The use of Intragastric Balloon to reduce weight in the management of Non-alcoholic Liver Disease and its

Effect on gastric ghrelin level

Shendy M. Shendy Sherif* and Nihal Al-Assaly** , Tropical, Hepatology and gastroenterology department*, Clinical biochemistry dep**, Theodor Bilharz research Institute

Conference: 8th International Annual Congress of the Egyptian Society of Hepatology, Gastroenterology and Infectious Diseases (ESHGID),in collaboration with Asian Pacific Association of study of liver diseases (APASL) and the Egyptian Group of Colon and Rectal Surgeons. Helnan Palestine Hotel, Alexandria, Egypt, Sept 13-15, 2006

Abstract:Non-alcoholic liver disease is one of the components of the metabolic syndrome. Obesity and

insulin resistance are the most important etiological factors of accumulation of hepatocellular fat, hepatic inflammation and fibrogenesis. The most important effective treatment of NAFLD is weight reduction by all means, including diet and exercise. However, many patients do not respond to these lines of treatment and ask for medical or surgical intervention to lose more weight. The aim of this study is to evaluate the availability, the compliance, the efficacy and the safety of IGB as a method of weight reduction in patients with NAFLD. The effects of weight reduction by this manoeuvre on the liver affection, metabolic abnormalities and fasting ghrelin level are also studied. Patients and methods: the study included 36 adult obese or morbid obese patients with clinical evidences of steatohepatitis. All the patients are subjected to complete physical examination, including weight, height, waist size, calculated BMI, waist hip ratio, and other vital signs. Complete biochemical investigations, liver functions, abdominal ultrasound and H pylori were done repeatedly before and after insertion of Intragastric balloon and for 6 months after removal of the balloon. Results: The most common complaints of the patients after insertion were nausea for 2-12 days (in 100%), vomiting for 3-7 days in 89% of patients and epigastric pain for 3–34 days in 67% of patients. Symptomatic reflux was reported by 31% of patients. The effects of Intragastric balloon on all parameters of body weight, BMI, waist and waist/hip ratio, triceps skin fold, fasting serum gherlin level serum cholesterol, triglycerides, uric acid, fasting blood sugar and liver enzymes were highly significant (P <0.01). The mean weight loss was 20.98 ± 5.89 kg and the mean reduction of BMI was 7.55 ± 2.03 after 6 months. All patients showed reduction of ALT to below 1.5 the upper limit of normal. AST was normalized in all patients except two after 6 months. Normalization of liver enzyme ALT was found in 30/36 patients after 6 months and 32/36 patients 3-6 months after balloon removal. In all patients, AST was normalized after 3-6 months of balloon removal. The grade of liver echogenicity was also significantly decreased towards normal in all patients. The liver spans showed highly significant decrease after treatment (P <0.01). Conclusion: It is concluded from this study that intragastric balloon is an available, effective, acceptable as regards safety, and applicable method of weight reduction. It was also proved that sustained weight loss by intragastric balloon, diet restriction and exercise; is one of the key therapeutic interventions to limit the risks and comorbidities associated with the metabolic syndrome including clinical manifestations of steatohepatitis such as elevated liver enzymes, enlargement of the liver and increased echogenicity. The significant reduction in fasting ghrelin level may be related to the decreased appetite and improved some metabolic parameters.

Introduction:

Non-alcoholic fatty liver disease (NAFLD) has been recently recognized as a leading cause of chronic liver disease, with a prevalence estimated in some parts of the world of approximately 20%, far outweighing that of chronic hepatitis C virus (HCV) or alcoholic liver disease (Kim et al., 2002; Clark et al., 2003 and Lonardo et al., 2004). The disease is becoming recognized as a component of the metabolic syndrome and insulin resistance. Diagnosis of NAFLD can be made in a patient who has mild elevation of transaminases, features of Syndrome X (obesity, diabetes, and hyperlipidemia), insignificant alcohol consumption, no other liver disease, is not on potentially steatogenic medications and has signs of steatosis on a liver ultrasound scan (Reaven 2001). Typically, only a liver biopsy can confirm the diagnosis and determine the extent of disease. The disease is progressive and carries a risk for progressive fibrosis, cirrhosis, end-stage liver disease and even hepatocellular carcinoma (Tuma RS, 2005). The disease has a spectrum of histological lesions. One end of the spectrum is bland steatosis, considered to be the most benign form of NAFLD. On the other end of the spectrum is cirrhosis, which often may only be accompanied by mild steatosis. Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and varying degrees of inflammation, hepatocellular damage and sinusoidal and portal fibrosis (PF) (Ludwig et al., 1980 and Lee 1989).

Mechanisms responsible for the progression of fatty liver to NASH and cirrhosis are still not clearly understood. Insulin resistance appears to be the common underlying metabolic abnormality associated with NAFLD (Clark et al., 2002). It is assumed that obesity and insulin resistance are the key correlates of hepatic inflammation and fibrogenesis; and insulin resistance is an antecedent in the accumulation of hepatocellular fat. Also, excess intracellular fatty acids, oxidative stress, energy depletion, and mitochondrial dysfunction cause cellular injury in the steatotic liver. High serum free fatty acid concentrations allow greater hepatic fatty acid uptake. Increased fatty acid delivery to the liver affects hepatocytes, interfering with insulin function and mitochondrial beta-oxidation. Thus, obesity is the single most significant risk factor for the development of NASH (Kitade et al 2005, Kakajima et al., 2005 and Bailey et al., 2005).

