|Year : 2017 | Volume
| Issue : 3 | Page : 152-157
Evaluation of autonomic neuropathy in alcoholic liver disease in Manipur
SA Rajeev1, Robinson Ningshen1, RK Bikramjit Singh1, O Punyabati2, S Bhagyabati Devi1
1 Department of General Medicine, Regional Institute of Medical Sciences, Imphal, Manipur, India
2 Department of Physiology, Regional Institute of Medical Sciences, Imphal, Manipur, India
|Date of Web Publication||17-Aug-2017|
Mission Lane, Sanjenthong, Imphal - 795 001, Manipur
Source of Support: None, Conflict of Interest: None
Context: The prevalence of autonomic neuropathy in alcoholic liver disease and its correlation with severity of liver disease is not known in Manipur population.
Aims: The aim of this study was to study the prevalence of autonomic dysfunction in patients with chronic alcoholic liver disease and to determine the degree of severity of alcoholic liver disease by Child–Turcotte-Pugh scoring and its correlation with autonomic profile.
Settings and Design: A cross-sectional study involving eighty adult patients with chronic alcoholic liver attending Medicine out patient's Department in a tertiary care teaching hospital in Imphal, from October 2011 to September 2013.
Subjects and Methods: Autonomic profile included a preformed questionnaire and five autonomic function tests (3 parasympathetic and 2 sympathetic). Parasympathetic tests (heart rate variation to  deep and slow breathing,  Valsalva maneuver, and  standing) and sympathetic tests (blood pressure response to  postural change and  sustained isometric hand grip) were performed. Autonomic neuropathy detected was graded as normal, early, definite, severe, and atypical.
Results: Autonomic dysfunction was observed in 58 (72.5%) patients (early 30 [37.5%], definite 10 [12.5%], severe 18 [22.5%], normal 22 [27.5%]). Heart rate response to standing (30:15 ratio) was the most altered parasympathetic test in 39 (67.2%). The parameters that correlated with the severity of autonomic dysfunction were Child–Pugh scoring (P = 0.000), platelet count (P = 0.000, cirrhosis (P = 0.001), varices (P = 0.02), and portal hypertension (P = 0.000).
Conclusions: Screening of alcoholic liver disease patients with autonomic function tests directly correlated with the severity of alcoholic liver disease. Autonomic tests should be a part of patient work in alcoholic liver disease so that early intervention can be performed.
Keywords: Child–Turcotte–Pugh, sustained isometric hand grip, Valsalva maneuver
|How to cite this article:|
Rajeev S A, Ningshen R, Bikramjit Singh R K, Punyabati O, Devi S B. Evaluation of autonomic neuropathy in alcoholic liver disease in Manipur. J Med Soc 2017;31:152-7
|How to cite this URL:|
Rajeev S A, Ningshen R, Bikramjit Singh R K, Punyabati O, Devi S B. Evaluation of autonomic neuropathy in alcoholic liver disease in Manipur. J Med Soc [serial online] 2017 [cited 2018 Mar 19];31:152-7. Available from: http://www.jmedsoc.org/text.asp?2017/31/3/152/211098
| Introduction|| |
The harmful use of alcohol is a global problem which compromises both individual and social development. It results in 2.5 million deaths each year. Consumption of more than two standard drinks per day increases the risk of health problems in many organ systems. Heavy repetitive drinking, as is seen in alcohol abuse and dependence, cuts short the life span by an estimated decade in both genders, all cultural groups, and all socioeconomic strata. In Manipur, less than half of men (47%) and 2% of women drink alcohol. Forty-nine percent of men who drink consume alcohol once a week or more frequently. Long-term alcohol consumption may produce wide-ranging effects on almost all body tissues, including the autonomic and peripheral nervous systems. Clinical symptoms of autonomic failure generally appear when the polyneuropathy is severe. Autonomic involvement may contribute to the high mortality rates associated with alcoholism. Despite this observation, routine autonomic examination is not usually performed with high alcohol consumption. According to Thuluvath et al., the autonomic neuropathy appears unrelated to the toxic effects of chronic alcohol use because cross-sectional studies have shown an equal prevalence of autonomic neuropathy in alcohol and nonalcohol-related liver disease. Child–Turcotte–Pugh (CTP) scoring has been adopted widely for risk stratifying in patients with cirrhosis and 5-year survival rates for patients with alcoholic cirrhosis decrease dramatically as the CTP class becomes higher at the time of clinical presentation. Considering the high prevalence of liver disease of various etiologies in Manipur, especially alcoholic and viral (hepatitis B and hepatitis C) and lack of studies for autonomic damage, we undertook this study to (1) find out the prevalence of autonomic dysfunction in patients with chronic alcoholic liver disease and (2) to correlate the severity of alcoholic liver disease (CTP Class A, B, C) with autonomic profile.
