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Relationship between hepatic histology and conventional biochemical liver function test in chronic alcoholic patients
Drug and Alcohol Dependence,
Elsevier Scientific Publishers
28 (1991) 211-214 Ireland Ltd.
211
Relationship between hepatic histology and conventional biochemical liver function test in chronic alcoholic patients* Sisir K. Majumdara, aElmdene
Alcoholic
Treatment
and
Research
Histopathology,
Unit,
Nalini Diasa and E. J. Aps Bexley
Hospital.
Bezley.
Kent
DA5
ZBW
nn,d “I)Ppartmmt
01
Queen Mary’s Hospital. Sidcup. Kent IlJ.K.1
(Received April 22nd, 1991)
This paper explores the relationship between hepatic histology and conventional biochemical liver function tests in 125 chronic alcoholic patients. On the basis of the results obtained, it is suggested that abnormal biochemical liver function tests may offer important clues for further invasive investigations to establish the diagnosis of alcoholic liver disease. Key words: alcoholic liver disease; biochemical liver function tests
Introduction It is well known that there is a poor correlation between conventional biochemical liver function tests and various morphological patterns of alcoholic liver disease. It is also widely recognised that significant alcohol-induced hepatic damage may be present in the absence of symptoms, with or without abnormal physical and biochemical findings [ 1,2]. Serum aspartate transaminase (AST) was found to be most useful for detecting and monitoring patients with minimal alcoholic liver damage (steatosis) or alcoholic hepatitis [3]. Serum gamma glutamyl transpeptidase (GGT) activity may also detect early alcoholics [4] but, of course, elevated levels may reflect hepatic microsomal enzyme induction by alcohol rather than hepatocellular damage [5].
*Based on a paper presented at the NATO Advanced Study Institute on ‘The Molecular Pathology of Alcoholism’ held at I1 Ciocco, Tuscany, Italy, August 26-September 6, 1990. Correspondence to: Sisir K. Majumdar, Elmdene Alcoholic Treatment and Research Unit, Bexley Hospital, Bexley, Kent DA5 2BW, U.K. 0376-8716/91/$03.50 0 1991 Elsevier Scientific Publishers Printed and Published in Ireland
Elevated alkaline phosphatase (ALP) due to mild cholestasis is found in 5040% of patients with alcoholic hepatitis [6]. In spite of these observations, it is also suggested that abnormal liver function tests may give important clues to the diagnosis of asymptomatic alcoholic liver disease [7]. Hence, the aim of this paper is to explore the relationship between hepatic histology and conventional biochemical liver function tests in 125 chronic alcoholic patients. Methods and Patients One hundred and twenty-five patients (M = 110; F = 15) were selected for the study on the basis of clinical features suggestive of alcoholinduced liver damage, viz, hepatomegaly, liver palm and spider naevi. Average daily amount of alcohol intake was 100 g for about 5-20 years. Percutaneous liver biopsy was performed on each patient, along with conventional biochemical liver function tests by automated methods. Demographic details are given in the tables. Informed and written consent was obtained from each patient. Ireland Ltd.
212 Table I.
Alcoholic liver disease: relationship between hepatic histology and conventional biochemical liver function tests (Mean * S.D.; range of values).
Liw-r: normal histology: n = 28 (M = 26; F = 2) Age (years) Bilirubin (N = 3-1’7 pmolll) Alkaline phosphatase (ALP) (N = 5-40 Iv/l) Aspartate transaminase (AST) (N = 5-40 W/l) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 Albumin (iV = 30-50 g/l) Globulin (N = 18-35 g/l)
IV/l)
Mean I SD.
Range of values
Abnormal (010 patients)
40.38 9.15 64.88 24.30 30.28 45.41 26.50
20-61 3-18 32-20 9-116 7-87 39-55 19-36
3.57 3.57 7.14 17.85 NIL NIL
f f f f zt f f
10.42 3.46 32.49 20.49 23.77 3.66 4.55
N = norm.