At present, there is no effective treatment for NAFLD other than weight loss by diet and exercise, which would be advised regardless of the degree of liver disease in a patient who is overweight and/or diabetic (Mendeler et al., 2005). However, many patients do not respond to these lines of treatment and ask for medical or surgical intervention to lose more weight. Bariatric operations can be technically challenging in massively obese patients. In selected patients intragastric balloon can be used as effective and safe approach and could be a great help to induce weight loss and to prepare for surgery. In one study, placement of an intragastric balloon can reduce the excess weight by 10% within 3 months (Alfalah et al., 2006). It was also found a safe and effective device that achieved moderate weight loss in a Chinese study (Lik-Man et al., 2006). In the obese ethnic Chinese patients, median BW and BMI loss were 15.3 (range 5.3-30.9) kg and 5.6 (range 1.9-12.5) kg/m2 after IGB. The median waist circumference (WC) loss was 9 (range 4-23) cm, and 66.7% of patients were highly satisfied with the treatment.

The gastric hormone ghrelin has recently been identified as an important modulator of energy homeostasis. It is a 28-residue peptide hormone, secreted from the stomach. It is an endogenous growth hormone secretagogue (GHS). It has orexigenic and anabolic actions, which are independent from its ability to stimulate growth hormone (GH) secretion from the pituitary (Kojima et al., 1999). Ghrelin induces adiposity in rodents by increasing food intake and decreasing fat use (Tschop et al., 2000). More recently, ghrelin has also been shown to induce appetite and increase food intake in humans, thus responsible for long-term regulation of body weight (Wren et al., 2001) .Ghrelin regulation of energy balance is believed to be mediated by the hypothalamus (Horvath et al., 2001). Physiologically, ghrelin levels rise shortly before a meal and

drop rapidly after a meal. Ingestion of glucose but not water or protein reduces circulating ghrelin by 30–50%. Ghrelin concentrations have been reported to be indirectly correlated to BMI with reduced level in obesity that increases in response to weight loss (Wren et al., 2001, Cummings et al., 2001 and 2002, Caixas et al. 2002 and Shiiya et al. 2002). Short-term ghrelin application in man directly stimulates appetite for several hours and reduces postprandial satiety (Wren et al., 2001). Long-term infusion of ghrelin in animal models via centrally stimulating food intake increases body fat accumulation and causes adiposity (Wren et al., 2001, Tschop et al., 2000 and 2002). In humans in states of chronic malnutrition such as anorexia nervosa, serum ghrelin levels are increased whereas obesity is associated with decreased ghrelin concentrations that increase after weight loss (Otto et al. 2001, Tschop et al., 2001 and Hanssen et al., 2002).

In polycystic ovary syndrome; which is one of the features of metabolic syndrome associated with insulin resistance; the serum ghrelin level was found significantly lower compared with healthy controls, and this was strongly related to the degree of insulin resistance (Schofl et al., 2002). The plasma ghrelin level was found to increase with diet-induced weight loss while gastric bypass and intragastric balloons were associated with significantly suppressed ghrelin levels, possibly contributing to the weight-reducing effect of these procedures (Cummings et al., 2002 and Mion et al., 2005).

The role of intragastric balloon (IGB) in metabolic syndrome associated with steatohepatitis was not explored before. The simplicity, availability and lower cost of such measure in comparison to surgical intervention help to explore these effects in addition to reduction of body weight and BMI. Also the effect of weight reduction using this balloon on ghrelin level was not extensively studied and needs to be re-evaluated as a possible etiological factor and as a therapeutic target in weight control.

The aim of the work: The aim of this study is to evaluate the availability, the compliance, the efficacy and the safety

of IGB as a method of weight reduction in patients with NAFLD. The effects of weight reduction by this manoeuvre on the liver affection, metabolic abnormalities and fasting ghrelin level are also studied.

Materials and methods: This study is conducted in Elite Medical and Surgical centre; Riyadh, Saudi Arabia. It

included 36 adult patients with the following criteria:1- Body mass index (BMI) between 29-46 2- Elevated liver enzymes for at least 3 months3- Hepatic steatosis on abdominal ultrasound 4- Negative hepatitis markers for hepatitis viruses; HBV, HCV, HAV and HEV.5- No history of alcohol intake 6- No major medical illness; such as cardiac, renal, hepatic, endocrinological (except DM), or

psychological diseases.7- No recent history of medications that may increase body weight or affect liver function.8- Written and informed consent given by the patient9- Complete acceptance and expectation to the procedure and its side effects10- No reflux oesophagitis, active peptic ulcer, gastritis or H pylori infection on endoscopic

examination

All the patients were given complete data about the procedure, side effects and expected effect on the body weight and metabolic abnormalities. Written consent must be given by the patient.

Patients are followed for a period of 6 months when the balloon is removed and for more 6 months after removal of the balloon.

All patients are subjected to the following:1- History and complete physical examination including blood pressure, pulse, weight, height,

hip and waist sizes, waist/hip ratio, Calculation of BMI, and systemic examination including ECG.