| Subjects and Methods|| |
Before the study, prior permission was taken from the Institute Ethical Committee, affiliated to a Tertiary care Teaching hospital in Imphal, Manipur. The study was a cross-sectional study conducted on eighty patients with chronic alcoholic liver disease of both sexes, diagnosed on the basis of a detailed history of alcohol intake, clinical examination, and relevant laboratory investigations attending Medicine outpatient Department from October 2011 to September 2013. Battery of five autonomic function tests was carried out in the Department of Physiology Research Laboratory room having a quiet ambient temperature of 20°C–3°C at the appointed day between 9 a.m. and 4 p.m. All adult alcoholics (men >40–80 g/day and women 20–40 g/day) with high alcohol intake (for 10–12 years) with ultrasonogram evidence of liver disease and abnormal liver function tests for more than 6 months were recruited for the study. Patients with dysautonomia due to other diseases (diabetes, chronic renal failure, ischemic heart disease, hypertension, long standing HIV infection), drugs and other etiologies of liver diseases (Hepatitis B, Hepatitis C and autoimmune hepatitis) were excluded from the study. Relevant laboratory investigations including complete blood count, liver function tests including liver enzymes, random blood sugar, antinuclear antibody, hepatitis B surface antigen, anti-hepatitis C virus antibody, retroviral antibody, ascitic fluid analysis, ultrasound abdomen, and upper gastrointestinal endoscopy were performed before autonomic function testing.
CTP scoring was graded as A (5–6), B (7–9), and C (10–15). AST and ALT elevation >5 times were considered statistically significant. Spontaneous bacterial peritonitis was based on the presence of >250 polymorphs in ascitic fluid analysis. Ultrasound findings were graded as fatty liver and cirrhosis. Portal hypertension was defined as portal vein diameter >13 mm on ultrasound. The presence of esophageal varices or gastric varices on upper gastrointestinal endoscopy was considered statistically significant. Autonomic function tests were carried out in the department of Physiology using the Polyrite model no. 206, Recorders and Medicare Systems, Chandigarh.
Autonomic parameters measured included (1) baseline cardiorespiratory parameters including heart rate, respiratory rate, systolic pressure, and diastolic pressure, (2) parasympathetic parameters included (a) heart rate variation to deep and slow breathing (E: I ratio), (b) heart rate response of Valsalva maneuver (Valsalva ratio [VR]), and (c) heart rate response to standing (30:15 ratio), and (3) sympathetic parameters included (a) blood pressure response to postural change and (b) blood pressure response to sustained isometric handgrip.
E: I ratio was calculated as the ratio of maximum R-R interval during expiration to the minimum R-R interval during inspiration. VR was calculated as longest R-R interval after the maneuver (phase IV) to the shortest R-R interval during the maneuver (phase II) 30:15 ratio was calculated as the ratio of the longest R-R around the 30th beat after standing to the shortest R-R interval around the 15th beat after standing (Reference values). Blood pressure response to postural changes was graded as normal - 10 mmHg or less, borderline - 11–29 mm Hg, and abnormal - 30 mmHg or more. Blood pressure response to sustained isometric hand grip was graded as normal - 16 mmHg, borderline - 11–15 mm Hg, and abnormal - 10 mmHg or less.
