- Email: [email protected]
Natural history of autonomic neuropathy in chronic liver disease
1462
CLINICAL PRACTICE Natural history of autonomic neuropathy in chronic liver disease
To determine the natural history of autonomic neuropathy in chronic liver disease we used standard cardiovascular autonomic tests to evaluate prospectively 60 patients (33 male, 27 female) with initially well-preserved hepatic function. On initial testing, 27 patients (45%; median [range] age 56 [32-67] years) had vagal neuropathy. Autonomic dysfunction was equally common in patients with alcohol-related and nonalcoholic-related liver disease. The cumulative 4-year mortality rate in patients with vagal neuropathy was 30% compared with 6% in those with normal autonomic function. Multiple logistic regression analysis showed that presence of vagal neuropathy and severity of hepatic damage were independent predictors of mortality. Serial testing showed that whereas disease progression occurred in some patients, in others mild abnormalities in autonomic function were reversible. Vagal dysfunction is common in wellcompensated chronic liver disease and its presence identifies a subgroup of patients with a substantially worse
outlook.
Introduction Chronic liver disease is accompanied by several disturbances including impairment of cardiovascular autonomic reflexes. 1-3 Cross-sectional studies have shown an equal prevalence of autonomic neuropathy in alcohol-related and non-alcohol-related liver disease,4,5 but there are no longitudinal studies of this complication in chronic liver disease. In diabetic patients6,77 and chronic alcohol abusers,8 cardiovascular autonomic dysfunction is associated with a poor outlook, and similar abnormalities in patients with cirrhosis might result in inadequate responses to stressful events such as sepsis and haemorrhage.2,4 We set out to determine the natural history and prognostic significance of autonomic dysfunction in patients with chronic liver disease by prospective evaluation of such patients with standard cardiovascular autonomic
haemodynamic
hepatitis (9 autoimmune, 9 hepatitis B, 1 hepatitis C, and 4 cryptogenic; 46-9 [14’3] years). Patients were excluded if they had active
medical conditions known
to
affect autonomic
function, diabetes
(diagnosed by post-prandial blood glucose screen9), an abnormal electrocardiogram or history of cardiac disease, or were treated with diuretics or beta blockers. All patients were in a clinically stable state with no recent infection or haemorrhage, and alcohol-abusing patients had to have abstained from alcohol for at least 2 weeks before the study to be included. Hepatic function was assessed by the Child-Pugh classification;57 of the 60 patients were Child grade A. Four standard cardiovascular reflex tests were used; heart-rate variation on deep breathing and in response to the Valsalva manoeuvre, and blood pressure and heart-rate response to standing." We compared results with published normal ranges that were further validated in 29 age-matched controls.4 Borderline results were interpreted as normal. All tests were done on fasted patients and at the same time of day and in the same sequence at stable room temperature (21-23°C). Heart-rate tests were done with a cardiac monitor (Model 103, Roche, Watford, UK) linked to a microcomputer programmed to measure successive R-R intervals to an accuracy of 1 ms. All patients gave informed consent and local ethics committee approval was obtained. Patients were followed prospectively for a median of 50 (range 42-53) months; 2 patients were lost to follow-up after 12 months. In 37 of the 60 patients, autonomic tests were repeated 29 to 53 months after entry into the study (mean interval between tests 40-7 months). Details of complications, such as variceal haemorrhage or ascites, and of dates and causes of death were ascertained from hospital records, general practitioners, death certificates, and necropsy reports. Comparison between groups was by the Wilcoxon rank-sum test for continuous variables and chi-square analysis for categorical variables. Survival was computed by the Kaplan-Meier method and compared with the log-rank test. The date of initial autonomic tests was taken as the starting point of the study. Multiple logistic regression was used to determine factors independently related to mortality (both liver and non-liver-related); variables were entered into a model that predicted survival or death by a forward stepwise procedure and the score statistic. The suitability of the model was then assessed by comparison of predicted and observed outcomes. This is an appropriate method when analysis is done at a fixed time after entry into the study. 12 All tests were done with Statgraphics (Statistical Graphics Corp, Rockville, USA) and SPSS/PC (SPSS Inc, Chicago, USA) software.
Results Initial autonomic tests
tests.
