|Year : 2014 | Volume
| Issue : 2 | Page : 296-300
Study of the relation between diabetes mellitus and hepatic encephalopathy in patients with liver cirrhosis
Atef Abo El Soud Ali1, Hossam Ibrahim Mohamed1, Eman Abdel Fatah Badr2, Mohamed Abdel Moneim Mohamed1
1 Department of Tropical Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Medical Biochemistry, Menoufiya University, Menoufiya, Egypt
|Date of Submission||07-May-2013|
|Date of Acceptance||01-Oct-2013|
|Date of Web Publication||26-Sep-2014|
Hossam Ibrahim Mohamed
Tropical Medicine Department, Menoufiya University, Menoufiya
Source of Support: None, Conflict of Interest: None
This study was designed to determine the role of diabetes mellitus (DM) in the pathogenesis of hepatic encephalopathy (HE) in patients with liver cirrhosis.
DM and its complications may play a role in the mortality of hepatitis C virus (HCV)-related cirrhotic patients. DM is considered a comorbid disease in these patients and strict control of blood glucose level could improve survival in HCV-related cirrhosis.
Patients and methods
This study was carried out on 100 cirrhotic patients with DM [50 encephalopathic patients (group I) and 50 nonencephalopathic patients (group II)]. All patients in the study were subjected to a thorough assessment of history taking and thorough physical examination, laboratory investigations, including complete blood picture, liver function tests, liver, viral HBsAg and HCVAb, kidney function tests, serum sodium and potassium levels, abdominal ultrasonography, serum ammonia level, fasting and postprandial blood sugar levels, glycosylated hemoglobin (HbA1c) as well as tests to detect the presence of autonomic neuropathy (tilt-table test and diurnal variation of blood pressure measurements).
The present study found a significant positive tilt-table test result and diurnal variation in blood pressure measurements in the encephalopathic group in comparison with the nonencephalopathic group, and a highly significant positive correlation between duration of DM and HbA1c levels when compared with grades of HE in the encephalopathic group.
Cirrhotic patients with longstanding and uncontrolled DM are more likely to have higher grades of HE. Autonomic neuropathy, which may complicate cirrhotic patients with longstanding uncontrolled diabetes, may play a role in the pathogenesis of HE in these patients.
Keywords: Autonomic neuropath, diabetes mellitus, hepatitis C virus liver cirrhosis, hepatic encephalopathy
|How to cite this article:|
El Soud Ali AA, Mohamed HI, Badr EA, Mohamed MA. Study of the relation between diabetes mellitus and hepatic encephalopathy in patients with liver cirrhosis. Menoufia Med J 2014;27:296-300
|How to cite this URL:|
El Soud Ali AA, Mohamed HI, Badr EA, Mohamed MA. Study of the relation between diabetes mellitus and hepatic encephalopathy in patients with liver cirrhosis. Menoufia Med J [serial online] 2014 [cited 2020 Feb 24];27:296-300. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/296/141679
| Introduction|| |
Diabetes mellitus (DM) is very common in the cirrhotic population and it is more prevalent in patients with cirrhosis because of hepatitis C virus (HCV) than in those with cirrhosis because of other etiologic agents. Moreover, basal insulin values are higher in these patients, which could be explained by an increase in insulin resistance associated with an increase in iron deposits .
Hepatic encephalopathy (HE) in patients with hepatic insufficiency reflects the existence of a spectrum of neuropsychiatric manifestations related to a range of pathophysiological mechanisms. The most accepted theory of the pathogenesis of HE is that nitrogenous substances derived from the gut adversely affect brain function. These compounds gain access to the systemic circulation as a result of decreased hepatic function or portal-systemic shunts .
There are many factors that precipitate HE in patients with cirrhosis including constipation, gastrointestinal bleeding, dietary protein overload, electrolyte abnormalities, medications, and infections. HE is reversible in this situation when the precipitating factors are eliminated or corrected. The presence of DM may be another factor in the pathogenesis of HE, at least in patients with HCV cirrhosis .
| Objective|| |
The aim of the present study was to determine the presence of autonomic neuropathy in diabetic patients with liver cirrhosis and its role in the pathogenesis of HE in these patients.
| Patients and methods|| |
This study was carried out on 100 cirrhotic patients with DM recruited from the Inpatients Department of Shebin El Koum Fever Hospital during the period from October 2010 to August 2011. There were 60 men and 40 women; their age ranged from 25 to 65 years, mean age 50.4 ± 6.8 years. They were categorized into two groups according to the presence or absence of HE: group I that included 50 cirrhotic diabetic patients with HE and group II that included 50 cirrhotic diabetic patients without HE.