Results and comment
group grading downwards through hepatitis and steatosis groups to the normal histology group (Table VI). Hepatomegaly with normal histology could present with abnormal liver function tests (Table VI). At the other extreme of the spectrum, liver function tests could be absolutely normal in biopsy-proven long-standing cirrhosis. This is a biochemical dilemma where a clinical judgement should decide on the necessity for further invasive investigations. It is clear from the above results that the degree of abnormality of the liver function tests varies directly with the severity of alcoholinduced histological liver damage as reflected by the various parameters in the liver function tests profile. The alcoholic units and clinics are
In patients with normal hepatic histology, mean serum bilirubin, AST and GGT were all within normal range (Table I). Patients with hepatic steatosis showed raised mean serum bilirubin (19.83 pmol/l), AST (66.4 III/l) and GGT (87.63 IU/l) while in patients with alcoholic hepatitis, mean serum GGT was still higher (212.90 III/l) (Tables II and III). In alcoholic cirrhosis, mean serum GGT (416.62 IUII) was highest among all the histological groups (Table IV). Table V gives a comparative picture of the biochemical liver function tests in all different groups. Percentage of patients with abnormal liver function tests was highest in the cirrhotic
Table II. Alcoholic liver disease: relationship (Mean * S.D.; range of values).
between
hepatic histology and conventional
Mean + SD.
Liver: alcohdic steatosis: n = 58 (M = 50; F = 8) Age (years) Bilirubin (N = 3-17 bmol/l) Alkaline phosphatase (ALP) (N = 20-100 IU/l) Aspartate transaminase (AST) (N = 5-40 IU/l) Gamma glutamyl transaminase (Gamma GT): (N = lo-50 Albumin (N = 30-50 g/l) Globulin (AJ = 18-35 g/l) N = norm.
IV/l)
44.53 19.83 66.40 74.29 87.63 50.01 27.03
f f f f f f zt
9.49 42.42 22.48 123.55 102.32 5.37 4.74
biochemical liver function tests
Range
of values
Abnormal (010 patients)
23-61 7-50 24-154 6-376 11-538 32-51 18-46
20.68 5.17 51.72 43.10 NIL NIL
213 Table III. Alcoholic liver disease: relationship (Mean l S.D.; range of values).
between hepatic histology and conventional
Liver: alcoholic hepatitis: n = 28 (M = 19; F = 4) Age (years) Bilirubin (N = 3-17 pmolll) Alkaline phosphatase (ALP) (N = 20-100 W/l) Aspartate transaminase (AST) (N = 5-40 m/l) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
IU/l)
biochemical liver function tests
Mean * SD.
Range of values
Abnormal (O/O patients)
47.30 14.63 86.09 64.13 212.90 42.38 27.72
25-64 5-41 12-224 14-201 25-1256 26-51 21-38
26.08 26.08 52.17 60.86 4.34 (low) 4.34 (high)
f 11.02 ZIZ9.54 zt 49.03 zt 56.06 zt 289.05 zt 5.37 zt 3.81
N = norm. Table IV. Alcoholic liver disease: relationship (Mean * SD.; range of values).
between hepatic histology and conventional
Liver: alcoholic cirrhosis: n = 16; (M = 15; F = 1) Age (years) Bilirubin (N = 3-17 pmolll) Alkaline phosphatase (ALP) (N = 20-100 IUII) Aspartate transaminase (AST) (N = 5-40 IU/l) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
biochemical liver function tests
Mean * S.D.
Range of values
Abnormal (010 patients)
48.23 19.87 92.18 60.75 416.62 41.18 30.52
38-63 7-36 20-270 14-119 78-1270 27-46 22-41
43.75 25.00 68.75 100.00 6.25 (low) 31.25 (high)
W/l)
zt 7.55 + 8.29 += 57.80 f 27.50 zt 401.11 f 4.57 it 9.64
N = norm. Table V. Alcoholic liver disease: relationship (Mean f SD.; range of values).