27 of 60 (45 %) patients had evidence of vagal neuropathy
Patients and methods
with one or more abnormal heart-rate tests. 16 patients had
60 patients were studied, most of whom had been included in a previous cross-sectional study of autonomic neuropathy in chronic liver disease.4 All patients had biopsy-proven liver disease. 19 had alcoholic liver disease (15 with cirrhosis and 4 with alcoholic hepatitis with fibrosis; mean [SD] age 44[9.9] years), 18 had primary biliary cirrhosis (55-6 [7.8] years), and 23 had chronic
ADDRESS: Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, UK (M. T. Hendrickse, MRCP, P. J. Thuluvath, MRCP, Prof D. R. Triger, FRCP). Correspondence to Prof D. R. Triger, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
1463
TABLE I-PATIENT VARIABLES AT TIME OF INITIAL AUTONOMIC TESTS
Values given ascites.
*p <0.001;
as
median
(range).
No
Months
patient in either group had clinical evidence of
Fig 1-Kaplan-Meier survival
tp <0.05.
curves
in autonomic
neuropathy
of chronic liver disease. one
abnormal heart-rate test, 9 had two, and 2 had three.
Only 3 of 60 (5%) patients had substantial postural hypotension, all of whom had abnormal heart-rate tests. Heart-rate variation on deep breathing and the Valsalva ratio were the most frequently abnormal tests. Autonomic dysfunction was equally prevalent in patients with alcoholrelated (9/19, 47%) and non-alcohol-related (18/41, 44%) liver disease and was common in patients with all the major forms of chronic liver disease except for those with chronic hepatitis B virus infection (1 of 9 cases). Patients with vagal neuropathy were significantly older and tended to have lower serum albumin than those with normal cardiovascular tests, but there was no significant difference in the Child-Pugh score between the two groups (table i).
Mortality At the end of the study, 48 patients were known to be alive (including 1 who had a liver transplant for advanced primary biliary cirrhosis), 2 patients were lost to follow-up, and 10 had died. Vagal neuropathy was present on initial testing in 6 of 8 patients with liver-related deaths and in both with non-liver-related deaths (table n). Life-table analysis revealed a significantly increased 4-year mortality in patients with vagal neuropathy compared with those without vagal neuropathy (30% vs 6%, p < 002) (fig 1). This difference in survival remained significant (p < 0 04) even when the non-liver-related deaths were censored. Patients who died had a significantly lower Valsalva ratio (p < 0-028), heart-rate change on deep breathing (p < 0-033), and lying-standing (30:15) ratio (p < 0-002) on initial testing (fig 2). Multiple logistic TABLE II-CAUSES OF DEATH
Fig 2-Comparisons of intitial; autonomic tests in patients who died and in survivors. Medians and
interquartile ranges are shown
regression analysis showed that, after adjustment for the Child-Pugh score, mortality was related to the presence of vagal neuropathy. There was no significant association between mortality and age, diagnosis, duration of known liver disease, and serum creatinine (table ill).
Complications During follow-up, ascites developed in 5 of 27 (18-5%) patients in the vagal neuropathy group and in 6 of 33 (18-2%) in the non-neuropathy group. Variceal bleeding occurred in 2 patients with vagal neuropathy and in 5 without neuropathy, while infection of sufficient severity to merit hospital admission and treatment was diagnosed in 5 patients with and 3 without neuropathy. Haemorrhage and sepsis developed in 2 patients (1 in each group). Of those patients with sepsis or variceal bleeding, all 6 in the vagal neuropathy group died compared with 1 of 7 in the non-neuropathy group. TABLE III-MULTIPLE LOGISTIC REGRESSION ANALYSIS OF VARIABLES RELATED TO MORTALITY
I
logistic regression model on forward stepwise selection; this model correctly in > 90% of cases tRejected by stepwise selection procedure tstatistically significant. *Included
predicted
*Bronchial
carcinoma not
evident
on
initial assessment
in
the
outcome
1464
Repeat tests Repeat cardiovascular tests were done on 37 patients. Of those who were not tested a second time, 8 patients died before the tests could be repeated, 1 had been started on propranolol, 2 were lost to follow-up, and 12 refused to have repeat studies (largely because of the inconvenience involved in travelling to have the tests). 15 of the 37 patients had abnormal tests initially, and a further 5 had abnormal tests by the time of follow-up (2 with primary biliary cirrhosis and 3 who resumed alcohol abuse). 3 patients with initially mildly abnormal tests reverted to normal on follow-up; 2 had autoimmune chronic active hepatitis that responded to steroid therapy and the third was an alcoholabuser who remained abstinent. All the patients with more than one abnormal test initially had persistently abnormal results on follow-up. Hepatic function (as assessed by the Child-Pugh score) improved in 2 patients, deteriorated in 4, and remained the same in 31. There was no relation between changes in the Child-Pugh score and changes in autonomic tests.