2- H pylori serology, lipid profile, uric acid, fasting blood sugar and CBC.3- Liver function tests including ALT, AST, bilirubin, s albumin and prothrombin time4- HBs Ag, HCV Ab, HAV Ab and HEV Ab.5- Abdominal ultrasonography to evaluate size and echo-pattern of the liver, gall bladder and

other pathology. The echogenicity of the liver is graded roughly into normal, mildly increased, moderately increased and markedly increased grades (1,2,3, and 4 respectively).

6- Upper gastrointestinal endoscopy just before insertion of intragastric balloon to examine the oesophagus, cardia, stomach and duodenum in addition to taking antral biopsy for rapid urease test of H pylori and general evaluation for the proposed volume of the fluid in the balloon

7- Insertion of The BioEnterics Intragastric Balloon System (BIB, INAMED Corporation, Santa Barbara, CA, USA) which is a smooth, spherical, silicone elastomer balloon and its inflation with methylene blue-colored saline solution of 400-650 ml under direct vision. Mild sedation using midazolam (2-5 mg) with or without fentanyl 100 mg intravenously. Also, pulse, blood pressure and oxygen saturation were monitored all the time during procedure.

8- After the procedure, patient can return home within 30 minutes and given instructions for diet and possible medical treatment. Patients were given a balanced diet of 1000-1500 kcal/day starting with liquid diet for first 2 weeks followed by gradual return to usual diet elements. Patients are encouraged to stick to regular exercise of at least one hour daily for at least 5 days per week to increase their energy expenditure.

9- Follow up for one year with periodic examination, investigations of liver function, ultrasound and metabolic profile.

10- Serum Ghrelin level is measured by the Desacyl-Ghrelin ELISA which is an enzymatically amplified "two-step" sandwich-type immunoassay. In the assay, standards, controls and unknown plasma samples are incubated in microtitration wells which have been coated with anti-desacyl ghrelin monoclonal antibody. After incubation and washing, the wells are treated with another anti-ghrelin detection antibody labeled with the enzyme horseradish peroxidase (HRP). After a second incubation and washing step, the wells are incubated with the substrate tetramethylbenzidine (TMB). An acidic stopping solution is then added and the degree of enzymatic turnover of the substrate is determined by absorbance measurement at 450 nm. The absorbance measured is directly proportional to the concentration of desacyl ghrelin present. A set of desacyl ghrelin standards is used to plot a standard curve of absorbance versus desacyl ghrelin concentration from which the desacyl ghrelin concentrations in the unknowns can be calculated (Hosoda, H. et al. 2000 and Matsumoto, M. et al.2001)

Statistical AnalysisResults are expressed as absolute values and mean ± SD. Statistical analysis of the data was carried out

using the ANOVA test. For correlation studies, the Pearson correlation coefficient was used. A p -value of < 0.05 was considered significant. Statistical analysis was performed using the SPSS 12 for window statistical Package.

Results:This study included 39 patients; 22 males and 17 females. Three female patients were excluded

from the study due to removal of balloon prematurely after 3, 5, and 47 days; mostly due to intolerance to the abdominal pain and vomiting. The mean age of those who completed the study protocol (36 patients) was 33.25 ± 11.21 years. Other basal data including height, weight, body mass index (BMI) and waist circumference are shown in table 1. Biochemical data such as ALT, AST, cholesterol, triglyceride, uric acid, and fasting blood sugar are shown in table 2. Bilirubin and prothrombin time were found normal in all cases. Alkaline phosphatase was not done in these patients. H pylori antibody positivity was detected in 21/36 patients (58.35%) in addition to 6 patients found to have positive rapid urease test on gastric biopsies with negative antibody test . All positive patients (27 patients; 75%) were given eradication therapy for 2 weeks before the balloon insertion. Mean procedure time was 21 ± 2.63 minutes (range 16-26) and mean amount of fluids used for balloon inflation was 511.94 ± 38.48 ml of saline (range 450-600 ml) days. No serious complications related to IGB insertion were encountered. The most common complaints of the patients after insertion were nausea for 2-12 days (in 100%), vomiting for 3-7 days in 89% of patients and epigastric pain for 3–34 days in 67% of patients. Symptomatic reflux was reported by 31% of patients. Endoscopic evaluation for severe symptoms was performed only in 2 patients after 7 and 32 days. The first one of them was found to have severe reflux oesophagitis grade 2, and the other to have erosive gastritis with H pylori positive rapid urease test. All these side effects were managed by proton pump inhibitors in addition to anti-emetic medications (mainly ondansetron; Zofran 4mg every 12 hours) followed by triple therapy for H pylori positive case. Except for the three females in whom the balloon was removed, all were responding and continued for the recommended period. No spontaneous deflation or migration was detected. All balloons were deflated and removed after about 6 months of follow up. The mean time for removal was 25.64 ± 3.20 minutes (range 12-35 minutes).

The mean weight loss was 20.98 ± 5.89 kg and the mean reduction of BMI was 7.55 ± 2.03 after 6 months. The effects of Intragastric balloon on all parameters of body weight, BMI, waist and waist/hip ratio, triceps skin fold, fasting serum gherlin level serum cholesterol, triglycerides, uric acid, fasting blood sugar and liver enzymes were highly significant (P <0.01). Normalization of liver enzyme ALT was found in 30/36 patients after 6 months and 32/36 patients 3-6 months after balloon removal. All patients showed reduction of ALT to below 1.5 the upper limit of normal. AST was normalized in all patients except two after 6 months. In all patients, AST was normalized after 3-6 months of balloon removal. The grade of liver echogenicity was also significantly decreased towards normal in all patients. The liver spans showed highly significant decrease after treatment (P <0.01).

