577 BEHAVIOUR OF e ANTIGEN AND ANTIBODY DURING CHRONIC ACTIVE LIVER DISEASE
SIR,-We would like
to correct
the
assumptions
contained
in the letter from Dr Woolf and his colleagues (July 31, p. 257) about our paper (July 17, p. 126). The use of serological markers as indicators of aetiology in
chronic liver disease, while well established, is not yet an exact science. These markers have been used to indicate "autoimmune"’ or viral disease. For the hepatitis B virus these markers range from the core antigen, which is considered more sensitive than the surface antigen, to the B antibody (anti-HBs) which may be less sensitive.2-3 Collectively, these reflect disease which may have been initiated and/or perpetuated by the virus, and may thus appropriately be grouped together. Objections to including patients with anti-HBs are surprising since Dr Woolf’sco-signatories reported that in patients with chronic active liver disease (C.A.L.D.) and anti-HBs (with negative results for HBsAg from R.I.A.), anti-HBs was complexed with HBsAg in the serum in all instances.6 We know of no evidence that clearance of HBsAg in patients with C.A.L.D. "must be a rare event". Rather, a prospective study of 238 heroin addicts by Stimmel et al. showed that SO-60% of patients cleared HBsAg each year, although abnormal liver-function tests persisted in 80% of them. The disappearance of HBsAg in patients with unresolved viral hepatitis and chronic active hepatitis receiving treatment with corticosteroids has been reported by Klatskin8 as well as by ourselves. The two patients who cleared HBsAg would not by our criteria be classified as having acute hepatitis. We do not share the difficulty in
diagnosing C.A.L.D.
on
morphological grounds
(when functional and clinical information are available) that are "well known" to Dr Woolf and his associates. The first patient had documented and continuing liver disease for more than 6 months before entering our treatment programme and thereafter had three biopsies and functional abnormalities characteristic of chronic active hepatitis during 18 months of steroid therapy before his disease entered remission. The second patient had abnormal liver-function tests and bridging necrosis before beginning treatment with steroids. During 4 years of therapy, liver-function tests have remained abnormal and the features of chronic active hepatitis have been shown on four biopsies. This is not acute hepatitis by our criteria.9 To help resolve the scepticism of Dr Woolf and his associates that HBsAg-positive patients respond less well to steroid therapy than others with C.A.L.D., we refer them to Klatskin’s work. We ourselves have shown that HBs antigenaemia is amongst the factors responsible for failure of conventional steroid therapy in patients with c.n.l..o.,1° and details of their less frequent improvement with such therapy will soon be published." In conclusion, we emphasise that properly controlled and analysed studies yield evidence of statistical probabilities which not infrequently fail to coincide with previous perceptions and occasionally do not accord with the ultimate truth. Gastroenterology Unit, Mayo Clinic, Rochester, 55901, Minnesota, U.S.A.
A. J. M. VOGTEN W. H. J. SUMMERSKILL
1. Galbraith, R. M. and others New EngL. J. Med. 1974, 290, 63. 2. Hoofnagle, J. H., Gerety, R. J., Ni, L. Y., Barker, L. F. ibid.
1974, 290,
1336. 3 4.
Pagliaro, L. and others. Digestion, 1975, 12, 265. Zappi, T., Vernace, S. J., Gerber, M. A., Paronetto,
F.
Gastroenterology,
1976, 70, 997. 5. Hoofnagle, J. H., Gerety, R. J., Barker, G. F. Am. J. med. Sci. 1975, 270, 179. 6. Lee. W. H, Reed, W. D., Mitchell, C. G., Galbraith, R. M., Eddleston, A L. W F., Zuckerman, A. J., Williams, R. Br. med. J. 1975, i, 705. 7. Stimmel, B., Vernace, S., Schaffner, F. J. Am. med. Ass. 1975, 234, 1135. 8. Klatskin, G. Am. J. clin. Sci. 1975, 270, 33. 9. Soloway, R. D., and others, Gastroenterology, 1972, 63, 820. 10. Schalm, S. W., Ammon, H. V., Summerskill, W. H. J. Ann. clin. Res. 1976,
8, 221. 11. Schalm, S. W., Summerskill, W. H. J., Gitnick, G. L., Elveback, L. R. Gut in
the press).
e
ANTIGEN: PROGNOSTIC MARKER IN ACUTE VIRAL HEPATITIS B?