Patients with evident neurotic or psychiatric disorders, cardiopulmonary, renal, and endocrinal diseases, as well as patients who were taking benzodiazepines, narcotics, or other agents that could alter gastrointestinal motility were excluded from the present study. All patients were enrolled during the same period and provided consent to participate in the study, which was approved by the Investigations and Ethics Committee of the Faculty.
All patients were subjected to the following:
Thorough assessment of history and physical examination, laboratory investigations including complete blood picture, fasting and postprandial blood sugar, glycosylated hemoglobin (HbA1c), HBsAg and HCVAb, alanine transaminase, aspartate aminotransferase, serum albumin level, total and direct serum bilirubin, prothrombin concentration, blood urea and serum creatinine, serum sodium and potassium levels, serum ammonia level, abdominal ultrasonography, and applicable tests to detect autonomic neuropathy including:
(1) Testing for abnormalities of blood pressure (BP) regulation: BP was recorded from each individual about three times a day at 7-10 a.m., 2-3 p.m., and 7-9 p.m. The mean BP was calculated from the values of systolic and diastolic BP. The test was positive if the diurnal variation of BP was more than 15 mmHg  or if there was postural decrease of systolic BP more than 20 mmHg with presyncopal symptoms .
(2) Tilt-table test : Patients were strapped in a supine position to a tilt table. They were instrumented with a pulse oximeter and leads to monitor BP and heart rate. BP and pulse were recorded every minute for 5 min. Next, the patient was tilted 70°, head-up, and recording was continued for another 25 min. The test was terminated if there was syncope (fainting), a marked decrease in BP, a marked increase in pulse (especially above 160), chest pain or chest discomfort, nausea, and dyspnea. The criteria for a positive test include:
- heart rate × BP ≤9000 mmHg/min, for example, a BP of 100 and a pulse of 90;
- syncope or near syncope; and
- heart rate or BP decrease correlating with symptoms.
Results were collected, tabulated, and statistically analyzed using an IBM personal computer and statistical package SPSS (version 16; SPSS Inc., Chicago, Illinois, USA). Two types of statistics were determined .
| Results|| |
Obvious precipitating factors for HE were not recognized in 30% of group I patients [Table 1].
|Table 1: Grades, recurrence, and precipitating factors for hepatic encephalopathy in group I|
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There was no significant difference between the studied groups in liver function tests [Table 2].
The increase in the mean value of serum ammonia level in group I was significant compared with group II [Table 3].
There was a highly significant increase in blood sugar, HbA1c, and duration of DM in group I patients [Table 4].
Positive tilt-table test and positive diurnal variation of BP measurement (>15 mmHg diurnal variation or postural decrease of systolic BP>20 mmHg with presyncopal symptoms) were highly significant in group I patients [Table 5].
|Table 5: Tilt-table test and diurnal variation in blood pressure measurement in the studied groups|
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There was a highly significant positive correlation between duration of DM as well as HbA1c levels compared with grades of HE in the patients in group I [Table 6].
|Table 6: Spearman correlation between duration of diabetes mellitus and HbA1c levels with grade of hepatic encephalopathy among the patients in group I|
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| Discussion|| |
The present study showed that serum ammonia level was increased above the normal reference range, with a significant difference between the groups studied. This finding supported the accepted role of hyperammonemia in the pathogenesis of HE. Rose et al.  reported that ammonia exerts various potential direct and indirect toxic effects by interfering with inhibitory and excitatory neurotransmitter systems, resulting in adverse effects on consciousness and behavior. Moreover, Kruczek et al.  reported that ammonia plays a major role in the pathogenesis of HE and affects astrocyte function by triggering a self-amplifying cycle between osmotic and oxidative stress. The authors showed that hypo-osmotic astrocyte swelling rapidly stimulates nitric oxide production and increases intracellular free zinc concentration. One argument against the ammonia hypothesis is the observation that ~10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without encephalopathy. Also, ammonia does not induce the classic electroencephalographic changes associated with HE when it is administered to patients with cirrhosis .