Table 1: mean and SD of age, height, weight, body mass index (BMI) and waist circumference in patients studied.

Age (years) Height (cm) weight before ttt (kg) BMI before ttt Waist before ttt (cm)Mean 33.25 165.33 94.12 34.52 104.64Std D. 11.21 7.05 10.41 4.15 7.39

Table 2: mean and SD of ALT, AST, cholesterol, triglyceride, uric acid, and fasting blood sugar in patients studied.

ALT before

treatment(μ/dl)

AST before

treatment(μ/dl)

Cholesterol before

treatment(mg/dl)

Triglyceride before

treatment (mg/dl)

Uric acid before

treatment (mg/dl)

Fasting blood sugar before

treatment (mg/dl)

Mean 70.25 64.89 221.72 217.42 6.98 120.22Std D. 17.47 23.05 32.99 54.48 1.50 33.80

Table 3: the effect of Intragastric Balloon on the body weight and body mass index (BMI).

weight before

treatment

weight after 6 months

weight 3-6 months after removal of

balloon

BMI before

treatmentBMI after 6 months

BMI 3-6 months after removal of balloon

Mean 94.12 73.22 73.47 34.52 26.88 26.98Std Deviation 10.41 6.55 5.83 4.15 3.09 3.17

Table 4: the degree of loss and reduction of BMI after 6 month of Intragastric Balloon.Weight loss after 6 months Reduction of BMI after 6 months

Mean 20.98 7.55Std Deviation 5.89 2.03

Table 5: the effect of Intragastric Balloon on the waist circumference (cm) and waist/hip ratio.Waist before

treatment

Waist after 6 months

Waist 3-6 months after removal of

balloon

Waist/hip R before treatment

Waist/hip R after 6 months

Waist/hip R after 3-6 months of

removal of BalloonMean 104.64 97.47 96.94 1.14 1.06 1.06Std Deviation 7.39 6.80 5.88 .06 .06 .05

Table 6: the effect of Intragastric Balloon on the Alanine aminotransferase (μ/dl).

ALT before treatment

ALT after 1 month

ALT after 3 month

ALT after 6 month

ALT 3-6 month after removal of balloon

Mean 70.25 62.39 46.25 33.22 30.47Std Deviation 17.47 14.19 11.73 8.74 7.14

Table 7: the effect of Intragastric Balloon on the Alanine aminotransferase (μ/dl).AST before treatment

AST after 1 month

AST after 3 month

AST after 6 month AST after 9-12 month

Mean 64.89 52.03 41.39 30.22 27.22Std Deviation 23.05 15.31 11.18 7.14 4.88

Table 8: the effect of Intragastric Balloon on the S. cholesterol, triglycerides, and uric acids (mg/dL).Cholesterol

before treatment

Cholesterol after

treatment

Triglyceride before

treatment

Triglyceride after

treatment

Uric acid before

treatment

Uric acid after

treatmentMean 221.72 190.64 217.42 179.58 6.98 6.41Std Deviation 32.99 25.32 54.48 25.90 1.50 1.05

Table 9: the effect of Intragastric Balloon on the fasting blood sugar (mg/dl), F. gherlin level (pmol/L) and triceps skin fold (cm).

Fasting blood sugar before

treatment

Fasting blood sugar after treatment

Fasting Gherlin level before treatment

Fastin g Gherlin level

after treatment

Triceps skin fold before treatment

Triceps skin fold after treatment

Mean 120.22 109.94 293.17 237.03 2.62 2.22Std D. 33.80 27.59 73.44 56.82 .54 .44

Table 10: the effect of Intragastric Balloon on liver spans (cm) and echogenicity. Liver span in MCL before treatment

Liver span in MCL after treament

Liver span in ML before treatment

Liver span in ML after

treatment

Liver echogenicity

before treatment

Liver echogenicity

after treatmentMean 15.24 13.69 13.67 12.18 2.94 1.889Std D 1.36 .93 .95 .99 .75 .747

Discussion

Based on autopsy studies, estimates suggest that 20% to 30% of adults have excess fat accumulation in the liver and 2% to 3% of adults meet diagnostic criteria for NASH (Neuschwander-Tetri and Caldwell, 2003). In a prospective study of 241 consecutive patients in a primary care clinic, the prevalence of fatty liver was 37% (Dasarathy et al., 2005). Patients with NAFLD were more likely to be obese and have diabetes (54% vs. 4%), hypertension (41% vs 10%), and insulin resistance (54% vs. 20%). Obesity and insulin resistance are key factors in exacerbating hepatic inflammation and fibrogenesis in NASH. Weight loss was found the most effective measure in the management of this disease (Mendeler et al., 2005).

Intragastric balloons are a temporary non-surgical obesity treatment that induces short-term weight loss by partially filling the stomach to achieve satiety and reduce food intake. The time required for balloon insertion or removal was comparable to and even lower than the previous studies. In this study, the time required for insertion was 21 ± 2.63 minutes and for removal was 25.64 ± 3.20 minutes. In one previous study, the time of insertion was 25 minutes with hospital stay of average of 2 days (Lik-Man, et al., 2006). No patients were admitted in this series. Thus, this method can be applicable in the management of obesity associated with other comorbidity.