SIR,-The e antigen has become a focus of clinical interest since the demonstration that it had prognostic significance for viral hepatitis B. 2-4 We have looked for e antigen in 363 HBs Ag-positive sera from 107 patients with acute viral hepatitis B using the immunodiffusion technique. The findings were then correlated with clinical progress. e antigen was found in 11 patients (10.3%) one or more times during the HBs antigenaemia. Others2-4 have reported similar e antigen frequencies in acute viral hepatitis. However, the clinical course in the acute phase of the disease did not show any difference between e-antigen-positive and e-antigennegative cases. The highest laboratory values for transaminases, bilirubin, alkaline phosphatase, and prothrombin time and the values found on admission and at discharge did not indicate any difference between e-antigen-negative and e-antigen-positive patients with viral hepatitis B. We did find significantly higher e-antigen frequencies in patients with HBsAg-positive chronic liver disease, but a clinically relevant relationship between e-antigen demonstration in the acute phase of viral hepatitis B and the development of a chronic liver disease could not be confirmed. In follow-up studies the 11 e-antigen-positive patients, who had had acute hepatitis on average 31 ±13 months (range 17-47) previously, had all eliminated HBsAg from the serum. Development of chronic liver disease could be excluded in 10 of the 11I patients. Only in 1 patient was a picture of chronic active hepatitis with slight signs of activity found histologically one year after the acute illness, despite elimination of the HBsAg and normal laboratory findings. On the other hand, e-antigenpositive chronic liver disease did develop from e-antigen-negative acute viral hepatitis B in 3 patients followed up for several years. These investigations show that demonstration of e antigen does not indicate the development of a chronic liver disease with sufficient certainty. Moreover, absence of e antigen in the acute phase of viral hepatitis B does not exclude the development of an e-antigen-positive chronic active hepatitis. A prognostic significance in acute viral hepatitis B cannot be assigned to the e antigen, at least in the Heidelberg area. Department of Gastroenterology, Heidelberg University Hospital, 69 Heidelberg, West Germany
G. THAMER K. GMELIN B. KOMMERELL
DECREASING FREQUENCY OF e ANTIGEN WITH AGE IN SERUM OF SYMPTOM-FREE CARRIERS OF HEPATITIS B ANTIGEN
SIR,-Serum samples of 115 symptom-free carriers of hepa-
antigen (HBAg) were concentrated 3-fold by adding ’Lyphogel’ (50 mg/ml), and tested for the e antigen of Magnius and Espmark and antibody to e (anti-e) by immunodiffusion.. e antigen was detected in 32 (28%) and anti-e in 35 (30%); neither e antigen nor anti-e was found in the remaining 48. These carriers were divided into five groups according to age, and the percentages with e antigen and with anti-e were compared. As shown in the table, the prevalence of e antigen was highest in the youngest group (77%) and gradually decreased with age. In sharp contrast, the prevalence of anti-e was lowest at 15% in the youngest group, and gradually increased with age reaching the maximum of 54% in the highest age-group. Evidence has been accumulating to indicate that e antigen titis B
1. Magnius, L. O., Espmark, J. A. J. Immunl. 1972, 109, 1017. 2. Nielsen, J. O., Dietrichson, O., Juhl, E. Lancet, 1974, ii, 913. 3. Fay, O., Edwards, V. M., Mosley, J. W., Redeker, A. G. Gastroenterology, 1975, 68, 1081. 4. Norkrans, G., Magnius, L. O., Iwarson, S. Br. med. J. 1976, i, 740.
5.
Magnius, L. O., Espmark, J.
Å. J. Immun. 1972, 109, 1017.
578 expect the CG.M.P. determinations in various body fluids might well be auseful tool in the investigation, diagnosis, or monitor ing of treatment in cancer patients. Although we have investi gated only three patients, we believe the results to be promis ing enough to warrant further studies. We are now investigating plasma cG.M.P. levels and urinary excretion in patients with a wide range of tumours.
