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Oesophageal dysmotility in diabetic patients with varices
Arab Journal of Gastroenterology 11 (2010) 192–196
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Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original Article
Oesophageal dysmotility in diabetic patients with varices Ayman Eldesoky ⇑, Afaf Abd El-Hafez 1 Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Dakahliya, Egypt
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Article history: Received 13 July 2010 Accepted 13 September 2010
Keywords: Oesophageal motility Diabetes mellitus Portal hypertension
a b s t r a c t Background and study aims: Complications involving the gastrointestinal tract are important causes of morbidity in cirrhotic patients with diabetes mellitus. Our aim was to study the possible influences of varices on oesophageal motility in diabetic patients. Patients and methods: A total of 40 diabetic patients were recruited into two groups: group 1: 19 patients without varices; group 2: 21 patients with varices. Twenty healthy volunteers were selected as control. Oesophageal manometry was performed for patients and control subjects. Results: In comparison to control subjects, group 1 had lower residual pressure with incomplete relaxation of the lower oesophageal sphincter (LES) (p 6 0.001 and 0.005), longer wave duration and lower velocity in the distal oesophagus (p = 0.014 and 0.028) and lower wave velocity in the proximal oesophagus (<0.001); group 2 had lower resting and residual pressures with incomplete LES relaxation (p = 0.01, <0.001 and <0.001, respectively), lower wave amplitude, longer duration and lower velocity in the distal oesophagus (p = 0.002, 0.004 and <0.001), lower wave amplitude and lower velocity in the proximal oesophagus (all p < 0.001) and more frequent abnormal waves (p = 0.005). Lastly, group 2 had lower resting LES pressure than group 1 patients (p = 0.042). Conclusion: Among patients with diabetes and varices, changes in oesophageal motility are common but, with the exception of lower oesophageal sphincter hypotension, are related to diabetes rather than to the presence of varices. Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction The prevalence of gastrointestinal (GI) symptoms is reported to be higher in patients with diabetes mellitus (DM) than in the general population [1]. Although not generally considered as important causes of morbidity or mortality in DM patients, these symptoms can influence health-related quality of life and affect productivity and employment status [2,3]. Oesophageal manifestations of diabetic neuropathy, including abnormal peristalsis, spontaneous contractions and impaired lower oesophageal sphincter (LES) tone, result in heartburn and dysphagia [4,5]. The relationship between hyperglycaemia and dysmotility is not well established. Although many patients may have objective evidence of oesophageal dysmotility or reflux, symptoms only occur in a minority of patients with diabetes [6]. Viral hepatitis B and C (HBV and HCV) are established causes of chronic liver diseases and seem to occur more frequently in diabetics than in the general population. This association may reflect epidemiological circumstances because of the frequent parenteral exposures of diabetics [7]. On the other hand, the hepatitis viruses, ⇑ Corresponding author. Tel.: +20 50 2540609/9802279, mobile: +20 125147601. 1
E-mail address: [email protected] (A. Eldesoky). Tel.: +20 50 2536964.
particularly HCV, can affect not only the liver but also several tissues outside the liver, resulting in a wide spectrum of extrahepatic manifestations and morbid conditions to which DM has been included [8]. Among patients with HCV infection, older age, obesity, severe liver fibrosis and family history of diabetes are associated with the development of diabetes [9]. Abnormal gastro-oesophageal reflux was found in 37% of the patients with hepatic cirrhosis and oesophageal varices. Only typical gastro-oesophageal reflux disease symptoms predicted these findings [10]. The exact pathogenesis is still poorly defined; however, both reduction in the number and degeneration of ganglion cells at the Auerbach’s plexus were described in the oesophagus of cirrhotic patients with large varices, and these changes may contribute to the development of impaired motility of the oesophagus with large varices [11]. Furthermore, endoscopic sclerotherapy causes persistent manometric abnormalities and chronic inflammatory changes in the distal oesophagus, the severity of which seems to vary directly with the frequency of sclerotherapy and not the amount of the sclerosant injected [12]. Furthermore, variceal ligation causes alterations in oesophageal motility in the form of an increase in the amplitude and duration of the contractile waves [13]. In this work, we intended = to study the possible effects of varices on oesophageal motility parameters in diabetic patients.
1687-1979/$ - see front matter Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ajg.2010.09.003
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Patients and methods
Table 1 The scoring system of Ewing et al. for autonomic function tests [14].
Patients Inclusion criteria Forty adult patients were selected from those attending Mansoura Specialized Medical Hospital for management of either DM or chronic liver disease in the period between May 2008 and September 2009. Further, 20 age- and sex-matched healthy subjects were selected on a voluntary basis as the control group. The selected patients were classified into:
0 1 2
Exclusion criteria Patients with cerebrovascular accident, acute myocardial infarction, those on nasogastric feeding, haemodynamically unstable and who had oesophageal surgery were excluded from the study. Furthermore, non-compliant patients, patients with other systemic diseases such as endocrinal, cardiac, neurological, pulmonary disease, scleroderma and patients with therapies known to affect the GI motility were excluded. Methods 1. Medical history including the age, gender, duration of disease, height, weight and calculated body mass index (BMI). Symptoms related to the oesophagus (i.e. dysphagia, heartburn, regurgitation and retrosternal pain or any other symptoms) were evaluated and history of medications that influence oesophageal motility (prokinetic drugs, nitrates, anticholinergics, calcium channel blockers or sedatives) was also recorded. 2. Clinical examination included general examination (manifestations of DM and features of liver cirrhosis whether compensated or decompensated), local abdominal examination (for the liver, spleen and the presence or absence of ascites) and ocular fundus examination to detect retinopathy. 3. Examination for peripheral neuropathy was performed by evaluation of sensations (pinprick, touch, vibration and position sense) and reflexes (biceps, triceps, brachioradialis, knee and ankle). 4. Autonomic function tests included tests of sympathetic functions (postural hypotension and blood pressure response to sustained handgrip) and tests of parasympathetic function (heart rate response to Valsalva manoeuvre, heart rate variation during deep breathing and immediate heart rate response to standing). Definite diagnosis of autonomic neuropathy is achieved when the patient score is more than 5 according to the scoring system of Ewing et al., 1978 (Table 1) [14]. 5. Laboratory investigations included complete blood count (CBC), transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, prothrombin time (PT) and international normalised ratio (INR), and serum albumin), viral hepatitis serological markers, serum creatinine, urine examina-
D.B
S
S.H.G
P.H
>1.2 1.11–1.20 <1.10
>15 11–15 <10
>1.03 1.01–1.03 <1.10
>15 11–15 <10
<20 21–30 >31
V.R: Valsalva ratio. D.B: heart rate variation during deep breathing. S: heart rate response to standing. S.H.G: blood pressure response to sustained handgrip. P.H: postural hypotension.
