) orally was added to their treatment, diuresis was established within 24 h, and weight loss was progressive. When diuresis started, bendrofluazide was withdrawn in 6 patients and weight loss continued with frusemide treatment alone, the dose being progressively reduced in 4 patients. In 1 other patient the frusemide was also reduced but bendrofluazide was continued. Only 3 patients were discharged on both frusemide and bendrofluazide. 2 patients who were hyponatraemic on frusemide therapy before the introduction of bendrofluazide remained so; no other patient had hyponatraemia. 9 patients were normokalaemic on frusemide therapy and 1 was hyperkalaemic, but mild hypokalaemia developed in only 2 (both 29 mmol/1). In 6 the serum creatinine/ urea fell and in 3 small increases occurred which reversed after the drug was stopped. In 1 patient, with evidence of at least moderate renal impairment, there was a more pronounced increase in creatinine to 310 umol/1. In all patients fluid retention resolved with PATIENT DETAILS IN RELATION TO BENDROFLUAZIDE TREATMENT