Age (years) (Range) Bilirubin (N = 3-17
pmolll)
Alkaline phosphatase-ALP (N = 20-100 W/l) Aspartate transaminase (AST) (N = 5-40 IUII) Gamma glutamyl transaminase (Gamma GT) (N =: lo- 50) IU/l) Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
N = norm.
between
hepatic histology and conventional
biochemical liver function tests
Normal histology n = 28 (M = 26; F = 2)
Steatosis n = 58 (M = 50; F = 8)
Hepatitis n = 23 (M = 19; F = 4)
Cirrhosis n = 16 (M = 15; F = 1)
40.38 f 10.42 (20-61) 9.15 * 3.46 (3-18) 64.88 f 32.49 (32-209) 24.30 z!z20.49 (g-116) 30.28 f 23.77 (7-87)
44.53 f (23-61) 19.83 zt (7-50) 66.40 + (24-154) 74.29 zt (6-376) 87.63 zt (11-538)
47.30 f (25-64) 14.63 f (5-41) 86.09 zt (12-224) 64.13 f (14-201) 212.90 * (25-1256)
48.23 f (38-63) 19.87 zt (7-36) 92.18 f (20-270) 60.75 f (14-119) 416.62 f (78-1270)
45.41 zt 3.66 (39-55) 26.50 zt 4.55 (19-36)
50.01 f 5.37 (32-51) 27.03 zt 4.74 (18-46)
9.49 42.42 22.48 123.55 102.32
11.02 9.54 49.03 56.06 289.05
42.38 zt 5.37 (26-51) 27.72 zt 3.81 (21-38)
7.55 8.29 57.80 27.50 401.11
41.18 f 4.57 (27-46) 30.52 2 9.64 (22-41)
214 Table VI.
Conventional biochemical liver function test in alcoholic liver disease: percentage
of patients with abnormal results.
Hepatic histology
Normal n = 28 (M = 26; F = 2)
Steatosis n = 58 (&f = 50; F = 8)
Hepatitis n = 23 (M = 19; F = 4)
Cirrhosis n = 16 (M = 15; F = 1)
Age (years) + SD. (range) Bilirubin: (N = 3-17 pmol/l) Alkaline phosphatase (ALP) (N = 20-100 III/I) Aspartate transaminase (AST) (N = 5-40 run) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 III/l) Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
40.38 f 10.42 (20-61) 3.57%
44.53 f 9.49 (23-61) 20.68%
47.30 f 11.02 (25-64) 26.08%
48.23 f 7.55 (38-63) 43.75%
Comment
Higher
3.57%
5.17%
26.08%
25.0%
Higher
7.14%
51.72%
52.1790
68.75%
Higher
17.85% Nil Nil
43.10% Nil Nil
60.8690 4.34% 4.34%
100.00% 6.25% 31.25%
Higher Lower Higher
N = norm.
generally situated in psychiatric hospitals and early detection of alcoholism and alcoholinduced physical damage falls within the domain of psychiatrists and not of general physicians or hepatologists. Our results of liver function tests give sufficient objective clues for referral of alcoholic patients to the general physicianlhepatologist for further relevant tests for alcohol-induced liver damage. It will help in the early detection of alcoholic liver disease and also in formulating the strategy for further management of these patients. Acknowledgement Grateful thanks are due to Dr. G.K. Shaw, Director of the Unit, for allowing us to study the patients under his care.
References 1 2
3 4 5
6 7
Bruguera, M., Bordas, J.M. and Rodes, J. (1977) Arch. Pathol. Lab. Med. 101, 644. Leevy, C.M. and Tygstrup, N. (1976) Standardization of Nomenclature, Diagnostic Criteria and Diagnostic Morphology for Diseases of the Liver and Biliary Tract, p. 4. S. Karger, Basel. Galizzi, J., Morgan, M.Y., Chitranukroh, A. and Sherlock, S. (1978) Stand. J. Gastroenterol. 13, 827. Van Waes, L. and Lieber, C.S. (1977) Br. Med. J. 2, 1508. Ishii, H., Kanno, T., Shigeta, Y., Takagi, S., Yasuraoka, S., Kano, S., Takeshita, E. and Tsuchiya, M. (1976) Gastroenterology 71, 913. Lischner, M.W., Alexander, J.F. and Galambos, J.T. (1971) Am. J. Dig. Dis. 16, 481. Hislop, W.S., Bouchier, I.A.D., Allan, J.G., Brunt, P.W., Eastwood, M., Finlayson, N.D.C., James, O., Russell, RI. and Watkinson, G. (1983) Q. J. Med., New Series Lll, No. 206, 232.