group 1: 19 diabetic patients without oesophageal varices; and group 2: 21 diabetic patients with oesophageal varices. Diagnosis of DM was based on medical history and clinical examination with fasting blood glucose P 126 mg dl 1 or postprandial blood glucose P 200 mg dl 1. Diagnosis of oesophageal varices was based on upper GI endoscopy. The study protocol conformed to and was approved by the Medical Sciences Ethics Committee of Mansoura Faculty of Medicine. All the steps of the procedures were explained in detail for each patient and all the patients in both the groups gave their written informed consent.
V.R
6.
7.
8.
9.
tion for proteinuria, random blood sugar and glycosylated haemoglobin (HbA1c). Abdominal ultrasonography (with Doppler evaluation of the main portal vein, splenic vein and the hepatic veins) and electrocardiography. Barium swallow and meal were performed for diagnosis of hiatus hernia, other anatomical abnormality or evidence of reflux complications. Upper GI endoscopy was done for diagnosis of gastro-oesophageal varices and portal hypertensive gastropathy. Oesophagitis, if present, was classified according to Savary and Miller [15] into grade I, isolated erosions; grade II, confluent but not circumferential erosions; grade III, confluent and circumferential erosions; or grade IV, ulcers and stenosis. If the gastro-oesophageal junction was at least 2 cm above the diaphragmatic impression, the patient was considered to have hiatus hernia [16]. Oesophageal manometry: Following overnight fasting, an eightlumen water-perfused polyvinylchloride catheter with a 4.5mm diameter was connected to the Phoenix Mk2 computerised
Table 2 Demographic data in the studied groups. Parameters
Controls (n = 20)
Group 1 (n = 19)
Group 2 (n = 21)
p-Value
Age (years) Range Mean ± SD
20–55 39.7 ± 8.6
17–59 47.3 ± 9.2
28–56 44.8 ± 6.4
0.13
Sex M/F
13/7
11/8
14/7
0.83
Height (cm) Range Mean ± SD
151–182 167.4 ± 10.7
148–179 163.4 ± 12.3
145–177 161.7 ± 10.4
0.88
Weight (kg) Range Mean ± SD
50–86 64.5 ± 8.9
53–87 68.7 ± 9.5
46–83 62.0 ± 9.6
0.04
BMI Mean ± SD
23.2 ± 3.6
24.7 ± 3.9
21.6 ± 4.2
0.038
p 6 0.05 is significant.
Table 3 Gastrointestinal symptoms in the studied patients. Symptoms
Group 1 (n = 19)
Group 2 (n = 21)
p-Value
No symptoms Dyspepsia Nausea Episodic vomiting Epigastric discomfort Heart burn Chest pain Dysphagia Mixed symptoms
13 (68.4%) 9 (47.4%) 9 (47.4%) 2 (10.5%) 6(31.6%) 1 (5.2%) 0 4 (21%) 1 (5.2%)
12 (57.1%) 15 (71.4%) 12 (57.1%) 6 (28.6%) 10(47.6%) 1 (4.8%) 1 (4.8%) 2 (9.5%) 5 (23.8%)
0.31 0.12 0.53 0.15 0.31 0.94 0.95 0.56 0.23
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system (Albyn Medical Ltd., Scotland). Calibration of the transducers was done before starting the procedure. The test was performed using a pneumohydraulic capillary infusion system, which was continuously perfused with distilled water at a rate of 0.5 ml min 1 by a low compliance. The station pull-through technique was used as described earlier [17].
lated from the individual peristaltic amplitude. Duration was calculated from the onset to the end of peristaltic amplitude. Progression of the waves or velocity was calculated using the computer after the marking of commencement and end of the peristaltic waves. Statistical analysis
The peristaltic amplitude of the oesophageal body was measured from the oesophageal base line pressure. Mean was calcuTable 4 Clinicolaboratory parameters in the studied patients. Parameters
Group 1 (n = 19)
Group 2 (n = 21)
Duration of DM in years Therapy of DM Insulin Oral Diabetic retinopathy Diabetic nephropathy Autonomic neuropathy FBS PPS ALT AST Serum bilirubin Serum albumin INR HbA1c
8.11 ± 7.33
9.38 ± 5.66
p-Value 0.12
5 (26.3%) 14 (73.7%) 4 (21.1%) 2 (10.5%) 7 (36.8%) 137.49 ± 42.74 166.57 ± 88.13 37.31 ± 8.97 41.63 ± 7.33 0.99 ± 0.22 3.86 ± 0.569 1.1 ± 0.22 7.7 ± 1.2
13 (61.9%) 8 (38.1%) 8 (38.1%) 5 (23.8%) 11(52.4%) 129.1 ± 45.04 197.1 ± 65.38 62.71 ± 25.87 78.9 ± 30.42 2.35 ± 1.87 2.98 ± 1.1 1.47 ± 0.36 8.1 ± 1.8
0.02 0.24 0.26 0.32 0.55 0.21 <0.001 <0.001 <0.001 0.003 <0.001 0.41
Table 5 Endoscopic findings in the studied patients. Endoscopic findings
Group 1 (n = 19)
Group 2 (n = 21)
pValue
Free Reflux grade 1 Reflux grade II Reflux grade III Reflux grade VI Hiatus hernia Barrett’s oesophagus Bile in stomach with gastritis
11 (57.8%) 3 (15.8%) 2 (10.5%) 1 (5.2%) 1 (5.2%) 0 1 (5.2%) 2 (10.5%)
9 3 1 2 3 1 2 4
0.43 0.89 0.48 0.6 0.34 0.33 0.6 0.45
(42.8%) (14.3%) (4.8%) (9.5%) (14.3%) (4.8%) (9.5%) (19%)
Data were analysed using Statistical Package for Social Sciences (SPSS), Version 10. Qualitative data were presented in the form of number and percentage. Quantitative data were presented as mean ± SD. Unpaired Student’s t-test was used for comparison between variables. p < 0.05 was considered to be statistically significant. Results A total of 40 patients were included in this study. The mean age of the studied patients was 47.3 ± 9.2 years in group 1 and 44.8 ± 6.4 years in group 2 (p = 0.13). The male/female ratio was 11/8 in group 1 and 14/7 in group 2 (p = 0.83). The BMI was 24.7 ± 3.9 in group 1 and 21.6 ± 4.2 in group 2 (p = 0.038) (Table 2). No significant differences were found between groups 1 and 2 as regards the upper GI symptoms, including heart burn, chest pain, dysphagia and others (vomiting, hiccough and hoarseness of voice) (p = 0.94, 0.95, 0.56 and 0.23, respectively) (Table 3). Comparison of the clinicolaboratory parameters between groups 1 and 2 proved a significantly higher number of group 2 patients on insulin therapy (p = 0.02), higher serum bilirubin, ALT, AST and INR (all p = 0.001) and lower serum albumin (p = 0.003) (Table 4). Upper GI endoscopy did not reveal any significant differences between groups 1 and 2 as regards the four grades of endoscopic reflux (p = 0.89, 0.48, 0.6 and 0.34, respectively), hiatus hernia, Barrett’s oesophagus or excess bile in the stomach with bile gastritis (p = 0.33, 0.6 and 0.45, respectively) (Table 5). Group 1 patients had lower residual pressure with incomplete LES relaxation than control subjects (p 6 0.001 and 0.005, respectively); group 2 patients had lower resting and residual pressure of LES with incomplete relaxation than control subjects (p = 0.01,
