LIVER DYSFUNCTION IN HYPERTENSION

111

very similar in the three

study groups-21.7, 20 1, respectively, for the Caucasians and Japanese in Hawaii and the Japanese in Japan-which indicated that the weight of individual specimens was a fairly representative measurement in this study. There were negative correlations between stool weight and B.T.T. in the Caucasians in Hawaii and the Japanese in Akita. This finding was expected. However, for the Japanese in Hawaii the B.T.T. seemed to be independent of stool weight. Correlations between B.T.T. and estimated weekly consumption of 33 different food items were also investigated. The foods included beef, bacon, celery, tomatoes, lettuce, milk, rice, saimin (noodles), and green tea; consumption was estimated at the time of recruitment into the study. No food item correlated (P<0.05) with B.T.T. in all three groups. Furthermore, stool weights did not correlate with the estimated consumption of any food was

and 22.8hours,

Cancer Study, Kuakini Medical lulu, Hawaii 96817, U.S.A.

Center, 347N. Kuakini Street, Hono-

REFERENCES

Burkitt, D. P., Walker, A. R. P., Painter, N. S. Lancet, 1972, ii, 1408. Glober, G. A., Klein, K. L., Moore, J. O., Abba, B. C. ibid. 1974, ii, 80. 3. Doll, R., Muir, C., Waterhouse, J. (editors) Cancer Incidence in Five Continents. Berlin, 1970. 4. Stemmermann, G. N., Yatani, R. Cancer, 1973, 31, 1260. 5. Stato, E., Ouchi, A., Sasano, N., Ishidate, T. ibid. 1976, 37, 1316. 6. Walters, R. L., Baird, I. McL., Davies, P. S., Hill, M. J., Drasar, B. S., Southgate, D. A. T., Green, J., Morgan, B. Br. med. J. 1975, ii, 536. 7. Payler, D. K. Lancet, 1973, i, 1394. 8. Harvey, R. F., Pomare, E. W., Heaton, K. W. ibid. p. 1278. 1. 2.

LIVER DYSFUNCTION IN HYPERTENSION L. E. RAMSAY

item.

Glasgow Blood Pressure Clinic and Department of Medicine, Western Infirmary, Glasgow Discussion Colon cancer3 and colonic polyps and diverticulosis are more common in Japanese in Hawaii than in people in japan.4,5 Despite these substantial differences, the bowel transit-times were similar in the two Japanese groups. This supports the impression that B.T.T. is not related to the risk of common colonic diseases in the Japanese in Hawaii. The finding that stool weight was significantly different in the two Japanese groups suggested that this factor could be indirectly related to the occurrence of colon cancer, polyposis, or diverticulosis. However, Blacks in South Africa have much greater stool weights’1 than the Japanese in Japan (470 g/day, and 191 g/day, respectively) but the risk of colon cancer is similar in the two groups (10.8 and 11.8 cases per 100 000 per year,

Summary

Liver-function

tests

measured

routinely

in hypertensive patients attending the Glasgow Blood Pressure Clinic were abnormal in 15·8% of men and 6·2% of women. The patients studied appeared to be representative of the whole clinic population. Liver dysfunction was related to alcohol consumption, heavy body-weight, male sex, young age, and higher diastolic blood-pressure. It is suggested that alcohol and obesity were the principal causal factors and that fatty infiltration of the liver was the probable pathology. Liver dysfunction was unrelated to treatment. Alcohol use was found to be heavy in 12% of male patients attending the clinic, and this was probably an underestimate. The possibility that alcohol abuse may have a causal role in hypertension needs further study.

respectively2).

Introduction

The lack of correlation between stool weight and B.T.T. in the Japanese in Hawaii was an unexpected finding in view of the strong negative correlation in the other two groups and the common belief that large bulky stools have a rapid transit-time. Bran or bagasse (sugar-cane residue) have been the usual bulking agents used in investigations in which decrease in transit-time with a change in diet has been demonstrated.6-8 Because these types of dietary fibre are not common in the Japanese diet in Hawaii or Japan, further studies are needed to identify the main determinants of B.T.T. and stool weight in these two groups. There may be a B.T.T. factor in the Hawaii Japanese which is independent of stool weight and acts directly upon the intestinal mucosa or influences the secretion of gastrointestinal hormones which regulate intestinal water balance and motility. In either case, this factor is unlikely to be directly related to the pathogenesis of colon cancer. However, identification of the causes of stool-weight differences in indigenous and Hawaii Japanese may throw light on the causes of differences in intestinal disease risk between these two ethnically similar groups.