Autonomic neuropathy was graded based on the severity of damage as (1) normal - all 5 tests result normal or one borderline, (2) early involvement - 1 of the 3 heart rate tests abnormal and one borderline, (3) definite - 2 or more heart rate tests abnormal, (4) severe involvement - 2 or more heart rate tests abnormal with one or more blood pressure abnormal, (5) atypical - when it does not correspond to the above.
The data were processed through SPSS (Statistical Package for Social Sciences, version 20, IBM Corp, 2012). Chi square test and Fisher's exact test were used as tests of significance for finding if there was any correlation between the severity of liver disease (CTP Class A, B, and C) and autonomic neuropathy (presence or absence of autonomic dysfunction). P < 0.05 was considered to be statistically significant.
| Results|| |
Autonomic function tests were carried out on eighty patients and autonomic dysfunction was observed in 58 (72.5%) patients. Early autonomic involvement was found in 30 (37.5%), definite involvement in 10 (12.5%), severe involvement in 18 (22.5%) while normal autonomic function was documented in the remaining 22 (27.5%) patients. Parasympathetic involvement was noticed in 58 (100%) patients with autonomic neuropathy and abnormal sympathetic function was observed in 18 (33.3%). Heart rate response to standing (30:15 ratio) was the most altered parasympathetic test in 39 (67.2%) followed by heart rate response of Valsalva maneuver (VR) in 32 (55.2%) and heart rate variation to deep and slow breathing (E: I) in 29 (50%). Mean age of the study population was 46.16 ± 9.70 years. Males predominated the study population with 79 (98.8%) while only 1 (1.2%) female was included in the study. In the study population, normal body mass index (18.5–22.9) was observed in 40 (50%), <18.5 in 13 (16.3%), overweight (23–24.9) in 13 (16.3%), obese I (25–29.9) in 14 (17.5%), and obese II (>30) in none (0%). Smokers constituted only 23 (28.8%) of the study population. Mean alcohol intake was 762.5 ± 458.90 ml/day. Mean duration of alcohol intake was 12.06 ± 7.46 years. None of the participants had diabetes mellitus, hypertension, chronic kidney disease, or HIV infection.
Among autonomic symptoms, generalized weakness was most common in 63 (78.8%) followed by dizziness in 56 (70%), vasomotor symptoms in 52 (65%), and palpitation in 45 (56.3%). Mean resting heart rate of the study group was 87.62 ± 15.15 beats/min. Mean resting systolic blood pressure was 116.72 ± 17.38 mm Hg. Mean resting diastolic blood pressure was 78.6 ± 10.28 mm Hg. Anemia was observed in 55 (68.8%) of the study population. Anemia was graded into mild (9.5–13 g/dL), moderate (8–9.4 g/dL), and severe (<8 g/dL). Mild anemia was observed in 21 (26.3%), moderate in 26 (32.5%), and severe in 8 (10%). Leukocytosis (high total leukocyte >10,000) was found in 14 (17.5%). Thrombocytopenia (platelet count <1.5 lakh) was observed in 23 (28.8%).
Liver disease severity was graded into CTP Class A, B, and C. Study subjects were divided into Class A 26 (32.5%), Class B 19 (23.8%), and Class C 35 (43.7%). Significant rise in serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) (more than 5 times upper limit of normal) was found in 11 (13.8%) and 3 (3.8%), respectively. Spontaneous bacterial peritonitis was observed in 7 (8.8%) of the study population. Ultrasound findings were graded as either fatty liver or cirrhosis. Fatty liver was observed in 42 (52.5%) and cirrhosis in 38 (47.5%). Portal hypertension on ultrasound was found in 49 (61.3%). On upper gastrointestinal endoscopy, grade 1 or 2 varices were observed in 29 (36.25%) and grade 3 or 4 varices in 12 (15%).