Elsevier Scientific Publishers
28 (1991) 211-214 Ireland Ltd.
211
Relationship between hepatic histology and conventional biochemical liver function test in chronic alcoholic patients* Sisir K. Majumdara, aElmdene
Alcoholic
Treatment
and
Research
Histopathology,
Unit,
Nalini Diasa and E. J. Aps Bexley
Hospital.
Bezley.
Kent
DA5
ZBW
nn,d “I)Ppartmmt
01
Queen Mary’s Hospital. Sidcup. Kent IlJ.K.1
(Received April 22nd, 1991)
This paper explores the relationship between hepatic histology and conventional biochemical liver function tests in 125 chronic alcoholic patients. On the basis of the results obtained, it is suggested that abnormal biochemical liver function tests may offer important clues for further invasive investigations to establish the diagnosis of alcoholic liver disease. Key words: alcoholic liver disease; biochemical liver function tests
Introduction It is well known that there is a poor correlation between conventional biochemical liver function tests and various morphological patterns of alcoholic liver disease. It is also widely recognised that significant alcohol-induced hepatic damage may be present in the absence of symptoms, with or without abnormal physical and biochemical findings [ 1,2]. Serum aspartate transaminase (AST) was found to be most useful for detecting and monitoring patients with minimal alcoholic liver damage (steatosis) or alcoholic hepatitis [3]. Serum gamma glutamyl transpeptidase (GGT) activity may also detect early alcoholics [4] but, of course, elevated levels may reflect hepatic microsomal enzyme induction by alcohol rather than hepatocellular damage [5].
*Based on a paper presented at the NATO Advanced Study Institute on ‘The Molecular Pathology of Alcoholism’ held at I1 Ciocco, Tuscany, Italy, August 26-September 6, 1990. Correspondence to: Sisir K. Majumdar, Elmdene Alcoholic Treatment and Research Unit, Bexley Hospital, Bexley, Kent DA5 2BW, U.K. 0376-8716/91/$03.50 0 1991 Elsevier Scientific Publishers Printed and Published in Ireland
Elevated alkaline phosphatase (ALP) due to mild cholestasis is found in 5040% of patients with alcoholic hepatitis [6]. In spite of these observations, it is also suggested that abnormal liver function tests may give important clues to the diagnosis of asymptomatic alcoholic liver disease [7]. Hence, the aim of this paper is to explore the relationship between hepatic histology and conventional biochemical liver function tests in 125 chronic alcoholic patients. Methods and Patients One hundred and twenty-five patients (M = 110; F = 15) were selected for the study on the basis of clinical features suggestive of alcoholinduced liver damage, viz, hepatomegaly, liver palm and spider naevi. Average daily amount of alcohol intake was 100 g for about 5-20 years. Percutaneous liver biopsy was performed on each patient, along with conventional biochemical liver function tests by automated methods. Demographic details are given in the tables. Informed and written consent was obtained from each patient. Ireland Ltd.
212 Table I.
Alcoholic liver disease: relationship between hepatic histology and conventional biochemical liver function tests (Mean * S.D.; range of values).
Liw-r: normal histology: n = 28 (M = 26; F = 2) Age (years) Bilirubin (N = 3-1’7 pmolll) Alkaline phosphatase (ALP) (N = 5-40 Iv/l) Aspartate transaminase (AST) (N = 5-40 W/l) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 Albumin (iV = 30-50 g/l) Globulin (N = 18-35 g/l)
IV/l)
Mean I SD.
Range of values
Abnormal (010 patients)
40.38 9.15 64.88 24.30 30.28 45.41 26.50
20-61 3-18 32-20 9-116 7-87 39-55 19-36
3.57 3.57 7.14 17.85 NIL NIL
f f f f zt f f
10.42 3.46 32.49 20.49 23.77 3.66 4.55
N = norm.