A new strategy was followed for the first time in this work in which serological H pylori testing was performed pre-operatively for all patients. The objective is to treat this infection to avoid its activation in the presence of balloon leading to gastric inflammation or ulceration. These can add to the complaints of the patients particularly abdominal pain. Positive cases were given eradication therapy. Negative cases were again tested during endoscopy by rapid urease test and, if positive, eradication therapy was given before balloon implantation. Twenty one patients were positive by antibody testing while 6 patients were only positive by rapid urease test of antral biopsy. Therefore, it is recommended to do tissue-dependent tests for all patients; either rapid urease or breath test to avoid the false negative serology not uncommonly seen in these asymptomatic patients. Also, the prevalence of H pylori infection in these random of asymptomatic patients was 75 % which can be considered a reflection of the prevalence in the community.

Nausea, vomiting and abdominal pain are the most common complaints in these patients (100%, 89%, 67% respectively). These occurred predominantly in the first few days up to one week in most cases, rarely lasted longer, after balloon implantation. They were managed easily by common medications. Severe complications were rare in this study and endoscopy was rarely required to re-evaluate such severity, added to the early removal of balloons in 3 patients. The reflux symptoms and vomiting were most annoying to the patients but can be managed in all cases. It was known that chronic distension by an intragastric balloon increased reflux up to 10 week after placement because of an increase in the percentage of lower oesophageal sphincter relaxation time (TLESRs) accompanied by a reflux episode. In addition, prolonged balloon distension increased the rate of TLESRs and created a postprandial state even 10 wk after balloon placement. After 20 wk these effects largely resolved, illustrating adaptation to this artificial situation (Hirsch et al., 2003). Also, delayed gastric emptying may add to the severity of reflux as shown in one study in which it was found that gastric emptying rates were significantly decreased with the balloon in place, and returned to pre-implantation values after balloon removal (Mion et al., 2005). In one study, nausea and vomiting in the first week occurred in 77.2%, abdominal pain in 15.9 % and gastroesophageal reflux in 6.8%. Hypokalemia also occurred in 6.8%, functional renal insufficiency in 4.5 % in addition to one gastric perforation

that was treated laparoscopically after removal of the balloon, one gastric ulcer and 4 cases of intolerance (Al-Momen and El-Mogy, 2005). In another earlier study, 76.8% of the patients (41/69) complained of severe nausea and vomiting lasting an average of 1 week (1 day-6 months), resulting in 3 patients in early removal of the balloon (at 1 day, 1 week, 1 month after placement respectively). 2 patients suffered gastric perforation presenting as acute peritonitis 3 and 4 months after placement and were operated. Extraction of the balloon was performed in 3 patients after 3 months and in 66 patients after 6 months. In 11 patients (22%), esophagitis was present (8 grade 1, 2 grade II, 1 grade III), and one patient showed diffuse gastric erosion. One patient required removal of the balloon by rigid esphagoscopy following technical failure of the endoscopic extraction device (Totté et al., 2001).

In a big Italian experience of 2,515 patients, positioning of the Bioenteric Intragastric Balloon (BIB) was uncomplicated in all but two cases (0.08%), with acute gastric dilation treated conservatively. Overall complication rate was 70/2,515 (2.8%). Gastric perforation occurred in 5 patients (0.19%), 4 of whom had undergone previous gastric surgery: 2 died and 2 were successfully treated by laparoscopic repair after balloon removal. 19 gastric obstructions (0.76%) presented in the first week after positioning and were successfully treated by balloon removal. Balloon rupture (n=9; 0.36%) was not prevalent within any particular period of BIB treatment, and was also treated by BIB removal. Esophagitis (n=32; 1.27%) and gastric ulcer (n=5; 0.2%) presented in patients without a history of peptic disease and were treated conservatively by drugs. Preoperative co-morbidities were diagnosed in 1,394/2,471 patients (56.4%); these resolved in 617/1,394 (44.3%), improved (less pharmacological dosage or shift to other therapies) in 625/1,394 (44.8%), and were unchanged in 152/1,394 (10.9%) (Genco et al., 2005).

On the other hand, there are more complications after barietric surgery. In one study over a 20-year period of 32 adolescents, 3 had gastroplasty, 16 had gastric bypass, 3 had distal gastric bypass, and 10 had long-limb gastric bypass. Despite there were no postoperative deaths or leaks, early complications included 1 pulmonary embolus, 1 major wound infection, 4 minor wound problems, 3 stomal stenoses that were dilated endoscopically, and 4 marginal ulcers treated with acid suppression. Late complications included 1 bowel obstruction, 4 incisional hernias, and 1 sudden death 6 years after surgery. Two patients needed revisional surgery, 1 for malnutrition and 1 for inadequate weight loss (Vogin, 2002).

Most of the patients in this study were in the 4th decade of life with their BMI in the range of obesity or morbid obesity (39-46) and increased waist circumference. They had higher cholesterol and triglyceride levels than normal. Uric acid level was in the high normal range in most patients. Many cases are diabetic or having fasting hyperglycaemia. All these parameters, which are components of metabolic syndrome, showed highly significant improvement with reduction of body weight during early follow up period of the study and continued to improve after removal of balloon. Thus, reduction of body weight helps to correct many metabolic changes related to obesity and intragastric balloon showed a highly effect method in this situation.