Table 6 Oesophageal motility parameters in the studied groups. Parameters
LES pressure Resting LES pressure Residual LES pressure Incomplete relaxation Oesophageal body Distal oesophagus Wave amplitude Wave duration Wave velocity
Controls (n = 25)
30.95 ± 17.1 0.94 ± 0.83 1(4%)
Group 1 (n = 19)
25.4 ± 8.76 3.9 ± 2.3 7 (36.8%)
Group 2 (n = 21)
20.8 ± 4.61 4.3 ± 1.24 9 (42.8%)
p-Values p1
p2
p3
0.2 <0.001 0.005
0.01 <0.001 0.001
0.042 0.49 0.69
62.5 ± 14.9 2.52 ± 0.94 3.39 ± 1.3
57.54 ± 12.65 3.23 ± 0.87 2.44 ± 1.47
48.82 ± 16.21 3.50 ± 1.3 2.13 ± 0.98
0.25 0.014 0.028
0.002 0.004 <0.001
0.07 0.44 0.43
81.4 ± 29.18 4.43 ± 0.87 2.74 ± 1.1
65.96 ± 26.39 4.93 ± 1.56 1.46 ± 0.85
55.78 ± 19.52 4.99 ± 1.7 1.35 ± 1.04
0.07 0.18 <0.001
0.001 0.15 <0.001
0.17 0.23 0.71
51.5 ± 15.4 3.16 ± 1.58 3.89 ± 1.26
46.6 ± 12.4 2.33 ± 1.76 3.81 ± 1.1
0.17 0.008 0.86
0.02 <0.001 0.69
0.27 0.12 0.83
0.09
0.005
0.27
Proximal oesophagus Wave amplitude Wave duration Wave velocity
UES findings Resting pressure Residual pressure Relaxation time
59.84 ± 22.4 5.3 ± 3.1 3.96 ± 1.43
Abnormal peristalsis%
2 (8%)
5 (26.3%)
p1: group 1 vs. control; p2: group 2 vs. control; p3: group 1 vs. group 2.
9 (42.8%)
A. Eldesoky, A.A. El-Hafez / Arab Journal of Gastroenterology 11 (2010) 192–196
<0.001, 0.001, respectively); and group 2 patients had lower resting LES than those in group 1 (p = 0.042). As regards the oesophageal body, group 1 patients had longer wave duration and lower wave velocity in the distal oesophagus (p = 0.014 and 0.028), lower wave velocity in the proximal oesophagus (<0.001) than controls; group 2 patients had lower wave amplitude, longer wave duration and lower wave velocity in the distal oesophagus (p = 0.002, 0.004 and <0.001, respectively), and lower wave amplitude and lower wave velocity in the proximal oesophagus (all p < 0.001) than controls. The manometric findings of the upper oesophageal sphincter (UES) in group 1 patients proved lower residual UES pressure compared to control subjects (p = 0.008); group 2 had lower resting and residual UES pressures (p = 0.02 and <0.001) than control subjects. Group 2 patients had lower resting LES pressure than those of group 1 (p = 0.042) and more frequent abnormal peristaltic waves (p = 0.005) than controls (Table 6). Discussion The interesting potential links between chronic HCV and DM has encouraged us to study the oesophageal motility parameters in this rather common association in a trial to identify the possible effects of varices on oesophageal function and characterisation of symptoms in such patients. To achieve this goal, oesophageal manometric data were obtained from two groups of diabetic patients either with or without varices and compared to base line data obtained from a group of healthy controls. Analysis of the demographic data and clinicolaboratory parameters in the studied groups proved no significant differences apart from heavier weight and higher BMI in group 1 than in group 2 and controls. Patients with cirrhosis and diabetes may show signs of increased insulin resistance and may require high doses of insulin to control their blood glucose levels [18]. In this study, control of diabetes was evaluated using serum HbA1c levels; mean values of HbA1c were nearly similar in both studied groups of patients. The control of the diabetic state was found to be achieved mainly by insulin in group 2 patients and by oral hypoglycaemic agents in group 1 patients. Many of the GI symptoms in diabetic patients suggest motor dysfunction and a neuropathic basis to those dysfunctions would be a reasonable explanation. A previous study conducted by Bytzer et al. suggested that GI symptoms in DM were associated with complications, particularly peripheral neuropathy [19]. However, other studies suggested that GI symptoms in diabetic patients were poorly related to diabetic neuropathy, and were instead related to psychiatric illness [20,21]. The duration of DM was also an important factor for GI symptoms, as longer duration tends to have more complications [22]. In the current study, no significant differences were found between diabetic patients either with or without varices regarding either the duration of diabetes or the presence of autonomic neuropathy. The oesophageal manometric values proved many differences in the LES pressures amongst diabetics and controls, as group 1 patients had lower residual pressure with incomplete LES relaxation. This observation is in parallel to the new classification of motility disorders, which shows low LES pressure in diabetics along with other groups of patients of scleroderma and gastro-oesophageal reflux disease (GERD) [23]. The percentage of relaxation of the LES was significantly lower in diabetics when compared to controls, which signifies poor relaxation of the LES in such patients. Neuropathy, as a common complication of DM, may affect the motor nerves and the autonomic nervous system [17,24]. Oesophageal disorders such as reduced amplitude of oesophageal contractions; less numerous peristaltic waves; decrease in velocity of peristalsis; increased number of spontaneous, spastic and repetitive contractions; appearance of multipeaked contractions; re-