Discussion We have shown that presence of autonomic neuropathy in patients with chronic liver disease is associated with significantly increased mortality, and that this association remains even after adjusting by multivariate analysis for the older age and lower serum albumin of patients with neuropathy. It has been suggested that the poor outlook of diabetics with autonomic neuropathy may be due to abnormal autonomic-reflex responses to hypoxia and hypoglycaemia, which predispose to cardiorespiratory arrest.13 An increased mortality, predominantly from cardiovascular causes, has also been reported in chronic alcohol abusers with vagal neuropathy.s The explanation for increased death rate in patients with chronic liver disease is unknown but it is possible that the presence of parasympathetic neuropathy could, by altering the afferent input from central volume receptors and baroreceptors,l4 result in defective responses to stressful events. The increased mortality from bleeding and sepsis in our patients with autonomic neuropathy is consistent with this hypothesis. Disturbances in systemic haemodynamic variables and increased sympathetic activity have been shown previously to be of prognostic importance in patients with cirrhosis and ascites,15,16 but the patients in our study (at least initially) had well-compensated liver disease with no evidence of fluid retention. The reproducibility of tests for autonomic function has been demonstrated previously in controls and diabetic subjects. 17 "’ Although we did not obtain serial data on autonomic function during progression of liver disease to death, there is evidence that more severe liver dysfunction is associated with a greater prevalence of autonomic disturbance.19 It may be noteworthy that of the 3 patients who had an improvement in autonomic function, 2 had autoimmune chronic hepatitis that responded to treatment with steroids and 1 was an abstinent alcohol abuser, suggesting that in mild disease there is potential for reversal of vagal neuropathy with improvement in hepatic function. Such a possibility is consistent with the observation that the vagal neuropathy associated with chronic alcohol abuse is reversible with abstinence.20 REFERENCES 1. Lunzer MR, Newman SP, Sherlock S. Skeletal muscle blood flow and neurovascular reactivity in liver disease. Gut 1973; 14: 354-59.
MR, Manghani KK, Newman SP, Sherlock S, Bernard AG, Ginsburg J. Impaired cardiovascular responsiveness in liver disease. Lancet 1975; ii: 382-85. 3. Anon. Autonomic neuropathy in liver disease. Lancet 1989, ii: 721-25. 4. Thuluvath PJ, Triger DR. Autonomic neuropathy in chronic liver disease. Q J Med 1989; 72: 737-47. 5. MacGilchrist AJ, Reid JL. Impairment of autonomic reflexes in cirrhosis. Am J Gastroenterol 1990; 85: 288-92. 6. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49: 95-108. 7. O’Brien IA, McFadden JP, Corrall RJM. The influence of autonomic neuropathy on mortality in insulin dependent diabetes. Q J Med 1991; 2. Lunzer
290: 495-502.
Johnson RH, Robinson BJ. Mortality in alcoholics with autonomic neuropathy. J Neurol Neurosurg Psychiatry 1988; 51: 476-80. 9. World Health Organisation. Diabetes mellitus: diagnosis and diagnostic criteria. WHO Tech Rep Ser 1985; 727: 10-14. 10. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1983; 60: 646-49. 11. Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and 8.
prognosis.
Clin Endocrinol Metab 1986; 15: 855-88.
Daly LE, Bourke GJ, McGilvray J. Interpretation and uses of medical statistics. Oxford: Blackwell Scientific, 1991: 258-62. 13. Page MMcB, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; i: 14-16. 14. Satchell PM. Pathophysiology of the vagus. In: Bannister R, ed. Autonomic failure. New York: Oxford University Press, 1988: 159-76. 15. Llach J, Gines P, Arroyo V, et al. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology 12.
1988; 94: 482-87.