Satisfactory weight loss was achieved in most patients of this study during the treatment

period and even during follow up after removal of balloon. The mean loss of body weight after 6 months was 20.98 ± 5.89 kg and mean reduction of BMI was 7.55 ± 2.03. These effects are more than expected from previous studies. Another important finding in this study is the maintenance of reduction of body weight and BMI without significant increase for about 6 months after removal. This stationary phase is very important to stabilize the patients and prevent rapid rebound of their initial measures and metabolic abnormalities. The strict follow up and

encouraging of patients to continue on diet restriction and exercise programs were the main factors behind this success. All the previous studies using this manoeuvre showed also significant reduction in body weight. The loss of excess weight ranged from 33.9 to 50.8%, the BMI was reduced by 4.8- 9 kg/m2 and the mean weight loss was 13.0- 33 kg. Weight loss was accompanied by an improvement of the diseases associated with obesity, in particular diabetes. The BIB system was found a safe and efficient measure of reducing weight in patients with mild or moderate obesity and as preoperative treatment for super-obese patients to reduce the surgical risk before LAGB ( laparoscopic gastric banding). In these studies, i t was concluded that BIB is an effective procedure with satisfactory weight loss and improvement in co-morbidities after 6 months (Totté et al. (2001, Doldi  et al., 2002, Al-Momen and El-Mogy, 2005 and Genco et al., 2005).

It was known that the level of Ghrelin rise in the fasting state immediately before the time of the meal then decreases in the postprandial period to the original level. In this study and in a previous study (Mion et al., 2005), the fasting level was found to decrease after reducing the weight by the intragastric balloon. As ghrelin has been shown to induce appetite and increase food intake in humans, it may be responsible for long-term regulation of body weight (Wren et al., 2001). The decrease in gastric emptying rates and gastric distension by the presence of the balloon may be the factors responsible for such effect. Ghrelin inhibition may explain part of the effect of the balloon on satiety. (Mion et al., 2005). However, it is unclear whether the decrease of ghrelin after balloon-induced weight reduction is an incidental finding or has a role in the whole process with improvement in many metabolic abnormalities such as insulin resistance, fasting blood sugar and lipid profile.

In vivo and in vitro data suggest a stimulatory action of ghrelin on insulin release (Broglio et al., 2001, Egido et al., 2002, Lee et al., 2002 and Date et al.,2002). On the other hand, insulin stimulates up-regulation of ghrelin mRNA in the stomach in vitro, but in vivo iv insulin has no impact on circulating ghrelin levels in humans, demonstrating a complex interplay between both hormones (Caixas et al., 2002, Toshinai et al., 2001). Thus, apart from its role in the control of appetite and body weight, ghrelin could be linked to insulin resistance in these patients.

In this study, it was found that ALT and to a less extent AST were elevated before weight reduction. They showed highly significant reduction and mostly normalized in most patients after 6 months of maintained weight reduction by the BIB system. Non-alcoholic fatty liver disease is becoming recognized as a component of the metabolic syndrome and insulin resistance. Elevations of ALT, AST, and ALK are common in individuals with type 2 diabetes as well as the metabolic syndrome. ALT was found to be the most specific marker of liver pathology and appears to be the best marker for liver fat accumulation in patients with NAFLD (Tiikkainen et al., 2003). In another study, ALT, but not aspartate aminotransferase levels were found to increase progressively with the increasing number of metabolic syndrome abnormalities and the levels of ALT and ALK were correlated with the number of metabolic disorders (Naveed Sattar et al., 2004).

It is concluded from this study that intragastric balloon is an available, effective, acceptable as regards safety, and applicable method of weight reduction. Also, close follow up and compliance of patients after balloon removal help to maintain weight loss beyond the recommended period of the balloon. It was also proved that sustained weight loss by intragastric balloon, diet restriction and exercise; is one of the key therapeutic interventions to limit the risks and comorbidities associated with the metabolic syndrome including clinical manifestations of steatohepatitis such as elevated liver enzymes, enlargement of the liver and increased echogenicity. The significant

reduction in fasting ghrelin level may be related to the decreased appetite and improved some metabolic parameters. References:1. Clark J M, Brancati F L, Diehl A M. The prevalence and etiology of elevated aminotransferase levels in

the United States. Am J Gastroenterol 2003; 98: 960–7. 2. Kim W R, Brown R S Jr, Terrault N A, El-Serag H. Burden of liver disease in the United States:

summary of a workshop. Hepatology 2002; 36: 227–42. 3. Lonardo A, Adinolfi L E, Loria P, Carulli N, Ruggiero G, Day C P. Steatosis and hepatitis C virus:

mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004; 126: 586–97.

4. Reaven G. Syndrome X. Curr Treat Options Cardiovasc Med 2001; 3: 323–32. 5. Tuma RS, 2005: Metabolic Syndrome Associated With More Severe Nonalcoholic Fatty Liver Disease.