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duced LES pressure; impaired oesophageal transit; and abnormal acid reflux occur commonly in patients with diabetic autonomic neuropathy [6–25]. The pathophysiology of these abnormalities is mainly caused by vagal nerve dysfunction [26]. Kinekawa and Lluch [6,27] found oesophageal motility disorders and gastrooesophageal reflux in diabetic patients to be at a higher prevalence than among the general population. In the current study, progression of the peristaltic waves of oesophageal body was slower amongst diabetics at the proximal and distal parts of the oesophagus when compared with control subjects. The prevalence of liver cirrhosis is high with marked morbidity and mortality [28]. Portal hypertension is responsible for the development of oesophageal and gastric varices [29]. The role of oesophageal varices as a factor for the development of oesophageal motor disorders and oesophageal dysfunctions in liver-cirrhotic patients has been previously studied [10,13]. Cirrhotic patients with varices showed decreased amplitude of motor waves in the lower half of the oesophagus, an increased duration of primary peristaltic waves along the entire length of the oesophagus and an increased peak-to-peak speed of primary peristaltic waves. Resting LES pressure and duration of sphincter relaxation were similar in patients and controls. The above-mentioned abnormalities were attributed to the mechanical effect of the presence of varices [30]. In the current study, diabetic patients with varices had lower resting and residual LES pressures with incomplete relaxation, lower wave amplitude, longer wave duration and velocity in the distal oesophagus, and lower wave amplitude and velocity in the proximal oesophagus when compared to controls. Thus, many of the diabetic patients with non-treated oesophageal varices present oesophageal motor disorders. However, the clinical relevance of these findings needs more research in the scope to define the real meaning of these abnormalities. The parameters of UES including resting pressure, residual pressure and total duration of relaxation were different in patients than in controls. While group 1 patients had lower residual pressure, group 2 patients had lower resting and residual pressures. Diabetics with peripheral neuropathy have been reported to have an increased incidence of peristaltic double-peaked pressure complexes [31]. In the current study, group 2 patients had more frequent abnormal peristaltic waves than controls. The significance of this finding remains to be determined because a previous study reported double-peaked waves in normal individuals and the high incidence of those waves noted in a group of diabetics has not been confirmed in other diabetics studied with oesophageal manometery [32]. Furthermore, other abnormalities such as aperistalsis of the oesophageal body, non-conducted waves or failed peristalsis, high amplitude and broad peristaltic waves were found in diabetics with or without oesophageal varices and not in controls. It is well known that either diabetes or oesophageal varices appears to lead to changes in the oesophageal motility parameters in the tubular oesophagus as well as in the oesophageal sphincters. Accordingly, concomitant presence of both conditions may lead to a more deleterious effect on the oesophageal functions in such patients and subsequently on their symptomatisation. It was astonishing that comparison of the oesophageal manometric findings between the two studied groups of patients at all levels proved only lower resting LES pressure in diabetic patients with varices. Therefore, most of the oesophageal motility abnormalities in diabetic patients with varices could be attributed to the presence of diabetes and its complications rather than to the concomitant varices. Thus, oesophageal varices, which were previously reported to influence many oesophageal motility parameters, have only little impact in the presence of diabetes, particularly on the lower oesophageal sphincter. Furthermore, the more frequent abnormal peristalsis in diabetic patients with varices may manifest
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by minor findings such as occasional non-transmitted swallows and spontaneous activity without major changes that could influence the symptomatology, as no significant differences were found between diabetic patients with or without varices either in the symptoms expression or in the endoscopic findings. In this regard, further trials in a large diabetic population and particularly in those with oesophageal varices with different therapeutic modalities and disease severity are strongly recommended. In conclusion, among patients with diabetes and varices, changes in oesophageal motility are common but, with the exception of lower oesophageal sphincter hypotension, are related to diabetes rather than to the presence of varices. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med 2001;161(16):1989–96. [2] Revicki DA, Wood M, Maton PN, et al. The impact of gastroesophageal reflux disease on health-related quality of life. Am J Med 1998;104(3):252–8. [3] Wahlqvist P. Symptoms of gastroesophageal reflux disease, perceived productivity and health-related quality of life. Am J Gastroenterol 2001;96(8 Suppl.):S57–61. [4] Rayner CK, Samsom M, Jones KL, et al. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 2001;24(2): 371–81. [5] Ebert EC. Gastrointestinal complications of diabetes mellitus. Dis Mon 2005;51(12):620–63. [6] Lluch I, Ascaso JF, Mora F, et al. Gastroesophageal reflux in diabetes mellitus. Am J Gastroenterol 1999;94(4):919–24. [7] Allison ME, Wreghitt T, Palmer CR, et al. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 1994;21(6):1135–9. [8] Hadziyannis SJ. The spectrum of extrahepatic manifestations in hepatitis C virus infection. J Viral Hepat 1997;4(1):9–28. [9] Petit JM, Bour JB, Galland Jos C, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol 2001;35(2):279–83. [10] Schechter RB, Lemme EMO, Coelho HSM. Gastroesophageal reflux in cirrhotic patients with esophageal varices without endoscopic treatment. Arq Gastroenterol 2007;44(2):145–50. [11] Koshino Y, Takai T, Moriwaki H, et al. Neuropathological study of the esophagus in cirrhotic patients with esophageal varices. Nippon Shokakibyo Gakkai Zasshi 1989;86(1):1–10. [12] Sharma P, Hagerstrand I, Sharma DK. Histologic and manometric studies on the esophagus following endoscopic sclerotherapy. Dig Dis Sci 2009;54(8): 1713–9.