Tage-Jensen J, Henriksen JH, Christensen E, et al. Plasma catecholamine level and portal venous pressure as guides to prognosis in patients with cirrhosis. J Hepatol 1988; 6: 350-58. 17. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests. Diabetes Care 1985; 8: 16.
491-98. 18. Schumer
M, Miller Crain G, Pfeifer MA. Diabetic autonomic neuropathy Part II. Am J Med 1988; 85 (suppl 5A): 144-46. 19. Hendrickse MT, Triger DR. Autonomic dysfunction and hepatic function in chronic liver disease. Gut 1990; 31: A1164. 20. Tan ETH, Johnson RH, Lambie DG, Whiteside EA. Alcoholic vagal neuropathy: recovery following prolonged abstinence. J Neurol Neurosurg Psychiatry 1984; 47: 1335-37.
From The Lancet Sleeplessness appears likely, sleeplessness is more characteristic of than those of our predecessors, or that, in accordance days with a scientific fashion, it is now more noticed, we certainly hear of its prevalence with somewhat startling frequency. The nostrums proposed for the cure of this disorder are numerous. Many, if not most of them-we do not for the moment speak of narcotic drugs-are empirical, and are cast upon the public intelligence without any conscious reference to causes actually at work upon the brain and other nervous tissues. It does not necessarily follow that they are valueless, and we should no more think of repudiating their ordinarily legitimate exercise than of refusing the occasional aid of such medicinal agents as may be trusted safely to discharge the same needful function. It is to be understood, however, that we would, wherever possible, avoid, and replace by simpler non-medicinal methods, even such occasionally useful aid. This attitude is but rational, if we consider that the true object of treatment is never by choice merely palliative, but curative, and for cure there is needed the detection and removal of an active cause. The revelation of the causes of insomnia is, indeed, no simple matter.... Where mental overactivity or irritation has to do with insomnia, the influence of change-that is, of a change in thought--should have a trial. It is no doubt a blind groping after this remedy that induces some to read themselves asleep. Better in several ways is the practice introduced by the German Kant, who spent some time before he retired for the night in cutting off by an effort of thought each mental occupation of the previous working hours.
Whether,
as
our own
(June 11,1892)
CLINICAL PRACTICE Natural history of autonomic neuropathy in chronic liver disease
To determine the natural history of autonomic neuropathy in chronic liver disease we used standard cardiovascular autonomic tests to evaluate prospectively 60 patients (33 male, 27 female) with initially well-preserved hepatic function. On initial testing, 27 patients (45%; median [range] age 56 [32-67] years) had vagal neuropathy. Autonomic dysfunction was equally common in patients with alcohol-related and nonalcoholic-related liver disease. The cumulative 4-year mortality rate in patients with vagal neuropathy was 30% compared with 6% in those with normal autonomic function. Multiple logistic regression analysis showed that presence of vagal neuropathy and severity of hepatic damage were independent predictors of mortality. Serial testing showed that whereas disease progression occurred in some patients, in others mild abnormalities in autonomic function were reversible. Vagal dysfunction is common in wellcompensated chronic liver disease and its presence identifies a subgroup of patients with a substantially worse
outlook.