Among the parasympathetic tests, mean E: I (heart rate response to deep breathing) was 1.10 ± 0.07, mean VR (heart rate response to Valsalva maneuver) was 1.27 ± 0.23, and mean 30:15 (heart rate response to standing) was 1.10 ± 0.10. Out of the two sympathetic tests performed, mean Δ DBP obtained after sustained handgrip for 4 min was 14.67 ± 10.48 mm Hg and mean Δ SBP (fall in blood pressure at 0.5 min of standing) was 8.78 ± 8.33 mm Hg. Autonomic neuropathy was graded into normal, early, definite, severe, or atypical. Normal autonomic function was observed in 22 (27.5%), early in 30 (37.5%), definite in 10 (12.5%), and severe in 18 (22.5%).
Correlation between CTP scoring and the severity of autonomic dysfunction was found to be statistically significant with a P = 0.000 [Figure 1]. Severe autonomic neuropathy was only seen in decompensated liver disease and as the severity of liver disease increases, incidence of autonomic neuropathy was also higher. This difference was statistically significant with a P = 0.000. All patients with thrombocytopenia (defined as platelet count <1.5 lakh) had autonomic neuropathy when compared to patients with normal platelet count (≥1.5 lakh) and the difference was statistically significant with P = 0.000 [Figure 2]. Autonomic neuropathy was present in 89.5% (34 of 38) of patients with cirrhosis as compared to 57.1% (24 of 42) patients without cirrhosis. This difference was statistically significant with a P = 0.001 [Figure 3]. Among 41 patients with varices on endoscopy, 36 (87.8%) had autonomic neuropathy when compared with 22 (56.4%) among 39 patients who did not have varices and it was statistically significant with P = 0.02 [Figure 4]. Among 49 patients who had portal hypertension on ultrasound, 44 (89.8%) had autonomic neuropathy when compared with 14 (45.2%) among 31 patients who had no portal hypertension and it was statistically significant with P = 0.000 [Figure 5]. Association of other parameters such as age (P = 0.139), total leukocyte count (P = 0.328), SGOT (P = 0.270), SGPT (P = 0.557), spontaneous bacterial peritonitis (P = 0.181), and generalized weakness (P = 0.220) with autonomic neuropathy was not significant.
|Figure 1: Bar chart showing the prevalence and correlation of autonomic neuropathy with Child–Turcotte–Pugh Scoring (A, B, C)|
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|Figure 2: Bar chart showing the correlation of autonomic dysfunction with platelet count|
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|Figure 3: Bar chart showing the correlation of ultrasound findings with autonomic dysfunction|
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|Figure 4: Bar chart showing the correlation of endoscopy findings with autonomic dysfunction|
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|Figure 5: Bar chart showing the correlation of portal hypertension (on ultrasound) with autonomic dysfunction|
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| Discussion|| |
Our study aimed at studying the involvement of autonomic nervous system in different spectrum of alcoholic liver disease based on the CTP score (Class A, B, and C). Only few Indian studies regarding this subject have been published.,,, Similar study has not been conducted in Manipur population before. However, the prevalence of autonomic dysfunction in cirrhosis of various etiologies has been studied by Bikramjitet al. which showed a prevalence of 92% autonomic dysfunction.
In our study, maximum cases were in the age group of 41–50 years with 25 cases (38.75%) followed by 51–60 years with 22 cases (27.5%). Mean age of the study population was 46.16 ± 9.70 years. These data are comparable with previous studies by Joye Varghese et al. where the mean age was 39.64 ± 10.6 years for males. Males predominated our study group 79 (98.75%), with only one case being female (1.25%). Older patients (>40 years) appeared to have more autonomic dysfunction (44 [77.2%] vs. 14 [60.9%]) compared to patients with age <40 years. However, the difference was not statistically significant.