At 1 of 4 hospitals participating in the Glasgow Blood PresClinic’ (the Western Infirmary) liver-function tests are performed when hypertensive patients first attend, then annually. The results are stored in a computer. A printout of all results from March, 1975, to October, 1976, was the basis of this study. Since the "compliance" rate for routine screening varied around 80-90% of patients eligible, the investigation possibly contained an element of selection, and the study method was chosen to nullify this. Serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase (S.G.O.T.), and aspartate aminotransferase (S.G.P.T.) were measured,2-4 and the limits of normal quoted by the laboratory were used (table i). The criteria for liver dysfunction were: (1) two or more individual liver-function tests elevated in one estimate, or (2) a single abnormal result in more than one estimate, excluding elevated alkaline phosphatase.

We thank Dr Grant N. Stemmermann for his critical review of the paper and the study participants for their cooperation. This study was supported by grants (NO1 CP 33216 and N01 CP 23213) from the Biometry Branch, National Cancer Institute, U.S.A. Requests for reprints should be addressed to A.N., Japan-Hawaii

Subjects and Controls A sample of 100 hypertensive patients was drawn from the same printout by means of random numbers. Selection for "routine" liver-function tests would affect patients with liver

REVIEW of the results of routine liver-function tests in

hypertensive patients attending the Glasgow Blood Pressure Clinic’ showed a high frequency of abnormalities. The reasons for this have been investigated. Methods sure

112

dysfunction and random controls equally. A sample of 200 patients entering all 4 hospitals of the clinic (100 consecutive entries early in 1970 and 100 late in 1975) was also studied. Patients with liver dysfunction entered the clinic between 1969

TABLE III—PATTERN OF DRUGS TAKEN

PAST,

CURRENTLY, AND IN THE

BY HYPERTENSIVE PATIENTS WITH LIVER DYSFUNCTION

AND BY RANDOM CONTROLS

(MEN AND WOMEN COMBINED, WITH EXCLUDED)

ORAL-CONTRACEPTIVE USE

and 1976. Clinical Data

These were taken from standard proformas completed at all clinic attendances. I,M Alcohol consumption was scored at first attendance (0=nil, 1=occasional, 2=frequent, 3=heavy/habitual) and was generally based on the patient’s own account. Liver-function-test results were not usually available when the score was determined. Standardisation of scoring between

physicians was not attempted. Results Patients with Liver Dysfunction

Liver-function tests

done 891 times in 582 i). Elevations of alkaline

were

hypertensive patients (table phosphatase (17.3%), S.G.P.T. (9-0%), and S.G.O.T. (9.9%) were common, but elevated bilirubin (2-3%) was not more common than the 2.5% expected in a healthy population. 61 (10.5%) patients had liver dysfunction as defined. This was first observed in a routine test in 57, -

the remainder having liver-function of hepatomegaly (1), abdominal pain

done because (1), or for unstated reasons (2). Abnormalities were confined to elevated transaminases in 41% of patients, and 1 transaminase was elevated at some stage in 93%. Repeat tests, available for 35 patients, were abnormal in 31 (89%). Liverfunction tests were followed until they returned to normal, or for 6 months, in 28 patients. In 9 (32%) liver dysfunction was transient (<6 months), and in 19 (68%) it persisted (>6 months). At least 11 patients (39%) had liver dysfunction for a year or more. TABLE

TABLE

tests

I-FREQUENCY OF ABNORMALLY HIGH

*Results for the

sexes

only

where

versus

random controls

drugs only, X2=5.45, D.F.=5,

Factors Related to Liver Dysfunction

Liver

6.2% of

dysfunction women

was

found in 15.8% of

(x2=14.2,

D.F.

they did

not

differ

(Student’s t test for unpaired groups).

1, P<0.001).

men

and

Patients

with liver dysfunction were younger (P<0.05), were in men, P<0.2 heavier by an average of 5 kg (P<0-02 in women), and had higher diastolic blood-pressures

(P<0.005) than random controls min was similar in the two groups.