Introduction Chronic liver disease is accompanied by several disturbances including impairment of cardiovascular autonomic reflexes. 1-3 Cross-sectional studies have shown an equal prevalence of autonomic neuropathy in alcohol-related and non-alcohol-related liver disease,4,5 but there are no longitudinal studies of this complication in chronic liver disease. In diabetic patients6,77 and chronic alcohol abusers,8 cardiovascular autonomic dysfunction is associated with a poor outlook, and similar abnormalities in patients with cirrhosis might result in inadequate responses to stressful events such as sepsis and haemorrhage.2,4 We set out to determine the natural history and prognostic significance of autonomic dysfunction in patients with chronic liver disease by prospective evaluation of such patients with standard cardiovascular autonomic
haemodynamic
hepatitis (9 autoimmune, 9 hepatitis B, 1 hepatitis C, and 4 cryptogenic; 46-9 [14’3] years). Patients were excluded if they had active
medical conditions known
to
affect autonomic
function, diabetes
(diagnosed by post-prandial blood glucose screen9), an abnormal electrocardiogram or history of cardiac disease, or were treated with diuretics or beta blockers. All patients were in a clinically stable state with no recent infection or haemorrhage, and alcohol-abusing patients had to have abstained from alcohol for at least 2 weeks before the study to be included. Hepatic function was assessed by the Child-Pugh classification;57 of the 60 patients were Child grade A. Four standard cardiovascular reflex tests were used; heart-rate variation on deep breathing and in response to the Valsalva manoeuvre, and blood pressure and heart-rate response to standing." We compared results with published normal ranges that were further validated in 29 age-matched controls.4 Borderline results were interpreted as normal. All tests were done on fasted patients and at the same time of day and in the same sequence at stable room temperature (21-23°C). Heart-rate tests were done with a cardiac monitor (Model 103, Roche, Watford, UK) linked to a microcomputer programmed to measure successive R-R intervals to an accuracy of 1 ms. All patients gave informed consent and local ethics committee approval was obtained. Patients were followed prospectively for a median of 50 (range 42-53) months; 2 patients were lost to follow-up after 12 months. In 37 of the 60 patients, autonomic tests were repeated 29 to 53 months after entry into the study (mean interval between tests 40-7 months). Details of complications, such as variceal haemorrhage or ascites, and of dates and causes of death were ascertained from hospital records, general practitioners, death certificates, and necropsy reports. Comparison between groups was by the Wilcoxon rank-sum test for continuous variables and chi-square analysis for categorical variables. Survival was computed by the Kaplan-Meier method and compared with the log-rank test. The date of initial autonomic tests was taken as the starting point of the study. Multiple logistic regression was used to determine factors independently related to mortality (both liver and non-liver-related); variables were entered into a model that predicted survival or death by a forward stepwise procedure and the score statistic. The suitability of the model was then assessed by comparison of predicted and observed outcomes. This is an appropriate method when analysis is done at a fixed time after entry into the study. 12 All tests were done with Statgraphics (Statistical Graphics Corp, Rockville, USA) and SPSS/PC (SPSS Inc, Chicago, USA) software.
Results Initial autonomic tests
tests.
27 of 60 (45 %) patients had evidence of vagal neuropathy
Patients and methods
with one or more abnormal heart-rate tests. 16 patients had
60 patients were studied, most of whom had been included in a previous cross-sectional study of autonomic neuropathy in chronic liver disease.4 All patients had biopsy-proven liver disease. 19 had alcoholic liver disease (15 with cirrhosis and 4 with alcoholic hepatitis with fibrosis; mean [SD] age 44[9.9] years), 18 had primary biliary cirrhosis (55-6 [7.8] years), and 23 had chronic
ADDRESS: Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, UK (M. T. Hendrickse, MRCP, P. J. Thuluvath, MRCP, Prof D. R. Triger, FRCP). Correspondence to Prof D. R. Triger, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
1463
TABLE I-PATIENT VARIABLES AT TIME OF INITIAL AUTONOMIC TESTS
Values given ascites.
*p <0.001;
as
median
(range).
No
Months
patient in either group had clinical evidence of
Fig 1-Kaplan-Meier survival
tp <0.05.
curves
in autonomic
neuropathy
of chronic liver disease. one
abnormal heart-rate test, 9 had two, and 2 had three.
Only 3 of 60 (5%) patients had substantial postural hypotension, all of whom had abnormal heart-rate tests. Heart-rate variation on deep breathing and the Valsalva ratio were the most frequently abnormal tests. Autonomic dysfunction was equally prevalent in patients with alcoholrelated (9/19, 47%) and non-alcohol-related (18/41, 44%) liver disease and was common in patients with all the major forms of chronic liver disease except for those with chronic hepatitis B virus infection (1 of 9 cases). Patients with vagal neuropathy were significantly older and tended to have lower serum albumin than those with normal cardiovascular tests, but there was no significant difference in the Child-Pugh score between the two groups (table i).