In our study, autonomic dysfunction was documented in 72.5% of patients. The data are similar to Bajaj et al. who studied autonomic function in hepatic cirrhosis with 80% autonomic involvement. In their study, only one patient belonged to CTP class A while the rest were Class B or C. Comparatively less autonomic involvement in our case might be due to the inclusion of more patients with CTP Class A in our study population. In the present study, parasympathetic involvement was predominant in 58 (100%) patients, while 18 (33%) had combined parasympathetic and sympathetic involvement. Hendrickse et al. in a study reported vagal neuropathy in 45% of the sixty patients with chronic liver disease. The lower frequency of neuropathy is probably due to inclusion of mostly CTP Class A patients in their study (57 of the sixty patients). In our study, 32% patients belonged to Class A, 24% patients belonged to Class B, and 44% belonged to Class C. Gentileet al. found autonomic neuropathy in 60% (71% in the alcoholic group and 57% in the nonalcoholic group) of the 113 cirrhotics studied. Similar to the present study, alteration of parasympathetic function was significantly more frequent than that of sympathetic function.
In the present study, impaired autonomic function was seen in 38.5%, 89.5%, and 88.6% of patients belonging to CTP Class A, B, and C, respectively. Severe autonomic neuropathy was documented in 0 (0%) in Class A, 7 (36.9%) in Class B, and 11 (31.4%) in Class C. There was a positive correlation between increasing CTP class and the severity of autonomic neuropathy (P < 0.001) in our study. These findings indicate the increasing frequency of autonomic dysfunction with increasing severity of liver damage as were reported in similar studies., Hendrickse and Triger reported a strong correlation between the abnormal tests and CTP score (P < 0.0001). In their study, they found autonomic neuropathy in 69% of CTP Class B and C patients and 23% in Class A patients (P < 0.0001). On the contrary, Gonzalez-Reimeret al. in their study of 33 alcoholics, 20 of them cirrhotics found a weak correlation between liver function and both autonomic and peripheral neuropathy.
In our study, the variables related to liver disease severity that correlated with autonomic neuropathy significantly were low-platelet count (P = 0.000), CTP score (P = 0.000), presence of cirrhosis on ultrasound (P = 0.001), portal hypertension on ultrasound (P = 0.000), and presence of varices on upper gastrointestinal endoscopy (P = 0.02). Thrombocytopenia, cirrhosis, portal hypertension, and varices are directly related to the duration and severity of liver disease, thus can predict the occurrence of autonomic neuropathy in similar populations. Meanwhile total leukocyte count (P = 0.328), the rise in liver enzymes (SGOT [P = 0.270] and SGPT [P = 0.557]), spontaneous bacterial peritonitis (P = 0.181), and autonomic symptoms (P = 0.220) correlated poorly with the autonomic neuropathy.
In our study, heart rate response to standing (30:15) was the most altered test in 39 (67.2%) followed by heart rate response to Valsalva maneuver in 32 (55.2%) and heart rate response to deep breathing (E: I) in 29 (50%). Bajaj et al. also reported that the most frequent abnormal test was heart rate response to standing (11 out of 20 patients). Similar reports were published by Barter and Tanner as well as Gentileet al. while Thuluvath and Triger in their study reported the heart rate response to deep breathing as the most sensitive test. However, it is noteworthy that deep breathing test depends on the cooperation of the subject and is thus not as reproducible as the heart rate response to standing. Gentileet al. remarked that deep breathing test and handgrip tests are the tests most influenced by the compliance of the patient.
In our study, varices were demonstrated on endoscopy in 41 (51.25%) patients. Among this subgroup of 41 patients with varices, 36 (87.8%) patients with varices showed autonomic neuropathy compared to 22 (56.4%) among 39 patients who did not have varices and this difference was statistically significant (P = 0.02). Sympathetic underactivity was the most likely factor for splanchnic pooling, predisposing the patients to a high risk of variceal bleed, and also for failed endoscopic and pharmacotherapy. Thus, autonomic nervous system function tests during the initial evaluation of patients with cirrhosis of liver can predict the outcome of variceal bleed apart from CTP grading and higher grades of varices.
| Conclusions|| |
Detection of this subset of patients with autonomic dysfunction in alcoholic liver disease identifies a high-risk group which needs more stringent management. Hence, autonomic function testing should be a part of routine workup for liver disease in the future and preference should be given to this high-risk population for early intervention.