(table n). Serum-albu-

Drugs showed no excess of Patients with liver dysfunction and controls did not differ in the number of drugs (x2=2.86, D.F. 2, P>0.1) or type of drug (table in) taken. Women with liver

oral-contraceptive

dysfunction

use.

582 HYPERTENSIVE

PATIENTS

DYSFUNCTION COMPARED WITH A RANDOMLY SELECTED

PATIENTS HAVING LIVER-FUNCTION TESTS MEASURED.

P<0.05

P<0.005 }

current

RESULTS FOR INDIVIDUAL LIVER-FUNCTION TESTS IN

100 HYPERTENSIVE

have been combined

For

P>0.5.

p>0.1.

II—MEAN (±S.D.) RESULTS IN 61 HYPERTENSIVE PATIENTS WITH LIVER GROUP OF

P<0.02

X2=1.90, D.F.=5,

significantly.

113 TABLE IV-ALCOHOL CONSUMPTION IN MEN WITH LIVER

DYSFUNCTION AND MALE RANDOM CONTROLS

excluded. Although the abnormalities are for liver dysfunction, they would generally be given this interpretation in ordinary practice. The picture was of mild but often persistent leakage of enzymes from the liver. Absence of severe hepatic impairment was suggested by the normal serum-albumin concentrations and the infrequency of high bilirubin levels.

ing7-were not specific

Causal Factors

High alcohol consumption and heavy body-weight (obesity) are possible causal factors in the liver dysfunction. Male sex and young age were related to high alcohol scores, and the higher diastolic blood-pressure may reflect measurement error in obese patients.s Fatty in-

x2=9.65, D.F.=2, P<0.01. Alcohol

dysfunction showed an excess of and "frequent" alcohol use, compared "heavy/habitual" with random controls (P<0.01, table iv). A similar but weaker trend was found in women (x2 =2.67, D.F. 2, P>0.1). Alcohol scores in women random controls and in female patients attending consecutively were very similar (X2=0.05). Women with liver dysfunction were also compared with this larger consecutive control group. Liver dysfunction and higher alcohol scores were significantly related (x2=6.70, D.F. 2, P<0.05). Men with liver

Consecutive Patients

Patients having liver-function tests appeared representative of consecutive clinic entries, and, in particular, alcohol scores in the two groups were similar (table v). Of consecutive male patients, 12% admitted heavy or habitual alcohol intake, and 30% frequent alcohol use. Less than 3% of women admitted more than occasional alcohol. Alcohol scores did not change between 1970 and 1975 and were unrelated to body-weight, bloodpressure, admission to hospital, source of referral, or smoking habits. High alcohol scores and young age were

associated, although not significantly. Discussion Liver dysfunction was present in 105% of patients studied and was persistent in many of these. It was related to male sex, young age, high diastolic blood-pressure, heavy body-weight, and high alcohol consumption, but not to treatment. The figures were not inflated by selection within the clinic. Natureof the Liver Dysfunction

The frequency of persistent abnormality and the distinct elevations of the transaminases suggest that spurious abnormalities-a problem with this type of screen-

*

Data missing for 2 patients.

TESTS,

AND

Why was Liver Dysfunction so Common? Heavy alcohol intake was admitted by a high proportion of men attending the clinic. Of the liver-function is the most sensitive to alcorise after single doses of alcohol (85g; 1/3 bottle of spirits),20 and elevations were found in only 3% of men drinking 1300 g (5 bottles of spirits) per month.18 S.G.O.T. is raised in only 50% of florid alcoholics.9, 17,19 It seems, therefore, that abnormal liverfunction tests generally indicate severe alcohol abuse. In this study liver dysfunction was related to "frequent" and even (in women) to "occasional" alcohol scores, suggesting that alcohol consumption was underestimated. As 12% of men entering the clinic were assessed as heavy drinkers, the true prevalence of alcohol abuse is probably much higher. The high frequency of liver dysfunction and alcohol abuse may reflect a high prevalence in the population served or selective referral to the clinic. There is, howtests

measured,

hol.17—19 It does

S.G.O.T. not

61 PATIENTS WITH LIVER DYSFUNCTION, 100 RANDOMLY SELECTED PATIENTS HAVING 200 PATIENTS ENTERING THE GLASGOW BLOOD PRESSURE CLINIC CONSECUTIVELY