Mortality At the end of the study, 48 patients were known to be alive (including 1 who had a liver transplant for advanced primary biliary cirrhosis), 2 patients were lost to follow-up, and 10 had died. Vagal neuropathy was present on initial testing in 6 of 8 patients with liver-related deaths and in both with non-liver-related deaths (table n). Life-table analysis revealed a significantly increased 4-year mortality in patients with vagal neuropathy compared with those without vagal neuropathy (30% vs 6%, p < 002) (fig 1). This difference in survival remained significant (p < 0 04) even when the non-liver-related deaths were censored. Patients who died had a significantly lower Valsalva ratio (p < 0-028), heart-rate change on deep breathing (p < 0-033), and lying-standing (30:15) ratio (p < 0-002) on initial testing (fig 2). Multiple logistic TABLE II-CAUSES OF DEATH
Fig 2-Comparisons of intitial; autonomic tests in patients who died and in survivors. Medians and
interquartile ranges are shown
regression analysis showed that, after adjustment for the Child-Pugh score, mortality was related to the presence of vagal neuropathy. There was no significant association between mortality and age, diagnosis, duration of known liver disease, and serum creatinine (table ill).
Complications During follow-up, ascites developed in 5 of 27 (18-5%) patients in the vagal neuropathy group and in 6 of 33 (18-2%) in the non-neuropathy group. Variceal bleeding occurred in 2 patients with vagal neuropathy and in 5 without neuropathy, while infection of sufficient severity to merit hospital admission and treatment was diagnosed in 5 patients with and 3 without neuropathy. Haemorrhage and sepsis developed in 2 patients (1 in each group). Of those patients with sepsis or variceal bleeding, all 6 in the vagal neuropathy group died compared with 1 of 7 in the non-neuropathy group. TABLE III-MULTIPLE LOGISTIC REGRESSION ANALYSIS OF VARIABLES RELATED TO MORTALITY
I
logistic regression model on forward stepwise selection; this model correctly in > 90% of cases tRejected by stepwise selection procedure tstatistically significant. *Included
predicted
*Bronchial
carcinoma not
evident
on
initial assessment
in
the
outcome
1464
Repeat tests Repeat cardiovascular tests were done on 37 patients. Of those who were not tested a second time, 8 patients died before the tests could be repeated, 1 had been started on propranolol, 2 were lost to follow-up, and 12 refused to have repeat studies (largely because of the inconvenience involved in travelling to have the tests). 15 of the 37 patients had abnormal tests initially, and a further 5 had abnormal tests by the time of follow-up (2 with primary biliary cirrhosis and 3 who resumed alcohol abuse). 3 patients with initially mildly abnormal tests reverted to normal on follow-up; 2 had autoimmune chronic active hepatitis that responded to steroid therapy and the third was an alcoholabuser who remained abstinent. All the patients with more than one abnormal test initially had persistently abnormal results on follow-up. Hepatic function (as assessed by the Child-Pugh score) improved in 2 patients, deteriorated in 4, and remained the same in 31. There was no relation between changes in the Child-Pugh score and changes in autonomic tests.
Discussion We have shown that presence of autonomic neuropathy in patients with chronic liver disease is associated with significantly increased mortality, and that this association remains even after adjusting by multivariate analysis for the older age and lower serum albumin of patients with neuropathy. It has been suggested that the poor outlook of diabetics with autonomic neuropathy may be due to abnormal autonomic-reflex responses to hypoxia and hypoglycaemia, which predispose to cardiorespiratory arrest.13 An increased mortality, predominantly from cardiovascular causes, has also been reported in chronic alcohol abusers with vagal neuropathy.s The explanation for increased death rate in patients with chronic liver disease is unknown but it is possible that the presence of parasympathetic neuropathy could, by altering the afferent input from central volume receptors and baroreceptors,l4 result in defective responses to stressful events. The increased mortality from bleeding and sepsis in our patients with autonomic neuropathy is consistent with this hypothesis. Disturbances in systemic haemodynamic variables and increased sympathetic activity have been shown previously to be of prognostic importance in patients with cirrhosis and ascites,15,16 but the patients in our study (at least initially) had well-compensated liver disease with no evidence of fluid retention. The reproducibility of tests for autonomic function has been demonstrated previously in controls and diabetic subjects. 17 "’ Although we did not obtain serial data on autonomic function during progression of liver disease to death, there is evidence that more severe liver dysfunction is associated with a greater prevalence of autonomic disturbance.19 It may be noteworthy that of the 3 patients who had an improvement in autonomic function, 2 had autoimmune chronic hepatitis that responded to treatment with steroids and 1 was an abstinent alcohol abuser, suggesting that in mild disease there is potential for reversal of vagal neuropathy with improvement in hepatic function. Such a possibility is consistent with the observation that the vagal neuropathy associated with chronic alcohol abuse is reversible with abstinence.20 REFERENCES 1. Lunzer MR, Newman SP, Sherlock S. Skeletal muscle blood flow and neurovascular reactivity in liver disease. Gut 1973; 14: 354-59.