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Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original Article
Oesophageal dysmotility in diabetic patients with varices Ayman Eldesoky ⇑, Afaf Abd El-Hafez 1 Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Dakahliya, Egypt
a r t i c l e
i n f o
Article history: Received 13 July 2010 Accepted 13 September 2010
Keywords: Oesophageal motility Diabetes mellitus Portal hypertension
a b s t r a c t Background and study aims: Complications involving the gastrointestinal tract are important causes of morbidity in cirrhotic patients with diabetes mellitus. Our aim was to study the possible influences of varices on oesophageal motility in diabetic patients. Patients and methods: A total of 40 diabetic patients were recruited into two groups: group 1: 19 patients without varices; group 2: 21 patients with varices. Twenty healthy volunteers were selected as control. Oesophageal manometry was performed for patients and control subjects. Results: In comparison to control subjects, group 1 had lower residual pressure with incomplete relaxation of the lower oesophageal sphincter (LES) (p 6 0.001 and 0.005), longer wave duration and lower velocity in the distal oesophagus (p = 0.014 and 0.028) and lower wave velocity in the proximal oesophagus (<0.001); group 2 had lower resting and residual pressures with incomplete LES relaxation (p = 0.01, <0.001 and <0.001, respectively), lower wave amplitude, longer duration and lower velocity in the distal oesophagus (p = 0.002, 0.004 and <0.001), lower wave amplitude and lower velocity in the proximal oesophagus (all p < 0.001) and more frequent abnormal waves (p = 0.005). Lastly, group 2 had lower resting LES pressure than group 1 patients (p = 0.042). Conclusion: Among patients with diabetes and varices, changes in oesophageal motility are common but, with the exception of lower oesophageal sphincter hypotension, are related to diabetes rather than to the presence of varices. Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction The prevalence of gastrointestinal (GI) symptoms is reported to be higher in patients with diabetes mellitus (DM) than in the general population [1]. Although not generally considered as important causes of morbidity or mortality in DM patients, these symptoms can influence health-related quality of life and affect productivity and employment status [2,3]. Oesophageal manifestations of diabetic neuropathy, including abnormal peristalsis, spontaneous contractions and impaired lower oesophageal sphincter (LES) tone, result in heartburn and dysphagia [4,5]. The relationship between hyperglycaemia and dysmotility is not well established. Although many patients may have objective evidence of oesophageal dysmotility or reflux, symptoms only occur in a minority of patients with diabetes [6]. Viral hepatitis B and C (HBV and HCV) are established causes of chronic liver diseases and seem to occur more frequently in diabetics than in the general population. This association may reflect epidemiological circumstances because of the frequent parenteral exposures of diabetics [7]. On the other hand, the hepatitis viruses, ⇑ Corresponding author. Tel.: +20 50 2540609/9802279, mobile: +20 125147601. 1
E-mail address: [email protected] (A. Eldesoky). Tel.: +20 50 2536964.
particularly HCV, can affect not only the liver but also several tissues outside the liver, resulting in a wide spectrum of extrahepatic manifestations and morbid conditions to which DM has been included [8]. Among patients with HCV infection, older age, obesity, severe liver fibrosis and family history of diabetes are associated with the development of diabetes [9]. Abnormal gastro-oesophageal reflux was found in 37% of the patients with hepatic cirrhosis and oesophageal varices. Only typical gastro-oesophageal reflux disease symptoms predicted these findings [10]. The exact pathogenesis is still poorly defined; however, both reduction in the number and degeneration of ganglion cells at the Auerbach’s plexus were described in the oesophagus of cirrhotic patients with large varices, and these changes may contribute to the development of impaired motility of the oesophagus with large varices [11]. Furthermore, endoscopic sclerotherapy causes persistent manometric abnormalities and chronic inflammatory changes in the distal oesophagus, the severity of which seems to vary directly with the frequency of sclerotherapy and not the amount of the sclerosant injected [12]. Furthermore, variceal ligation causes alterations in oesophageal motility in the form of an increase in the amplitude and duration of the contractile waves [13]. In this work, we intended = to study the possible effects of varices on oesophageal motility parameters in diabetic patients.
1687-1979/$ - see front matter Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ajg.2010.09.003
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Patients and methods
Table 1 The scoring system of Ewing et al. for autonomic function tests [14].
Patients Inclusion criteria Forty adult patients were selected from those attending Mansoura Specialized Medical Hospital for management of either DM or chronic liver disease in the period between May 2008 and September 2009. Further, 20 age- and sex-matched healthy subjects were selected on a voluntary basis as the control group. The selected patients were classified into:
0 1 2
Exclusion criteria Patients with cerebrovascular accident, acute myocardial infarction, those on nasogastric feeding, haemodynamically unstable and who had oesophageal surgery were excluded from the study. Furthermore, non-compliant patients, patients with other systemic diseases such as endocrinal, cardiac, neurological, pulmonary disease, scleroderma and patients with therapies known to affect the GI motility were excluded. Methods 1. Medical history including the age, gender, duration of disease, height, weight and calculated body mass index (BMI). Symptoms related to the oesophagus (i.e. dysphagia, heartburn, regurgitation and retrosternal pain or any other symptoms) were evaluated and history of medications that influence oesophageal motility (prokinetic drugs, nitrates, anticholinergics, calcium channel blockers or sedatives) was also recorded. 2. Clinical examination included general examination (manifestations of DM and features of liver cirrhosis whether compensated or decompensated), local abdominal examination (for the liver, spleen and the presence or absence of ascites) and ocular fundus examination to detect retinopathy. 3. Examination for peripheral neuropathy was performed by evaluation of sensations (pinprick, touch, vibration and position sense) and reflexes (biceps, triceps, brachioradialis, knee and ankle). 4. Autonomic function tests included tests of sympathetic functions (postural hypotension and blood pressure response to sustained handgrip) and tests of parasympathetic function (heart rate response to Valsalva manoeuvre, heart rate variation during deep breathing and immediate heart rate response to standing). Definite diagnosis of autonomic neuropathy is achieved when the patient score is more than 5 according to the scoring system of Ewing et al., 1978 (Table 1) [14]. 5. Laboratory investigations included complete blood count (CBC), transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, prothrombin time (PT) and international normalised ratio (INR), and serum albumin), viral hepatitis serological markers, serum creatinine, urine examina-
D.B
S
S.H.G
P.H
>1.2 1.11–1.20 <1.10
>15 11–15 <10
>1.03 1.01–1.03 <1.10
>15 11–15 <10
<20 21–30 >31
V.R: Valsalva ratio. D.B: heart rate variation during deep breathing. S: heart rate response to standing. S.H.G: blood pressure response to sustained handgrip. P.H: postural hypotension.