FREQUENCIES OF e ANTIGEN AND ANTIBODY TO e AMONG SYMPTOM-FREE HBAg CARRIERS OF DIFFERENT AGE-GROUPS
Department of Chemical Pathology, University of Stellenbosch, P.O. Box 63, Tygerberg 7505, South Africa
closely associated with the infectivity of hepatitis B virus (H.B.v.). Vertical transmission of H.B.v. was observed only for symptom-free carrier mothers whose serum was positive for e antigen,* and the prevalence of e antigen was especially high in the serum of uraemic patients on maintenance haemodialysis, which is highly contagious.’I The decreasing prevalence of e antigen and increasing prevalence of anti-e with age may be reflected in the difference in infectivity of young and old carriers; younger HBAg carriers may be much more contagious than those in older agegroups. These results seem to call for special caution in the care of children with e antigen in .the serum because of their possible high infectivity. The fact that an epidemic of Gianotti’s disease which was associated with H.B.v. of special subtype occurred among children without evidence of vertical
A. C. NEETHLING B. C. SHANLEY
is
infection supports the view that horizontal infection tends prevail among children. Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan Immunology Division, Jichi Medical School, Tochigi-ken Hepatitis Division, the Tokyo Metropolitan, Institute of Medical Science, Tokyo
to
INHIBITION OF PHYTOHÆMAGGLUTININ TRANSFORMATION BY SERUM OF PATIENTS WITH FULMINANT VIRAL HEPATITIS
SIR,-Bailey et aLl reported the presence in serum of patients with fulminant hepatic failure of a factor inhibiting the metabolic activity of the leucocyte hexose-monophosphate shunt. Prompted by the high mortality of children with fulminant hepatitis due to bacterial infections (8/21) we studied the lymphocyte transformation to phytohæmagglutinin (P.H.A.) in 9 patients during the evolution of their disease. Lymphocyte transformation was performed as described elsewhere.2 In each experiment, done in triplicate, patient’s and control cells were tested with and without P.H.A. in the presence of 20% decomplemented patient’s and control serum.
AKIRA OHBAYASHI
YUJI MATSUO TOSHIJI MOZAI MITSUNOBU IMAI
MAKOTO MAYUMI
CYCLIC G.M.P. EXCRETION AND HEPATOMA
SiR,—A study claiming increased urinary excretion of cyclic guanosine-3,’ 5’-phosphate (CG.M.P.) in rats bearing explants of Morris hepatoma 3924 A," prompted us to measure urinary cG.M.p. excretion in patients with primary hepatoma. CG.M.P. was
measured in twelve normal males, twelve normal females
(laboratory staff), and three male patients with histologically proven hepatomas by a radioimmunoassay (Radiochemical Centre, Amersham), and creatinine was measured by a standard automated method (Technicon ’AutoAnalyzer II’). The results show a significantly higher excretion (P
SIR,-We would like
to correct
the
assumptions
contained
in the letter from Dr Woolf and his colleagues (July 31, p. 257) about our paper (July 17, p. 126). The use of serological markers as indicators of aetiology in
chronic liver disease, while well established, is not yet an exact science. These markers have been used to indicate "autoimmune"’ or viral disease. For the hepatitis B virus these markers range from the core antigen, which is considered more sensitive than the surface antigen, to the B antibody (anti-HBs) which may be less sensitive.2-3 Collectively, these reflect disease which may have been initiated and/or perpetuated by the virus, and may thus appropriately be grouped together. Objections to including patients with anti-HBs are surprising since Dr Woolf’sco-signatories reported that in patients with chronic active liver disease (C.A.L.D.) and anti-HBs (with negative results for HBsAg from R.I.A.), anti-HBs was complexed with HBsAg in the serum in all instances.6 We know of no evidence that clearance of HBsAg in patients with C.A.L.D. "must be a rare event". Rather, a prospective study of 238 heroin addicts by Stimmel et al. showed that SO-60% of patients cleared HBsAg each year, although abnormal liver-function tests persisted in 80% of them. The disappearance of HBsAg in patients with unresolved viral hepatitis and chronic active hepatitis receiving treatment with corticosteroids has been reported by Klatskin8 as well as by ourselves. The two patients who cleared HBsAg would not by our criteria be classified as having acute hepatitis. We do not share the difficulty in
diagnosing C.A.L.D.
on
morphological grounds
(when functional and clinical information are available) that are "well known" to Dr Woolf and his associates. The first patient had documented and continuing liver disease for more than 6 months before entering our treatment programme and thereafter had three biopsies and functional abnormalities characteristic of chronic active hepatitis during 18 months of steroid therapy before his disease entered remission. The second patient had abnormal liver-function tests and bridging necrosis before beginning treatment with steroids. During 4 years of therapy, liver-function tests have remained abnormal and the features of chronic active hepatitis have been shown on four biopsies. This is not acute hepatitis by our criteria.9 To help resolve the scepticism of Dr Woolf and his associates that HBsAg-positive patients respond less well to steroid therapy than others with C.A.L.D., we refer them to Klatskin’s work. We ourselves have shown that HBs antigenaemia is amongst the factors responsible for failure of conventional steroid therapy in patients with c.n.l..o.,1° and details of their less frequent improvement with such therapy will soon be published." In conclusion, we emphasise that properly controlled and analysed studies yield evidence of statistical probabilities which not infrequently fail to coincide with previous perceptions and occasionally do not accord with the ultimate truth. Gastroenterology Unit, Mayo Clinic, Rochester, 55901, Minnesota, U.S.A.