MR, Manghani KK, Newman SP, Sherlock S, Bernard AG, Ginsburg J. Impaired cardiovascular responsiveness in liver disease. Lancet 1975; ii: 382-85. 3. Anon. Autonomic neuropathy in liver disease. Lancet 1989, ii: 721-25. 4. Thuluvath PJ, Triger DR. Autonomic neuropathy in chronic liver disease. Q J Med 1989; 72: 737-47. 5. MacGilchrist AJ, Reid JL. Impairment of autonomic reflexes in cirrhosis. Am J Gastroenterol 1990; 85: 288-92. 6. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49: 95-108. 7. O’Brien IA, McFadden JP, Corrall RJM. The influence of autonomic neuropathy on mortality in insulin dependent diabetes. Q J Med 1991; 2. Lunzer
290: 495-502.
Johnson RH, Robinson BJ. Mortality in alcoholics with autonomic neuropathy. J Neurol Neurosurg Psychiatry 1988; 51: 476-80. 9. World Health Organisation. Diabetes mellitus: diagnosis and diagnostic criteria. WHO Tech Rep Ser 1985; 727: 10-14. 10. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1983; 60: 646-49. 11. Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and 8.
prognosis.
Clin Endocrinol Metab 1986; 15: 855-88.
Daly LE, Bourke GJ, McGilvray J. Interpretation and uses of medical statistics. Oxford: Blackwell Scientific, 1991: 258-62. 13. Page MMcB, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; i: 14-16. 14. Satchell PM. Pathophysiology of the vagus. In: Bannister R, ed. Autonomic failure. New York: Oxford University Press, 1988: 159-76. 15. Llach J, Gines P, Arroyo V, et al. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology 12.
1988; 94: 482-87.
Tage-Jensen J, Henriksen JH, Christensen E, et al. Plasma catecholamine level and portal venous pressure as guides to prognosis in patients with cirrhosis. J Hepatol 1988; 6: 350-58. 17. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests. Diabetes Care 1985; 8: 16.
491-98. 18. Schumer
M, Miller Crain G, Pfeifer MA. Diabetic autonomic neuropathy Part II. Am J Med 1988; 85 (suppl 5A): 144-46. 19. Hendrickse MT, Triger DR. Autonomic dysfunction and hepatic function in chronic liver disease. Gut 1990; 31: A1164. 20. Tan ETH, Johnson RH, Lambie DG, Whiteside EA. Alcoholic vagal neuropathy: recovery following prolonged abstinence. J Neurol Neurosurg Psychiatry 1984; 47: 1335-37.
From The Lancet Sleeplessness appears likely, sleeplessness is more characteristic of than those of our predecessors, or that, in accordance days with a scientific fashion, it is now more noticed, we certainly hear of its prevalence with somewhat startling frequency. The nostrums proposed for the cure of this disorder are numerous. Many, if not most of them-we do not for the moment speak of narcotic drugs-are empirical, and are cast upon the public intelligence without any conscious reference to causes actually at work upon the brain and other nervous tissues. It does not necessarily follow that they are valueless, and we should no more think of repudiating their ordinarily legitimate exercise than of refusing the occasional aid of such medicinal agents as may be trusted safely to discharge the same needful function. It is to be understood, however, that we would, wherever possible, avoid, and replace by simpler non-medicinal methods, even such occasionally useful aid. This attitude is but rational, if we consider that the true object of treatment is never by choice merely palliative, but curative, and for cure there is needed the detection and removal of an active cause. The revelation of the causes of insomnia is, indeed, no simple matter.... Where mental overactivity or irritation has to do with insomnia, the influence of change-that is, of a change in thought--should have a trial. It is no doubt a blind groping after this remedy that induces some to read themselves asleep. Better in several ways is the practice introduced by the German Kant, who spent some time before he retired for the night in cutting off by an effort of thought each mental occupation of the previous working hours.
Whether,
as
our own
(June 11,1892)