The present study found a highly significant increase in fasting and postprandial blood sugar levels, HbA1c, and duration of DM in encephalopathic group in comparison with the other group. The present study also showed that autonomic neuropathy was significantly higher in group I patients as evidenced by a significant increase in the number of patients with a positive tilt-table test and a positive diurnal variation in BP measurement compared with the patients in group II. These results are in agreement with those of previous studies. Nathan et al.  reported that a high HbA1c (as an indicator for poor glucose control) increases the risk for the long-term vascular complications of DM. The endothelial cells lining the blood vessels take in more glucose than normal. They then form more surface glycoproteins than normal, and cause the basement membrane to grow thicker and weaker. Poor blood glucose control also increases the risk of short-term complications such as poor wound healing . Nathan et al.  reported that about 60-70% of patients with DM have some form of neuropathy. Patients with DM can develop nerve problems at any time, but the risk increases with age and longer duration of DM, presence of hypertension, obesity, or dislipidemia. It has been discovered that the serum of diabetics with neuropathy is toxic to nerves even if the blood sugar content is normal . Autonomic neuropathy affects the autonomic neurons of either or both of the parasympathetic and sympathetic nervous systems, and may occur in patients with poor control of DM. They are usually accompanied by somatic neuropathy but can be autonomic only . Diabetic autonomic neuropathy has a negative impact on the survival and quality of life of patients with DM. It is manifested by dysfunction of one or more organ systems .
Gastrointestinal problems in DM are common, but not commonly recognized in clinical practice. The duration of DM and the degree of glycemic control are major determinants in the incidence and severity of gastrointestinal problems. The entire gastrointestinal tract can be affected, leading to a variable symptom complex . Constipation is the most common gastrointestinal complication, affecting almost 60% of diabetic patients. This is believed to be because of diabetic autonomic neuropathy . Gastroparesis and small intestinal motility are real complications with short-term and long-term poor control of blood glucose, as evidenced by positive parasympathetic tests, and their frequency increases markedly with time . Previous studies have clearly shown that, in addition to autonomic neuropathy, acute metabolic derangements are likely to contribute toward disturbed motility . However, Töyry et al.  suggested that a high insulin level seems to play a predictive role in the development of parasympathetic autonomic neuropathy irrespective of obesity and glycemia.
The present study found a highly significant positive correlation between duration of DM and grade of encephalopathy as well as HbA1c and grade of encephalopathy in group I patients. These findings may suggest that autonomic neuropathy may be related to the development of HE in cirrhotic patients with longstanding uncontrolled DM. These results are in agreement with previous studies. Thuluvath  has been suggested that DM may contribute toward the presence and severity of HE independent of the severity of liver disease in patients with HCV cirrhosis. The author hypothesized that patients with autonomic neuropathy are more likely to develop HE because of prolonged intestinal transit time, resulting in small bowel bacterial overgrowth, hyperammonemia, and endotoxemia. Nutritional status, insulin resistance, and DM have been reported to affect cognition in patients with HCV cirrhosis awaiting liver transplantation and might be implicated in the pathogenesis of HE in these patients .
A previous study carried out by Kwon et al.  found that the frequency of nonhepatic causes of mortality was higher in the diabetic group with HCV cirrhosis and complications of DM may play a role in the mortality in these patients. Moreover, El-Serag et al.  suggested that DM is an unfavorable factor for the long-term prognosis of patients with cirrhosis without esophageal varices, diabetic patients dying more often as a result of liver failure than nondiabetic patients. Furthermore, DM has been identified as a risk factor of chronic liver disease or liver-related mortality. However, Holstein et al.  found that 51% of patients with hepatogenous DM died within a mean period of 5.6 years after histological diagnosis as a result of complications of liver cirrhosis; none died as a result of diabetic sequelae, suggesting that the short-term and medium-term prognosis of patients with cirrhosis and hepatogenous DM is determined by the primary hepatic disease and its complications.
Optimization of diabetic metabolic conditions is not only important to avoid typical diabetic late complications but also cirrhosis-associated complications, for example, gastrointestinal bleeding, HE, or the occurrence of hepatocellular carcinoma. Moreover, improving glycemic control would ameliorate any reversible effects on autonomic function, thus decreasing the incidence of HE .
| Conclusion|| |
There is a highly significant positive correlation between DM (duration and poor control) and grades of HE in patients with liver cirrhosis. Patients with longstanding and uncontrolled DM are more likely to have higher grades of HE. Autonomic neuropathy (evidenced by a positive tilt-table test and/or a positive diurnal variation in BP measurement), which may be a complication in cirrhotic patients with longstanding uncontrolled DM, may play a role in the pathogenesis of HE in these patients.