A. J. M. VOGTEN W. H. J. SUMMERSKILL
1. Galbraith, R. M. and others New EngL. J. Med. 1974, 290, 63. 2. Hoofnagle, J. H., Gerety, R. J., Ni, L. Y., Barker, L. F. ibid.
1974, 290,
1336. 3 4.
Pagliaro, L. and others. Digestion, 1975, 12, 265. Zappi, T., Vernace, S. J., Gerber, M. A., Paronetto,
F.
Gastroenterology,
1976, 70, 997. 5. Hoofnagle, J. H., Gerety, R. J., Barker, G. F. Am. J. med. Sci. 1975, 270, 179. 6. Lee. W. H, Reed, W. D., Mitchell, C. G., Galbraith, R. M., Eddleston, A L. W F., Zuckerman, A. J., Williams, R. Br. med. J. 1975, i, 705. 7. Stimmel, B., Vernace, S., Schaffner, F. J. Am. med. Ass. 1975, 234, 1135. 8. Klatskin, G. Am. J. clin. Sci. 1975, 270, 33. 9. Soloway, R. D., and others, Gastroenterology, 1972, 63, 820. 10. Schalm, S. W., Ammon, H. V., Summerskill, W. H. J. Ann. clin. Res. 1976,
8, 221. 11. Schalm, S. W., Summerskill, W. H. J., Gitnick, G. L., Elveback, L. R. Gut in
the press).
e
ANTIGEN: PROGNOSTIC MARKER IN ACUTE VIRAL HEPATITIS B?
SIR,-The e antigen has become a focus of clinical interest since the demonstration that it had prognostic significance for viral hepatitis B. 2-4 We have looked for e antigen in 363 HBs Ag-positive sera from 107 patients with acute viral hepatitis B using the immunodiffusion technique. The findings were then correlated with clinical progress. e antigen was found in 11 patients (10.3%) one or more times during the HBs antigenaemia. Others2-4 have reported similar e antigen frequencies in acute viral hepatitis. However, the clinical course in the acute phase of the disease did not show any difference between e-antigen-positive and e-antigennegative cases. The highest laboratory values for transaminases, bilirubin, alkaline phosphatase, and prothrombin time and the values found on admission and at discharge did not indicate any difference between e-antigen-negative and e-antigen-positive patients with viral hepatitis B. We did find significantly higher e-antigen frequencies in patients with HBsAg-positive chronic liver disease, but a clinically relevant relationship between e-antigen demonstration in the acute phase of viral hepatitis B and the development of a chronic liver disease could not be confirmed. In follow-up studies the 11 e-antigen-positive patients, who had had acute hepatitis on average 31 ±13 months (range 17-47) previously, had all eliminated HBsAg from the serum. Development of chronic liver disease could be excluded in 10 of the 11I patients. Only in 1 patient was a picture of chronic active hepatitis with slight signs of activity found histologically one year after the acute illness, despite elimination of the HBsAg and normal laboratory findings. On the other hand, e-antigenpositive chronic liver disease did develop from e-antigen-negative acute viral hepatitis B in 3 patients followed up for several years. These investigations show that demonstration of e antigen does not indicate the development of a chronic liver disease with sufficient certainty. Moreover, absence of e antigen in the acute phase of viral hepatitis B does not exclude the development of an e-antigen-positive chronic active hepatitis. A prognostic significance in acute viral hepatitis B cannot be assigned to the e antigen, at least in the Heidelberg area. Department of Gastroenterology, Heidelberg University Hospital, 69 Heidelberg, West Germany
G. THAMER K. GMELIN B. KOMMERELL
DECREASING FREQUENCY OF e ANTIGEN WITH AGE IN SERUM OF SYMPTOM-FREE CARRIERS OF HEPATITIS B ANTIGEN
SIR,-Serum samples of 115 symptom-free carriers of hepa-
antigen (HBAg) were concentrated 3-fold by adding ’Lyphogel’ (50 mg/ml), and tested for the e antigen of Magnius and Espmark and antibody to e (anti-e) by immunodiffusion.. e antigen was detected in 32 (28%) and anti-e in 35 (30%); neither e antigen nor anti-e was found in the remaining 48. These carriers were divided into five groups according to age, and the percentages with e antigen and with anti-e were compared. As shown in the table, the prevalence of e antigen was highest in the youngest group (77%) and gradually decreased with age. In sharp contrast, the prevalence of anti-e was lowest at 15% in the youngest group, and gradually increased with age reaching the maximum of 54% in the highest age-group. Evidence has been accumulating to indicate that e antigen titis B
1. Magnius, L. O., Espmark, J. A. J. Immunl. 1972, 109, 1017. 2. Nielsen, J. O., Dietrichson, O., Juhl, E. Lancet, 1974, ii, 913. 3. Fay, O., Edwards, V. M., Mosley, J. W., Redeker, A. G. Gastroenterology, 1975, 68, 1081. 4. Norkrans, G., Magnius, L. O., Iwarson, S. Br. med. J. 1976, i, 740.