group 1: 19 diabetic patients without oesophageal varices; and group 2: 21 diabetic patients with oesophageal varices. Diagnosis of DM was based on medical history and clinical examination with fasting blood glucose P 126 mg dl 1 or postprandial blood glucose P 200 mg dl 1. Diagnosis of oesophageal varices was based on upper GI endoscopy. The study protocol conformed to and was approved by the Medical Sciences Ethics Committee of Mansoura Faculty of Medicine. All the steps of the procedures were explained in detail for each patient and all the patients in both the groups gave their written informed consent.
V.R
6.
7.
8.
9.
tion for proteinuria, random blood sugar and glycosylated haemoglobin (HbA1c). Abdominal ultrasonography (with Doppler evaluation of the main portal vein, splenic vein and the hepatic veins) and electrocardiography. Barium swallow and meal were performed for diagnosis of hiatus hernia, other anatomical abnormality or evidence of reflux complications. Upper GI endoscopy was done for diagnosis of gastro-oesophageal varices and portal hypertensive gastropathy. Oesophagitis, if present, was classified according to Savary and Miller [15] into grade I, isolated erosions; grade II, confluent but not circumferential erosions; grade III, confluent and circumferential erosions; or grade IV, ulcers and stenosis. If the gastro-oesophageal junction was at least 2 cm above the diaphragmatic impression, the patient was considered to have hiatus hernia [16]. Oesophageal manometry: Following overnight fasting, an eightlumen water-perfused polyvinylchloride catheter with a 4.5mm diameter was connected to the Phoenix Mk2 computerised
Table 2 Demographic data in the studied groups. Parameters
Controls (n = 20)
Group 1 (n = 19)
Group 2 (n = 21)
p-Value
Age (years) Range Mean ± SD
20–55 39.7 ± 8.6
17–59 47.3 ± 9.2
28–56 44.8 ± 6.4
0.13
Sex M/F
13/7
11/8
14/7
0.83
Height (cm) Range Mean ± SD
151–182 167.4 ± 10.7
148–179 163.4 ± 12.3
145–177 161.7 ± 10.4
0.88
Weight (kg) Range Mean ± SD
50–86 64.5 ± 8.9
53–87 68.7 ± 9.5
46–83 62.0 ± 9.6
0.04
BMI Mean ± SD
23.2 ± 3.6
24.7 ± 3.9
21.6 ± 4.2
0.038
p 6 0.05 is significant.
Table 3 Gastrointestinal symptoms in the studied patients. Symptoms
Group 1 (n = 19)
Group 2 (n = 21)
p-Value
No symptoms Dyspepsia Nausea Episodic vomiting Epigastric discomfort Heart burn Chest pain Dysphagia Mixed symptoms
13 (68.4%) 9 (47.4%) 9 (47.4%) 2 (10.5%) 6(31.6%) 1 (5.2%) 0 4 (21%) 1 (5.2%)
12 (57.1%) 15 (71.4%) 12 (57.1%) 6 (28.6%) 10(47.6%) 1 (4.8%) 1 (4.8%) 2 (9.5%) 5 (23.8%)
0.31 0.12 0.53 0.15 0.31 0.94 0.95 0.56 0.23
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system (Albyn Medical Ltd., Scotland). Calibration of the transducers was done before starting the procedure. The test was performed using a pneumohydraulic capillary infusion system, which was continuously perfused with distilled water at a rate of 0.5 ml min 1 by a low compliance. The station pull-through technique was used as described earlier [17].
lated from the individual peristaltic amplitude. Duration was calculated from the onset to the end of peristaltic amplitude. Progression of the waves or velocity was calculated using the computer after the marking of commencement and end of the peristaltic waves. Statistical analysis
The peristaltic amplitude of the oesophageal body was measured from the oesophageal base line pressure. Mean was calcuTable 4 Clinicolaboratory parameters in the studied patients. Parameters
Group 1 (n = 19)
Group 2 (n = 21)
Duration of DM in years Therapy of DM Insulin Oral Diabetic retinopathy Diabetic nephropathy Autonomic neuropathy FBS PPS ALT AST Serum bilirubin Serum albumin INR HbA1c
8.11 ± 7.33
9.38 ± 5.66
p-Value 0.12
5 (26.3%) 14 (73.7%) 4 (21.1%) 2 (10.5%) 7 (36.8%) 137.49 ± 42.74 166.57 ± 88.13 37.31 ± 8.97 41.63 ± 7.33 0.99 ± 0.22 3.86 ± 0.569 1.1 ± 0.22 7.7 ± 1.2
13 (61.9%) 8 (38.1%) 8 (38.1%) 5 (23.8%) 11(52.4%) 129.1 ± 45.04 197.1 ± 65.38 62.71 ± 25.87 78.9 ± 30.42 2.35 ± 1.87 2.98 ± 1.1 1.47 ± 0.36 8.1 ± 1.8
0.02 0.24 0.26 0.32 0.55 0.21 <0.001 <0.001 <0.001 0.003 <0.001 0.41
Table 5 Endoscopic findings in the studied patients. Endoscopic findings
Group 1 (n = 19)
Group 2 (n = 21)
pValue
Free Reflux grade 1 Reflux grade II Reflux grade III Reflux grade VI Hiatus hernia Barrett’s oesophagus Bile in stomach with gastritis
11 (57.8%) 3 (15.8%) 2 (10.5%) 1 (5.2%) 1 (5.2%) 0 1 (5.2%) 2 (10.5%)
9 3 1 2 3 1 2 4
0.43 0.89 0.48 0.6 0.34 0.33 0.6 0.45
(42.8%) (14.3%) (4.8%) (9.5%) (14.3%) (4.8%) (9.5%) (19%)
Data were analysed using Statistical Package for Social Sciences (SPSS), Version 10. Qualitative data were presented in the form of number and percentage. Quantitative data were presented as mean ± SD. Unpaired Student’s t-test was used for comparison between variables. p < 0.05 was considered to be statistically significant. Results A total of 40 patients were included in this study. The mean age of the studied patients was 47.3 ± 9.2 years in group 1 and 44.8 ± 6.4 years in group 2 (p = 0.13). The male/female ratio was 11/8 in group 1 and 14/7 in group 2 (p = 0.83). The BMI was 24.7 ± 3.9 in group 1 and 21.6 ± 4.2 in group 2 (p = 0.038) (Table 2). No significant differences were found between groups 1 and 2 as regards the upper GI symptoms, including heart burn, chest pain, dysphagia and others (vomiting, hiccough and hoarseness of voice) (p = 0.94, 0.95, 0.56 and 0.23, respectively) (Table 3). Comparison of the clinicolaboratory parameters between groups 1 and 2 proved a significantly higher number of group 2 patients on insulin therapy (p = 0.02), higher serum bilirubin, ALT, AST and INR (all p = 0.001) and lower serum albumin (p = 0.003) (Table 4). Upper GI endoscopy did not reveal any significant differences between groups 1 and 2 as regards the four grades of endoscopic reflux (p = 0.89, 0.48, 0.6 and 0.34, respectively), hiatus hernia, Barrett’s oesophagus or excess bile in the stomach with bile gastritis (p = 0.33, 0.6 and 0.45, respectively) (Table 5). Group 1 patients had lower residual pressure with incomplete LES relaxation than control subjects (p 6 0.001 and 0.005, respectively); group 2 patients had lower resting and residual pressure of LES with incomplete relaxation than control subjects (p = 0.01,