Results and comment
group grading downwards through hepatitis and steatosis groups to the normal histology group (Table VI). Hepatomegaly with normal histology could present with abnormal liver function tests (Table VI). At the other extreme of the spectrum, liver function tests could be absolutely normal in biopsy-proven long-standing cirrhosis. This is a biochemical dilemma where a clinical judgement should decide on the necessity for further invasive investigations. It is clear from the above results that the degree of abnormality of the liver function tests varies directly with the severity of alcoholinduced histological liver damage as reflected by the various parameters in the liver function tests profile. The alcoholic units and clinics are
In patients with normal hepatic histology, mean serum bilirubin, AST and GGT were all within normal range (Table I). Patients with hepatic steatosis showed raised mean serum bilirubin (19.83 pmol/l), AST (66.4 III/l) and GGT (87.63 IU/l) while in patients with alcoholic hepatitis, mean serum GGT was still higher (212.90 III/l) (Tables II and III). In alcoholic cirrhosis, mean serum GGT (416.62 IUII) was highest among all the histological groups (Table IV). Table V gives a comparative picture of the biochemical liver function tests in all different groups. Percentage of patients with abnormal liver function tests was highest in the cirrhotic
Table II. Alcoholic liver disease: relationship (Mean * S.D.; range of values).
between
hepatic histology and conventional
Mean + SD.
Liver: alcohdic steatosis: n = 58 (M = 50; F = 8) Age (years) Bilirubin (N = 3-17 bmol/l) Alkaline phosphatase (ALP) (N = 20-100 IU/l) Aspartate transaminase (AST) (N = 5-40 IU/l) Gamma glutamyl transaminase (Gamma GT): (N = lo-50 Albumin (N = 30-50 g/l) Globulin (AJ = 18-35 g/l) N = norm.
IV/l)
44.53 19.83 66.40 74.29 87.63 50.01 27.03
f f f f f f zt
9.49 42.42 22.48 123.55 102.32 5.37 4.74
biochemical liver function tests
Range
of values
Abnormal (010 patients)
23-61 7-50 24-154 6-376 11-538 32-51 18-46
20.68 5.17 51.72 43.10 NIL NIL
213 Table III. Alcoholic liver disease: relationship (Mean l S.D.; range of values).
between hepatic histology and conventional
Liver: alcoholic hepatitis: n = 28 (M = 19; F = 4) Age (years) Bilirubin (N = 3-17 pmolll) Alkaline phosphatase (ALP) (N = 20-100 W/l) Aspartate transaminase (AST) (N = 5-40 m/l) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
IU/l)
biochemical liver function tests
Mean * SD.
Range of values
Abnormal (O/O patients)
47.30 14.63 86.09 64.13 212.90 42.38 27.72
25-64 5-41 12-224 14-201 25-1256 26-51 21-38
26.08 26.08 52.17 60.86 4.34 (low) 4.34 (high)
f 11.02 ZIZ9.54 zt 49.03 zt 56.06 zt 289.05 zt 5.37 zt 3.81
N = norm. Table IV. Alcoholic liver disease: relationship (Mean * SD.; range of values).
between hepatic histology and conventional
Liver: alcoholic cirrhosis: n = 16; (M = 15; F = 1) Age (years) Bilirubin (N = 3-17 pmolll) Alkaline phosphatase (ALP) (N = 20-100 IUII) Aspartate transaminase (AST) (N = 5-40 IU/l) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
biochemical liver function tests
Mean * S.D.
Range of values
Abnormal (010 patients)
48.23 19.87 92.18 60.75 416.62 41.18 30.52
38-63 7-36 20-270 14-119 78-1270 27-46 22-41
43.75 25.00 68.75 100.00 6.25 (low) 31.25 (high)
W/l)
zt 7.55 + 8.29 += 57.80 f 27.50 zt 401.11 f 4.57 it 9.64
N = norm. Table V. Alcoholic liver disease: relationship (Mean f SD.; range of values).