5.
Magnius, L. O., Espmark, J.
Å. J. Immun. 1972, 109, 1017.
578 expect the CG.M.P. determinations in various body fluids might well be auseful tool in the investigation, diagnosis, or monitor ing of treatment in cancer patients. Although we have investi gated only three patients, we believe the results to be promis ing enough to warrant further studies. We are now investigating plasma cG.M.P. levels and urinary excretion in patients with a wide range of tumours.
FREQUENCIES OF e ANTIGEN AND ANTIBODY TO e AMONG SYMPTOM-FREE HBAg CARRIERS OF DIFFERENT AGE-GROUPS
Department of Chemical Pathology, University of Stellenbosch, P.O. Box 63, Tygerberg 7505, South Africa
closely associated with the infectivity of hepatitis B virus (H.B.v.). Vertical transmission of H.B.v. was observed only for symptom-free carrier mothers whose serum was positive for e antigen,* and the prevalence of e antigen was especially high in the serum of uraemic patients on maintenance haemodialysis, which is highly contagious.’I The decreasing prevalence of e antigen and increasing prevalence of anti-e with age may be reflected in the difference in infectivity of young and old carriers; younger HBAg carriers may be much more contagious than those in older agegroups. These results seem to call for special caution in the care of children with e antigen in .the serum because of their possible high infectivity. The fact that an epidemic of Gianotti’s disease which was associated with H.B.v. of special subtype occurred among children without evidence of vertical
A. C. NEETHLING B. C. SHANLEY
is
infection supports the view that horizontal infection tends prevail among children. Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan Immunology Division, Jichi Medical School, Tochigi-ken Hepatitis Division, the Tokyo Metropolitan, Institute of Medical Science, Tokyo
to
INHIBITION OF PHYTOHÆMAGGLUTININ TRANSFORMATION BY SERUM OF PATIENTS WITH FULMINANT VIRAL HEPATITIS
SIR,-Bailey et aLl reported the presence in serum of patients with fulminant hepatic failure of a factor inhibiting the metabolic activity of the leucocyte hexose-monophosphate shunt. Prompted by the high mortality of children with fulminant hepatitis due to bacterial infections (8/21) we studied the lymphocyte transformation to phytohæmagglutinin (P.H.A.) in 9 patients during the evolution of their disease. Lymphocyte transformation was performed as described elsewhere.2 In each experiment, done in triplicate, patient’s and control cells were tested with and without P.H.A. in the presence of 20% decomplemented patient’s and control serum.
AKIRA OHBAYASHI
YUJI MATSUO TOSHIJI MOZAI MITSUNOBU IMAI
MAKOTO MAYUMI
CYCLIC G.M.P. EXCRETION AND HEPATOMA
SiR,—A study claiming increased urinary excretion of cyclic guanosine-3,’ 5’-phosphate (CG.M.P.) in rats bearing explants of Morris hepatoma 3924 A," prompted us to measure urinary cG.M.p. excretion in patients with primary hepatoma. CG.M.P. was
measured in twelve normal males, twelve normal females
(laboratory staff), and three male patients with histologically proven hepatomas by a radioimmunoassay (Radiochemical Centre, Amersham), and creatinine was measured by a standard automated method (Technicon ’AutoAnalyzer II’). The results show a significantly higher excretion (P