Table 6 Oesophageal motility parameters in the studied groups. Parameters
LES pressure Resting LES pressure Residual LES pressure Incomplete relaxation Oesophageal body Distal oesophagus Wave amplitude Wave duration Wave velocity
Controls (n = 25)
30.95 ± 17.1 0.94 ± 0.83 1(4%)
Group 1 (n = 19)
25.4 ± 8.76 3.9 ± 2.3 7 (36.8%)
Group 2 (n = 21)
20.8 ± 4.61 4.3 ± 1.24 9 (42.8%)
p-Values p1
p2
p3
0.2 <0.001 0.005
0.01 <0.001 0.001
0.042 0.49 0.69
62.5 ± 14.9 2.52 ± 0.94 3.39 ± 1.3
57.54 ± 12.65 3.23 ± 0.87 2.44 ± 1.47
48.82 ± 16.21 3.50 ± 1.3 2.13 ± 0.98
0.25 0.014 0.028
0.002 0.004 <0.001
0.07 0.44 0.43
81.4 ± 29.18 4.43 ± 0.87 2.74 ± 1.1
65.96 ± 26.39 4.93 ± 1.56 1.46 ± 0.85
55.78 ± 19.52 4.99 ± 1.7 1.35 ± 1.04
0.07 0.18 <0.001
0.001 0.15 <0.001
0.17 0.23 0.71
51.5 ± 15.4 3.16 ± 1.58 3.89 ± 1.26
46.6 ± 12.4 2.33 ± 1.76 3.81 ± 1.1
0.17 0.008 0.86
0.02 <0.001 0.69
0.27 0.12 0.83
0.09
0.005
0.27
Proximal oesophagus Wave amplitude Wave duration Wave velocity
UES findings Resting pressure Residual pressure Relaxation time
59.84 ± 22.4 5.3 ± 3.1 3.96 ± 1.43
Abnormal peristalsis%
2 (8%)
5 (26.3%)
p1: group 1 vs. control; p2: group 2 vs. control; p3: group 1 vs. group 2.
9 (42.8%)
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<0.001, 0.001, respectively); and group 2 patients had lower resting LES than those in group 1 (p = 0.042). As regards the oesophageal body, group 1 patients had longer wave duration and lower wave velocity in the distal oesophagus (p = 0.014 and 0.028), lower wave velocity in the proximal oesophagus (<0.001) than controls; group 2 patients had lower wave amplitude, longer wave duration and lower wave velocity in the distal oesophagus (p = 0.002, 0.004 and <0.001, respectively), and lower wave amplitude and lower wave velocity in the proximal oesophagus (all p < 0.001) than controls. The manometric findings of the upper oesophageal sphincter (UES) in group 1 patients proved lower residual UES pressure compared to control subjects (p = 0.008); group 2 had lower resting and residual UES pressures (p = 0.02 and <0.001) than control subjects. Group 2 patients had lower resting LES pressure than those of group 1 (p = 0.042) and more frequent abnormal peristaltic waves (p = 0.005) than controls (Table 6). Discussion The interesting potential links between chronic HCV and DM has encouraged us to study the oesophageal motility parameters in this rather common association in a trial to identify the possible effects of varices on oesophageal function and characterisation of symptoms in such patients. To achieve this goal, oesophageal manometric data were obtained from two groups of diabetic patients either with or without varices and compared to base line data obtained from a group of healthy controls. Analysis of the demographic data and clinicolaboratory parameters in the studied groups proved no significant differences apart from heavier weight and higher BMI in group 1 than in group 2 and controls. Patients with cirrhosis and diabetes may show signs of increased insulin resistance and may require high doses of insulin to control their blood glucose levels [18]. In this study, control of diabetes was evaluated using serum HbA1c levels; mean values of HbA1c were nearly similar in both studied groups of patients. The control of the diabetic state was found to be achieved mainly by insulin in group 2 patients and by oral hypoglycaemic agents in group 1 patients. Many of the GI symptoms in diabetic patients suggest motor dysfunction and a neuropathic basis to those dysfunctions would be a reasonable explanation. A previous study conducted by Bytzer et al. suggested that GI symptoms in DM were associated with complications, particularly peripheral neuropathy [19]. However, other studies suggested that GI symptoms in diabetic patients were poorly related to diabetic neuropathy, and were instead related to psychiatric illness [20,21]. The duration of DM was also an important factor for GI symptoms, as longer duration tends to have more complications [22]. In the current study, no significant differences were found between diabetic patients either with or without varices regarding either the duration of diabetes or the presence of autonomic neuropathy. The oesophageal manometric values proved many differences in the LES pressures amongst diabetics and controls, as group 1 patients had lower residual pressure with incomplete LES relaxation. This observation is in parallel to the new classification of motility disorders, which shows low LES pressure in diabetics along with other groups of patients of scleroderma and gastro-oesophageal reflux disease (GERD) [23]. The percentage of relaxation of the LES was significantly lower in diabetics when compared to controls, which signifies poor relaxation of the LES in such patients. Neuropathy, as a common complication of DM, may affect the motor nerves and the autonomic nervous system [17,24]. Oesophageal disorders such as reduced amplitude of oesophageal contractions; less numerous peristaltic waves; decrease in velocity of peristalsis; increased number of spontaneous, spastic and repetitive contractions; appearance of multipeaked contractions; re-