TABLE V-ALCOHOL CONSUMPTION IN LIVER-FUNCTION

filtration of the liver is the commonest alcohol-induced hepatic abnormality9 and also relates well to bodyweight 9,10 without alcohol abuse. There is a correlation between hepatic fat content and serum-transaminases.11 Fatty infiltration characteristically causes mild liver dysfunction which is chronic but not progressive.9,12 In this study the pattern, time-course, and mildness of liver dysfunction, and its relationship with alcohol and bodyweight, suggest that fatty infiltration might be the predominant liver disorder. Methyldopa can cause liver dysfunction"" and chronic active hepatitis,16 but there was no evidence that this, or any other drug, was a common cause of abnormal liver-function tests in this study. Since methyldopa was not used less frequently in patients with liver dysfunction, the precaution of doing liver-function tests before starting a patient on the drugl6 does not seem to be generally observed.

114 ever,

some

evidence that

they

are not

merely local prob-

ALCOHOL AND HYPERTENSION

lems, since unexplained elevations of S.G.O.T. have been reported in 24% of hypertensive patients.21 Three popu-

D. G. BEEVERS*

lation studies22-24 have shown an association between heavy alcohol consumption and raised blood-pressure in males, and Mathews24 suggested that heavy alcohol intake could account for 30% of hypertension in developed countries. The syndrome of alcohol-induced corticosteroid excess15 provides one mechanism through which alcohol abuse could cause hypertension. The patients described were obese and hypertensive, and had mild liver

dysfunction.25

Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT

_

Practical Implications

Routine liver-function tests in hypertension seem worthwhile. Abnormalities should raise the question of alcohol abuse, which is often unrecognised or underestimated.26 This may need treatment in its own right and can cause difficulties in managing the hypertension.26 Possible effects of alcohol abuse on treatment compliance and defaulting, and of liver dysfunction on drug metabolism and effectiveness, need consideration. Abnormal liver-function tests should not be attributed too readily to drug toxicity, but they probably -contraindicate methyldopa treatment.16 The hypothesis that alcohol abuse is an important cause of hypertension24deserves serious consideration.

Liver-function data were compared in 158 unselected hypertensives and 105 normotensives aged 45-64 years. Serum concentrations of alanine and aspartate aminotransferase (S.G.O.T. and S.G.P.T.) were higher, and more often raised, in the hypertensive patients. Serum bilirubin and alkaline phosphatase concentrations were similar in both groups. In hypertensive patients aminotransferase concentrations tended to be higher in those with increased alcohol intake. Introduction

Summary

A HOSPITAL-BASED

study in hypertensive patients sugassociation between alcohol intake, liver dysgests and raised function, blood-pressure.1 A control group of with normal subjects blood-pressure was not available for comparison, and the findings could simply reflect the drinking habits of the Glasgow population. However, in the Renfrew Health Centre Blood Pressure Clinic2 data from a group of unselected hypertensive patients and a normotensive control group were available for comparian

son.

grateful to the many physicians in the Western Infirmary, Royal Infirmary, Stobhill Hospital, and Southern General Hospital, Glasgow, who collected the data on which this study was based, and to the many people involved in the editing, data processing, and computing sections of the Glasgow Blood Pressure Clinic. The Glasgow I

am

Blood Pressure Clinic has received financial support from the Western Regional Hospital Board, the Board of Management of the Western Infirmary and Gartnavel Hospital, the Medical Research Council, Ciba Ltd., I.C.I. Ltd., and Searle Ltd. The author is a Searle research fellow in clinical pharmacology. REFERENCES 1. Glasgow Blood Pressure Clinic, Jl. R. Coll. Physns Lond. 1972, 7, 87. 2. Endrassik, L., Grof, P. Biochem. J. 1938, 297, 81. 3. Axelsson, H., Ekman, B., Knutson, D. in Automation in Analytical Chemistry (edited by L. T. Skeggs). Technicon Symposium. New York, 1965. 4. Kasslcr, G., Rush, R., Leon, L., Delean, A., Cupiola, R. in Advances in Automated Analysis. Technicon International Congress, 1970, vol. i, p. 66. 5. Kennedy, F., Cleary, J. J., Roy, A. D., Kay, A. W. Lancet, 1968, ii, 1230. 6. Kennedy, F. Scott. med. J. 1970, 15, 391. 7. Grams, R. R. A. Rev. Med. 1976, 27, 199. 8. King, G. E. J. Am. med. Ass. 1969, 209, 1902. 9. Sherlock, S. Diseases of the Liver and Biliary System; p. 413. Oxford, 1968. 10. Maclagan, N. F. in Biochemical Disorders in Human Disease (edited by R. H. S. Thompson and I. D. P. Wootton); p. 150. London, 1970. 11. Lundquist, A., Wiebe, T., Belfrage, P. Acta med. scand. 1973, 194, 501. 12. Hilden, M., Juhl, E., Thomsen, A. C., Christoffersen, P. ibid. p. 485. 13. Irvine, R. O. H., O’Brien, K. P., North, J. D. K. Lancet, 1962, i, 300. 14. Colwill, J. M., Morrissey, J., Yu, P. N. New Engl. J. Med. 1964, 271, 696. 15. Leonard, J. W., Gifford, R. W., Humphrey, D. C. Am. Heart J. 1965, 69, 610. 16. Toghill, P. J., Smith, P. G., Benton, P., Brown, R. C., Mathews, H. L. Br.