Age (years) (Range) Bilirubin (N = 3-17
pmolll)
Alkaline phosphatase-ALP (N = 20-100 W/l) Aspartate transaminase (AST) (N = 5-40 IUII) Gamma glutamyl transaminase (Gamma GT) (N =: lo- 50) IU/l) Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
N = norm.
between
hepatic histology and conventional
biochemical liver function tests
Normal histology n = 28 (M = 26; F = 2)
Steatosis n = 58 (M = 50; F = 8)
Hepatitis n = 23 (M = 19; F = 4)
Cirrhosis n = 16 (M = 15; F = 1)
40.38 f 10.42 (20-61) 9.15 * 3.46 (3-18) 64.88 f 32.49 (32-209) 24.30 z!z20.49 (g-116) 30.28 f 23.77 (7-87)
44.53 f (23-61) 19.83 zt (7-50) 66.40 + (24-154) 74.29 zt (6-376) 87.63 zt (11-538)
47.30 f (25-64) 14.63 f (5-41) 86.09 zt (12-224) 64.13 f (14-201) 212.90 * (25-1256)
48.23 f (38-63) 19.87 zt (7-36) 92.18 f (20-270) 60.75 f (14-119) 416.62 f (78-1270)
45.41 zt 3.66 (39-55) 26.50 zt 4.55 (19-36)
50.01 f 5.37 (32-51) 27.03 zt 4.74 (18-46)
9.49 42.42 22.48 123.55 102.32
11.02 9.54 49.03 56.06 289.05
42.38 zt 5.37 (26-51) 27.72 zt 3.81 (21-38)
7.55 8.29 57.80 27.50 401.11
41.18 f 4.57 (27-46) 30.52 2 9.64 (22-41)
214 Table VI.
Conventional biochemical liver function test in alcoholic liver disease: percentage
of patients with abnormal results.
Hepatic histology
Normal n = 28 (M = 26; F = 2)
Steatosis n = 58 (&f = 50; F = 8)
Hepatitis n = 23 (M = 19; F = 4)
Cirrhosis n = 16 (M = 15; F = 1)
Age (years) + SD. (range) Bilirubin: (N = 3-17 pmol/l) Alkaline phosphatase (ALP) (N = 20-100 III/I) Aspartate transaminase (AST) (N = 5-40 run) Gamma glutamyl transaminase (Gamma GT) (N = lo-50 III/l) Albumin (N = 30-50 g/l) Globulin (N = 18-35 g/l)
40.38 f 10.42 (20-61) 3.57%
44.53 f 9.49 (23-61) 20.68%
47.30 f 11.02 (25-64) 26.08%
48.23 f 7.55 (38-63) 43.75%
Comment
Higher
3.57%
5.17%
26.08%
25.0%
Higher
7.14%
51.72%
52.1790
68.75%
Higher
17.85% Nil Nil
43.10% Nil Nil
60.8690 4.34% 4.34%
100.00% 6.25% 31.25%
Higher Lower Higher
N = norm.
generally situated in psychiatric hospitals and early detection of alcoholism and alcoholinduced physical damage falls within the domain of psychiatrists and not of general physicians or hepatologists. Our results of liver function tests give sufficient objective clues for referral of alcoholic patients to the general physicianlhepatologist for further relevant tests for alcohol-induced liver damage. It will help in the early detection of alcoholic liver disease and also in formulating the strategy for further management of these patients. Acknowledgement Grateful thanks are due to Dr. G.K. Shaw, Director of the Unit, for allowing us to study the patients under his care.
References 1 2
3 4 5
6 7
Bruguera, M., Bordas, J.M. and Rodes, J. (1977) Arch. Pathol. Lab. Med. 101, 644. Leevy, C.M. and Tygstrup, N. (1976) Standardization of Nomenclature, Diagnostic Criteria and Diagnostic Morphology for Diseases of the Liver and Biliary Tract, p. 4. S. Karger, Basel. Galizzi, J., Morgan, M.Y., Chitranukroh, A. and Sherlock, S. (1978) Stand. J. Gastroenterol. 13, 827. Van Waes, L. and Lieber, C.S. (1977) Br. Med. J. 2, 1508. Ishii, H., Kanno, T., Shigeta, Y., Takagi, S., Yasuraoka, S., Kano, S., Takeshita, E. and Tsuchiya, M. (1976) Gastroenterology 71, 913. Lischner, M.W., Alexander, J.F. and Galambos, J.T. (1971) Am. J. Dig. Dis. 16, 481. Hislop, W.S., Bouchier, I.A.D., Allan, J.G., Brunt, P.W., Eastwood, M., Finlayson, N.D.C., James, O., Russell, RI. and Watkinson, G. (1983) Q. J. Med., New Series Lll, No. 206, 232.