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duced LES pressure; impaired oesophageal transit; and abnormal acid reflux occur commonly in patients with diabetic autonomic neuropathy [6–25]. The pathophysiology of these abnormalities is mainly caused by vagal nerve dysfunction [26]. Kinekawa and Lluch [6,27] found oesophageal motility disorders and gastrooesophageal reflux in diabetic patients to be at a higher prevalence than among the general population. In the current study, progression of the peristaltic waves of oesophageal body was slower amongst diabetics at the proximal and distal parts of the oesophagus when compared with control subjects. The prevalence of liver cirrhosis is high with marked morbidity and mortality [28]. Portal hypertension is responsible for the development of oesophageal and gastric varices [29]. The role of oesophageal varices as a factor for the development of oesophageal motor disorders and oesophageal dysfunctions in liver-cirrhotic patients has been previously studied [10,13]. Cirrhotic patients with varices showed decreased amplitude of motor waves in the lower half of the oesophagus, an increased duration of primary peristaltic waves along the entire length of the oesophagus and an increased peak-to-peak speed of primary peristaltic waves. Resting LES pressure and duration of sphincter relaxation were similar in patients and controls. The above-mentioned abnormalities were attributed to the mechanical effect of the presence of varices [30]. In the current study, diabetic patients with varices had lower resting and residual LES pressures with incomplete relaxation, lower wave amplitude, longer wave duration and velocity in the distal oesophagus, and lower wave amplitude and velocity in the proximal oesophagus when compared to controls. Thus, many of the diabetic patients with non-treated oesophageal varices present oesophageal motor disorders. However, the clinical relevance of these findings needs more research in the scope to define the real meaning of these abnormalities. The parameters of UES including resting pressure, residual pressure and total duration of relaxation were different in patients than in controls. While group 1 patients had lower residual pressure, group 2 patients had lower resting and residual pressures. Diabetics with peripheral neuropathy have been reported to have an increased incidence of peristaltic double-peaked pressure complexes [31]. In the current study, group 2 patients had more frequent abnormal peristaltic waves than controls. The significance of this finding remains to be determined because a previous study reported double-peaked waves in normal individuals and the high incidence of those waves noted in a group of diabetics has not been confirmed in other diabetics studied with oesophageal manometery [32]. Furthermore, other abnormalities such as aperistalsis of the oesophageal body, non-conducted waves or failed peristalsis, high amplitude and broad peristaltic waves were found in diabetics with or without oesophageal varices and not in controls. It is well known that either diabetes or oesophageal varices appears to lead to changes in the oesophageal motility parameters in the tubular oesophagus as well as in the oesophageal sphincters. Accordingly, concomitant presence of both conditions may lead to a more deleterious effect on the oesophageal functions in such patients and subsequently on their symptomatisation. It was astonishing that comparison of the oesophageal manometric findings between the two studied groups of patients at all levels proved only lower resting LES pressure in diabetic patients with varices. Therefore, most of the oesophageal motility abnormalities in diabetic patients with varices could be attributed to the presence of diabetes and its complications rather than to the concomitant varices. Thus, oesophageal varices, which were previously reported to influence many oesophageal motility parameters, have only little impact in the presence of diabetes, particularly on the lower oesophageal sphincter. Furthermore, the more frequent abnormal peristalsis in diabetic patients with varices may manifest
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by minor findings such as occasional non-transmitted swallows and spontaneous activity without major changes that could influence the symptomatology, as no significant differences were found between diabetic patients with or without varices either in the symptoms expression or in the endoscopic findings. In this regard, further trials in a large diabetic population and particularly in those with oesophageal varices with different therapeutic modalities and disease severity are strongly recommended. In conclusion, among patients with diabetes and varices, changes in oesophageal motility are common but, with the exception of lower oesophageal sphincter hypotension, are related to diabetes rather than to the presence of varices. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med 2001;161(16):1989–96. [2] Revicki DA, Wood M, Maton PN, et al. The impact of gastroesophageal reflux disease on health-related quality of life. Am J Med 1998;104(3):252–8. [3] Wahlqvist P. Symptoms of gastroesophageal reflux disease, perceived productivity and health-related quality of life. Am J Gastroenterol 2001;96(8 Suppl.):S57–61. [4] Rayner CK, Samsom M, Jones KL, et al. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 2001;24(2): 371–81. [5] Ebert EC. Gastrointestinal complications of diabetes mellitus. Dis Mon 2005;51(12):620–63. [6] Lluch I, Ascaso JF, Mora F, et al. Gastroesophageal reflux in diabetes mellitus. Am J Gastroenterol 1999;94(4):919–24. [7] Allison ME, Wreghitt T, Palmer CR, et al. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 1994;21(6):1135–9. [8] Hadziyannis SJ. The spectrum of extrahepatic manifestations in hepatitis C virus infection. J Viral Hepat 1997;4(1):9–28. [9] Petit JM, Bour JB, Galland Jos C, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol 2001;35(2):279–83. [10] Schechter RB, Lemme EMO, Coelho HSM. Gastroesophageal reflux in cirrhotic patients with esophageal varices without endoscopic treatment. Arq Gastroenterol 2007;44(2):145–50. [11] Koshino Y, Takai T, Moriwaki H, et al. Neuropathological study of the esophagus in cirrhotic patients with esophageal varices. Nippon Shokakibyo Gakkai Zasshi 1989;86(1):1–10. [12] Sharma P, Hagerstrand I, Sharma DK. Histologic and manometric studies on the esophagus following endoscopic sclerotherapy. Dig Dis Sci 2009;54(8): 1713–9.
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