med. J. 1974, iii, 545. 17. Rosalki, S. B., Rau, D., Lehmann, D., Prentice, M. Lancet, 1970, ii, 1139. 18. Myrhed, M., Bergstrom, K. Acta med. scand. 1976, 200, 87. 19. Konttinen, A., Hartel, G., Lauhija, A. ibid. 1970, 188, 257. 20. Bang, N. V., Iversen, K., Jagt, T., Madsen, S. J. J. Am. med. Ass. 1958, 168, 156. 21. Smith, W. M., Bachman, B., Galante, J. G., Hannawell, E. G., Johnson, W. P., Koch, C. E., Korfmacher, S. D., Thurn, R. H., Brower, L. Ann. intern. Med. 1966, 65, 657. 22. Shah, V. V. in Epidemiology of Hypertension (edited by J. Stamler, R. Stamler, and T. N. Pullman); p. 204. New York, 1967. 23. Dawber, T. R., Kannel, W. B., Kagan, A., Donabedian, R. K., McNamara, P. M., Pearson, G. ibid. p. 255. 24. Mathews, J. D. Clin. Sci. molec. Med. 1976, 51, suppl. p 661s. 25. Smals, A. G., Kloppenborg, P. W., Njo, K. T., Knoben, J. M., Ruland, C. M. Br. med. J. 1976, IV, 1298. 26. Mahler, R., Evans, M. Medicine, Lond. 1975, no. 13, p. 582.

Methods After a screening survey in 45-64-year-old male and female residents of Renfrew, Scotland,3 a special clinic was establishedto investigate all cases with diastolic blood-pressure of 105 mm Hg or more. 78.8% of those eligible attended the screening, and 178 (78.4%) of the 227 unselected hypertensive patients who were identified within the range attended the clinic. All were managed by means of the computerised records system of the Glasgow Blood Pressure Clinic.4 All cases were routinely asked about their drinking habits-i.e., whether they were non-drinkers, occasional drinkers, or frequent drinkers. Routine biochemical screening at entry was done only in hypertensive patients who were untreated or whose treatment was temporarily withheld. Thus biochemical data were available from 158 cases (males 74). This was 69.6% of the eligible hypertensive patients. Serum bilirubin, alkaline phosphatase, aspartate and alanine aminotransferases (S.G.P.T. and S.G.O.T.) were measured. All measurements were made in the same laboratory as part of the Technicon SMA 12/60 automated programme. The normotensive control group came from the same screened population. It consisted of 105 subjects (males 52) with diastolic blood-pressure consistently below 90 mm Hg in the untreated state. The male/female ratio in any 10-year agerange was approximately the same in both hypertensive and control groups. The mean ages of hypertensive and normotensive men were 54.5 (±6.0) and 54-2 (±62) years, and for hypertensive and normotensive women 56.2 (±5.5) and 53.4 (±5-8) years, respectively. No clinical cases of overt hepatic cirrhosis were identified in any group. In the normotensive group, no inquiries were made into drinking habits since an’ investigation of liver disease was not contemplated at the time.

Results

Comparison of Liver-function

Tests in

Hypersensives

andnormotensives S.G.O.T.

male

and

S.G.P.T.

concentrations were higher in than in normotensive men

hypertensive patients

*Present address:

Dudley Road Hospital, Birmingham B18 7QH.