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 At this stage, ANA (1in 40) and SMA (1in 80) first appeared in serum and IFN was withdrawn.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

923

2 patients subsequently died after of severe refractory heart failure in 1 and pulmonary embolism in the other. Our patients had resistant oedema from severe congestive cardiac failure. All responded to the addition of bendrofluazide therapy by diuresis and resolution of the oedema. Unlike Kiyingi et al, we did not start with a low dose of thiazide-like diuretic but chose 10 mg of bendrofluazide in 9 and 5 mg in 1. This was not associated with profound or dangerous electrolyte disturbances. It is important to avoid overdiuresis in such patients since this causes a fall in cardiac output with subsequent prerenal failure. Treatment should be monitored by daily measurements of weight and serum creatinine, urea, and electrolytes. Metolazone is more than fifteen times more expensive than bendrofluazide, and our data suggest that it offers little advantage.

bendrofluazide therapy. recurrence

Cardiology Department, Royal Hallamshire Hospital,

KEVIN S. CHANNER MICHAEL RICHARDSON

Sheffield S10 2JF, UK

ROB CROOK

Cardiology Department, Bristol Royal Infirmary

JOHN V. JONES

1. Gunstone

RF, Wing AJ, Shani HGP, Njemo D, Sabuka EMW. Clinical experience with metolazone in 52 African patients: synergy with furosemide. Postgrad Med J 1971; 47: 789-93.

Effects of coronary risk reduction

on

vascular deaths in the placebo group and 461/4295 (10-7%) in the aspirin group. The reduction in mortality was greatest in patients treated within 4 h of symptom onset. The early use of aspirin in AMI is thus of demonstrated value and further randomised placebo-controlled trial seems unnecessary. Cardiac Department, London Chest Hospital, London E2 9JX, UK

STEPHEN J. D. BRECKER

1. ISIS-2 Collaborative

Group. Randomised trial of intravenous streptokinase, oral neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. aspirin, both,

or

B*This letter has been shown follows.-ED. L.

to

Dr

Elwood, whose reply

SIR,-In ISIS-2 the use of aspirin in hospital patients with acute myocardial infarction was clearly shown to be of benefit. The suggestion I had commented on was that a single dose of aspirin taken at the onset of chest pain would be beneficial. However, extrapolation from the one situation to the other is probably not unreasonable. MRC Epidemiology Unit (South Wales), 4 Richmond Road, Cardiff CF2 3AS, UK

P. C. ELWOOD

Why more keloids on back than on front of

mortality

earlobe

SIR,-On the basis of the observed relation between cholesterol concentrations and mortality in the Whitehall study, Professor Rose and Mr Shipley (Feb 3, p 275) predict substantial decreases in

SIR,-Keloid scarring is a common,",2 potentially severe cosmetic problem associated with surgical or accidental trauma. Despite advances in knowledge of the biochemistry and histology of keloids,

deaths from all causes for men in whom cholesterol concentrations are lowered by intervention in which cholesterol lowering has been achieved. These intervention trials, like the predictions of Rose and Shipley, apply to high risk, middleaged men. They reflect over 100 000 man-years of observation in eight studies and have been remarkably consistent in their findings-non-fatal coronary heart disease events are diminished in the experimental groups, deaths from heart disease are less clearly affected, and overall mortality is

unchanged. Even if cholesterol lowering does reduce mortality and if these studies have failed to demonstrate this advantage because they are not of sufficient duration, the findings still cast doubt on Rose and Shipley’s predictions. The intervention studies have lasted for up to 11 years and show no favourable mortality trends for the treated group.

Why the intervention studies have failed to demonstrate the effect mortality that would be predicted from cholesterol/mortality relations, such as those seen in the Whitehall study, remains debatable. Such studies are, nevertheless, most pertinent to predictions of the effects cholesterol lowering and need to be considered when such predictions are made. on

Medical Service, New York VA Medical Center, New York, NY 10010, USA

Early aspirin

NORTON SPRITZ

in

myocardial infarction

SiR,—Dr Elwood (Feb 24, p 486) suggests that there is insufficient evidence to justify the early use of aspirin in acute myocardial infarction (AMI) and he asks for a randomised controlled trial. The Second International Study of Infarct Survival (ISIS-2)1 was designed to evaluate the separate and combined effects of intravenous streptokinase and oral aspirin in patients presenting with suspected AMI. 4300 patients were treated with placebo infusion and tablets and 4295 patients with aspirin and placebo infusion. During the first 5 weeks there were 568/4300 (13-2%)

little is known of what will prevent keloid formation. Our knowledge has been greatly hindered by the fact that the only animal model available consists of athymic mice carrying transplanted human keloid cells. 3,4 Although results with this model clearly implicate abnormal fibroblasts in the maintenance of keloid tissue, they do not tell us much about the pathogenesis. I report a "natural experiment" that raises questions about the primary fibroblast-transforming event in keloids. In a predominantly Puerto Rican, Dominican, and AfroAmerican population in New York City, I have noted that earlobe keloids secondary to ear piercing occur more commonly on the back than on the front of the earlobe. I confirmed this impression by a brief review of surgical records. Fourteen consecutive patients had 19 keloids. Of 16 keloids in which the position was specified, only 1 was anterior. Assuming random placement, this should occur less than 1 % of the time. If one thinks of the two sides of the earlobe as matched-pair wound sites this observation is puzzling. Clearly host factors such as genetic make-up and age are identical. There is no tension or motion of the skin at either site. Presumably the frequency of infection is much the same since the wound sites are close and there is little, if any, barrier between them. What local factor induces the posterior keloid? Alternatively, what factor allows anterior lobe wounding without scar formation in patients with a keloid diathesis proven by the keloid on the posterior aspect? One explanation for the observation is that there is a difference in biochemical milieu between the anterior and posterior earlobe, resulting from peculiarities of the structure or ultrastructure of the organ. For obvious reasons the anatomy of the earlobe has not been explored in great detail; however, such a study might prove worthwhile. Another possibility is that preferential exposure to sun, soap, make-up, or other environmental factor protects the anterior aspect. A third possibility is that the mechanism of trauma is the differentiating factor. The wounds from earlobe piercing are produced, in the USA, by driving a sharp gold-plated hollow peg in an anterior to posterior direction with a mechanical punch. The peg is then held in place with a posterior fastener. Such a mechanism implies that the anterior wound occurs in the superficial to deep direction whereas the reverse is true for the posterior wound. We could speculate that a factor from the deep dermis must be brought