AASLD 56th Annual Meeting: Abstract 1056. Presented Nov. 14, 2005.6. Ludwig J, Viggiano T R, McGill DB, Oh B J. Nonalcoholic steatohepatitis: Mayo Clinic experiences

with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434–8. 7. Lee R G. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989; 20: 594–8. 8. Clark J M, Brancati F L, Diehl A M. Nonalcoholic fatty liver disease. Gastroenterology 2002; 122:

1649–57. 9. Mendler M H; Kanel G; Govindarajan S. (2005):Proposal for a Histological Scoring and Grading

System for Non-Alcoholic Fatty Liver Disease. Liver Int.  2005; 25 (2): 294-304.  10. Alfalah H; Philippe B; Ghazal F; Jany T; Arnalsteen L; Romon M; Pattou F (2006); Intragastric balloon

for preoperative weight reduction in candidates for laparoscopic gastric bypass with massive obesity. Obes. Surg. 16 (2): 147-150.

11. Lik-Man M W; So WY; Yau PY; Lam CH; Yung MY; Cheng AY; Chow FC; Ng EK (2006): Intragastric balloon in ethnic obese Chinese: initial experience. Obes. Surg. 16 (3): 308-13

12. Kitade M, Yoshiji H, Yoshii J, et al. The roles of interaction between leptin, oxidative stress, and angiogenesis in hepatic fibrogenesis in the rat model of nonalcoholic fatty liver disease. Hepatology. 2005;42:633A [Abstract #1112]

13. Kakajima T, Moriguchi M, Nishikawa T, et al. Excessive telomere shortening and impaired regenerative response in hepatocytes of NAFLD patients. Hepatology. 2005;42:612A. [Abstract #1059]

14. Bailey S, Robinson G, Pinner A, et al. Mitochondrial dysfunction and NASH in response to a high-fat diet in mice: A functional proteomics approach. Hepatology. 2005;42:630A. [Abstract #1103]

15. Horvath, TL, Diano, S, Sotonyi, P, Heiman, M, Tschöp, M. (2001) Ghrelin and the regulation of energy balance—a hypothalamic perspective Endocrinology 142,4163-4169

16. Kojima, M, Hosoda, H, Date, Y, Nakazato, M, Matsuo, H, Kangawa, K. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach Nature 402,656-660

17. Tschöp, M, Smiley, DL, Heiman, ML. (2000) Ghrelin induces adiposity in rodents Nature 407,908-91318. Wren, AM, Seal, LJ, Cohen, MA, et al (2001) Ghrelin enhances appetite and increases food intake in

humans J Clin Endocrinol Metab 86,599219. D.E., Weigle D S., Frayo R.S,. Breen PA, Ma MK, Dellinger E.P, and Purnell JQ. (2002): Plasma

Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery. The New England J. of Med.; 346(21):1623-1630.

20. D.E., Weigle D S., Frayo R.S,. Breen PA, Ma MK, Dellinger E.P, and Purnell JQ. (2002): Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery. The New England J. of Med.; 346(21):1623-1630.

21. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS 2001 A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714–1719.

22. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ 2002 Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 346:1623–1630.

23. Caixás A, Bashore C, Nash W, Pi-Sunyer F, Laferrére B 2002 Insulin, unlike food intake, does not suppress ghrelin in human subjects. J Clin Endrocrinol Metab 87:1902–1906.

24. Hosoda, H. et al. : Biochem. Biophys. Res. Commun., 279 : 909, 200025. Matsumoto, M. et al. : Biochem. Biophys. Res. Commun., 287 : 142, 2001

26. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S 2002 Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 87:240–244.

27. Tschöp M, Smiley DL, Heiman ML 2000. Ghrelin induces adiposity in rodents. Nature 407:908–91328. Tschöp M, Statnick MA, Suter TM, Heiman ML 2002. GH-releasing peptide-2 increases fat mass in

mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology 143:558–568

29. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschop M 2001 Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 145:669–673 .

30. Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML 2001 Circulating ghrelin levels are decreased in human obesity. Diabetes 50:707–709.

31. Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS, Jorgensen JO 2002 Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol (Oxf) 56:203–206.

32. Schöfl C, Horn R, Schill T,. Schlösser HW,. Müller MJ and Brabant G (2002): Circulating Ghrelin Levels in Patients with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 10 4607-4610.

33. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, Deghenghi R, Ghigo E (2001): Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 86:5083–5086.

34. Egido EM, Rodriguez-Gallardo J, Silvestre RA, Marco J (2002): Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion. Eur J Endocrinol 146:241–244.

35. Lee H, Wang G, Englander EW, Kojima M, Greeley Jr GH (2002): Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 143:185–190.

36. Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H, Yada T, Matsukura S (2002): Ghrelin is present in pancreatic -cells of humans and rats and stimulates insulin secretion. Diabetes 51:124–129.

37. Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima M, Kangawa K, Matsukura S (2001): Upregulation of ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 281:1220–1225

38. Allison C, (2002): Intragastric balloons: a temporary treatment for obesity. Issues Emerg. Health Technol. 79:1-4.).

39. Hirsch DP; Mathus-Vliegen EM; Dagli U; Tytgat GN (2003); Boeckxstaens GE. Effect of prolonged gastric distention on lower esophageal sphincter function and gastroesophageal reflux. Am J Gastroenterol. 98 (8): 1696-704.

40. Al-Momen A; and El-Mogy I (2005): Intragastric balloon for obesity: a retrospective evaluation of tolerance and efficacy. Obes. Surgery; 15 (1): 101-5.