Health education should be provided on preventive measures (diet control, weight reduction, and suitable physical exercises), early detection, and good control of DM in patients with liver cirrhosis to prevent or delay the complications of DM in these patients. Strict follow-up should be performed of cirrhotic patients with DM for early detection and adequate treatment of acute and chronic complications of DM (including autonomic neuropathy) in these patients. Future studies should be carried out on cirrhotic patients with DM to determine the exact pathogenic role of DM in the occurrence and progression of HE in these patients.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
|1.||Garrido SA, Guerrero IF, Lepe Jiménez JA. Hyperinsulinemia in cirrhotic patients infected with hepatitis C virus. Gastroenterol Hepatol 2001; 24 :127-131. |
|2.|| Riggio O, Efrati C, Catalano C. High prevalence of spontaneous portal-systemic shunts in persistent HE encephalopathy: a case-control study. Hepatology 2005; 42 :1158-1165. |
|3.|| Sigal SH, Stanca CM, Kontorinis N, Bodian C, et al. Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis. Am J Gastroenterol 2006; 101 :1490-1496. |
|4.|| Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc 2007; 82 :308-313. |
|5.|| Gehrking JA, Hines SM, Benrud-Larson LM, et al. What is the minimum duration of head-up tilt necessary to detect orthostatic hypotension? Clin Auton Res 2005; 15 :71-75. |
|6.|| Brignole M, Menozzi C, et al. New classification of heamodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of pre-syncope phase of the tilt test without and with nitroglycerine challenge. Vasovagal syncope international study. Europace 2000; 2 :66-67. |
|7.|| Lind DM, Marchal WG, Wathen SA. Statistical techniques in business and economics. 12th ed. McGraw-Hill Irwin Publication; 2005. |
|8.|| Rose C, Kresse W, Kettenmann H. Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J Biol Chem 2005; 280 :20937-20944. |
|9.|| Kruczek C, Görg B, Keitel V, Bidmon HJ, et al. Ammonia increases nitric oxide, free Zn(2+), and metallothionein mRNA expression in cultured rat astrocytes. Biol Chem 2011; 392 :1155-1165. |
|10.||Cordoba J, Blei A. Hepatic encephalopathy. Diseases of the liver. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2007. 569-599. |
|11.||Nathan DM, Kuenen J, Borg R, Zheng H, et al. Translating the A1C assay into estimated average glucose values. Diabetes Care 2008; 31 : 1473-1478. |
|12.||Rich SS. Genetics of diabetes and its complications. J Am Soc Nephrol 2006; 17 :353-360. |
|13.||Nathan DM, Cleary PA, Backlund JY. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353 :2643-2653. |
|14.||Ichinose K, Kawasaki E, Eguchi K. Recent advancement of understanding pathogenesis of type 1 diabetes and potential relevance to diabetic nephropathy. Am J Nephrol 2007; 27 :554-564. |
|15.||Low PA. Laboratory evaluation of autonomic function. Suppl Clin Neurophysiol 2004; 57 :358-368. |
|16.||Boulton AJ, Vinik AI, Arezzo JC, Bril V, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28 :956-962. |
|17.||Wolosin JD, Edelman SV. Diabetes and the gastrointestinal tract. Clin Diabet 2000; 18 . |
|18.||Vinik AI, Erbas T. Recognizing and treating diabetic autonomic neuropathy. Cleve Clin J Med 2001; 68 :928-930, 932, 934-944. |
|19.||Moldovan C, Dumitrascu DL, Demian L, Brisc C, et al. Gastroparesis in diabetes mellitus: an ultrasonographic study. Rom J Gastroenterol 2005; 14 :19-22. |
|20.||Abrahamsson H, Andersson S, Ringström G, Elfvin A, et al. Temporary percutaneous gastric electrical stimulation (GES). A new technique to test response to GES. Neurogastroenterol Motil 2009; 18 :668. |
|21.||Töyry JP, Niskanen LK, Mäntysaari MJ, Länsimies EA. Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM. Ten-year follow-up from the diagnosis. Diabetes 2001; 45 :308-315. |
|22.||Thuluvath PJ. Higher prevalence and severity of hepatic encephalopathy in patients with HCV cirrhosis and diabetes mellitus: is presence of autonomic neuropathy the missing part of the puzzle? Am J Gastroenterol 2006; 101 :2244-2246. |
|23.||Kalaitzakis E, Olsson R, Henfridsson P, Hugosson I, et al. Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis. Liver Int 2007; 27 :1194-1201. |
|24.||Kwon SY, Kim SS, Kwon OS, Kwon KA, et al. Prognostic significance of glycaemic control in patients with HBV and HCV-related cirrhosis and diabetes mellitus. Diabet Med 2005; 22 :1530-1535. |
|25.||El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126:460-468. |
|26.||Holstein A, Hinze S, Thiessen E. Clinical implications of hepatogenous diabetes in liver cirrhosis. J Gastroenterol Hepatol 2002; 17 :677-681. |
|27.||Gundling F, Schumm-Draeger PM, Schepp W. Hepatogenousdiabetes - diagnostics and treatment. J Gastroenterol 2009; 4:436-445. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]