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Conflicts of interest
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| References|| |
Schuckit MA. Alcohol and alcoholism. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison's Principle of Internal Medicine. 17th
ed. Vol. 2. New York: McGraw Hill; 2008. p. 2724-9.
International Institute for Population Sciences (IIPS) and Macro International. National Family Health Survey (NFHS-3), India, 2005-2006: Manipur, Mumbai: IIPS; 2008. Available from: http://www.nfhsindia.org/manipur_report.shtml
. [Last accessed on 2011 Aug 21].
Monforte R, Estruch R, Valls-Solé J, Nicolás J, Villalta J, Urbano-Marquez A. Autonomic and peripheral neuropathies in patients with chronic alcoholism. A dose-related toxic effect of alcohol. Arch Neurol 1995;52:45-51.
Thuluvath PJ, Triger DR. Autonomic neuropathy in chronic liver disease. Q J Med 1989;72:737-47.
Carithers RL Jr., McClain CJ. Alcoholic liver disease. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 9th
ed. Philadelphia: Saunders Elsevier; 2010. p. 1383-400.
Punyabati O, Deepak KK, Sharma MP, Dwivedi SN. Autonomic nervous system reactivity in irritable bowel syndrome. Indian J Gastroenterol 2000;19:122-5.
Wieling W, Karemaker JM. Measurement of heart rate and blood pressure to evaluate disturbances in neurocardiovascular control. In: Mathias CJ, Bannister R, editors. Autonomic Failure. 4th
ed. Oxford: Oxford University Press; 1999. p. 196-210.
Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J (Clin Res Ed) 1982;285:916-8.
Khosla SN, Sanyal S, Nand N. Autonomic function tests and clinical significance of dysautonomia in chronic liver disease. J Assoc Physicians India 1991;39:924-6.
Bajaj BK, Agarwal MP, Ram BK. Autonomic neuropathy in patients with hepatic cirrhosis. Postgrad Med J 2003;79:408-11.
Bikramjit Singh RK, Robinson N, Devi SB, Devi MR, Romeo Singh K, Devi D. Autonomic dysfunction in hepatic cirrhosis. Indian Med J 2006;100:161-4.
Singh G, Singh K, Manchanda KC, Sharma RC. Assessment of autonomic nervous activity in chronic liver disease. Biomed Res 2011;22:85-9.
Joye Varghese S, Balan N, Naveen B, Caroline Selvi K, Jayapalan K, Jayanthi V. Does autonomic dysfunction in cirrhosis liver influence variceal bleed? Ann Hepatol 2007;6:104-7.
Hendrickse MT, Thuluvath PJ, Triger DR. Natural history of autonomic neuropathy in chronic liver disease. Lancet 1992;339:1462-4.
Gentile S, Marmo R, Peduto A, Montella F, Coltorti M. Autonomic neuropathy in liver cirrhosis: Relationship with alcoholic aetiology and severity of the disease. Ital J Gastroenterol 1994;26:53-8.
Chaudhry V, Corse AM, O'Brian R, Cornblath DR, Klein AS, Thuluvath PJ. Autonomic and peripheral (sensorimotor) neuropathy in chronic liver disease: A clinical and electrophysiologic study. Hepatology 1999;29:1698-703.
Fawi GH, Khalifa GA, Abo Dahab LH. Autonomic and peripheral neuropathies in chronic liver diseases: Clinical and Neurophysiological study. Egypt J Neurol Psychiatry Neurosurg 2005;42:187-200.
Hendrickse MT, Triger DR. Autonomic dysfunction and hepatic function in chronic liver disease. Gut1990;31:1164.
Gonzalez-Reimers E, Alonso-Socas M, Santolaria-Fernandez F, Hernandez-Peña J, Conde-Martel A, Rodriguez-Moreno F. Autonomic and peripheral neuropathy in chronic alcoholic liver disease. Drug Alcohol Depend 1991;27:219-22.
Barter F, Tanner AR. Autonomic neuropathy in an alcoholic population. Postgrad Med J 1987;63:1033-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]