41. Genco A; Bruni T; Doldi SB; Forestieri P; Marino M; Busetto L; Giardiello C; Angrisani L; Pecchioli L; Stornelli P; Puglisi F; Alkilani M; Nigri A; Di Lorenzo N; Furbetta F; Cascardo A; Cipriano M; Lorenzo M; Basso N. (2005): BioEnterics Intragastric Balloon: The Italian Experience with 2,515 Patients. Obes. Surgery; 15 (8): 1161-4.

42. Totté E; Hendrickx L; Pauwels M; Van Hee R ( 2001): Weight reduction by means of intragastric device: experience with the bioenterics intragastric balloon. Obes. Surgery; 11 (4): 519-23.

43. Mion F; Napoléon B; Roman S; Malvoisin E; Trepo F; Pujol B; Lefort C; Bory RM ( 2005): Effects of intragastric balloon on gastric emptying and plasma ghrelin levels in non-morbid obese patients. Obes. Surgery; 15 (4): 510-16.

44. Vogin,GD (2002): New Hope for Morbid Obesity DDW Annual Meeting: Abstracts 100609, 100427. May 20 and May 22, 2002. Medscape Medical News 2002.

45. Doldi SB; Micheletto G; Perrini MN; Librenti MC; Rella S (2002): Treatment of morbid obesity with intragastric balloon in association with diet. Obes. Surg. 12 (4): 583-7.

46. Tiikkainen M, Bergholm R, Vehkavaara S, Rissanen A, Hakkinen AM, Tamminen M, Teramo K, Yki-Jarvinen H: Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 52:701-707,2003.

47. Naveed Sattar; Olga Scherbakova; Ian Ford; Denis St. J. O'Reilly; Adrian Stanley; Ewan Forrest; Peter W. MacFarlane; Chris J. Packard; Stuart M. Cobbe; James Shepherd (2004): Elevated Alanine Aminotransferase Predicts New-Onset Type 2 Diabetes Independently of Classical Risk Factors, Metabolic Syndrome, and C-Reactive Protein in the West of Scotland Coronary Prevention Study. Diabetes 53(11):2855-2860, 2004.

48. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202-1219.

49. Dasarathy , Dasarathy J, Thiruppathi S, et al. Prevalence of non alcoholic fatty liver disease in the United States: a prospective study. Gastroenterology. 2005;128(suppl 2):A-543. [Poster T1752]

مرض لعالج كوسيلة الوزن النقاص المعدة بالون استخدامالكبدى التشمع

الغرلي مستوى على وتأثيرها كحولى بالدم نالغير المعدي .

. لألبحاث بلهارس تيودور معهد المتوطنة األمراض قسم شريف شندى محمد شندىالكيمياء قسم العسالى لألبحاث اإلكلينيكيةنهال بلهارس تيودور معهد

وان الغذائى التمثيل متالزمة مكونات أحد كحولى الغير الكبدى التشمع مرض يعتبرقى الدهون لتراكم المسببة العوامل أهم هى لألنسولين االستجابة وعدم السمنة

. ف ثم ومن وتليفه التهابه ثم ومن الكبد الحمية ٳخاليا باستخدام الوزن إنقاص نهذا لعالج اإلطالق على الفعالة الوسائل أهم يعتبر الرياضة وممارسة الغذائية

يستجيبو. ال المرضى هؤالء من الكثير ولكن يبحثون نالمرض ما وعادة الوسائل لذه . من الهدف كان وقد للوزن أكثر انقاص فى للمساعدة جراحى أو دوائي تدخل عنفى الوسيلة هذه مع المرضى وتأقلم وأمان واستعمال كفاءة تقييم هو البحث هذا

و الكبد حالة على الوزن انقاص فى وتأثيرها كحولى الغير الكبدى التشمع مرضىالغرلي مستوى و الغذائى التمثيل . نخلل الدراسة شملت وقد بالدم ٣٦المعدي

الكبدى االلتهاب دالئل وجود مع المفرطة السمنة أو السمنة من يعانون بالغا مريضامعدل. و الخاصر محيط و والطول الوزن لمعرفة اكلينيكا فحصهم تم وقد التشمعى

الخاصر عند المحيط الى الحوض مفصل عند المحيط ونسبة الحسابى الجسم كتلةالكبد ووظائف الكيميائية الفحوص الى باالضافة هذا األخري، الحيوية والعالمات

البوابية الحلزونية والبكتريا صوتية الفوق وبعد والموجات وجود أثناء و قبل وذلكلمدة البالون . ٦إزالة والقئ أشهر بالغثيان الشعور أن البحث هذا فى لوحظ وقد

البالون تركيب بعد المرضى منها اشتكى التى األعراض أكثر كانت المعدة وأالمفى الترتيب حسب حدثت الترتيب ٦٧و٪ ٨٩و٪ ١٠٠وقد حسب تتراوح مدة فى وذلك ٪

من . ٣٤־٣و ٧־٣و ١٢ ־ ٢أيضا فى المرئ المعدي االرتداد من شكوى وحدثت ٪.٣١يومامحيط و الوزن من كل على إحصائية داللة ذو المعدة لبالون االيجابى التأثير وكان

الى الحوض مفصل عند المحيط ونسبة الحسابى الجسم كتلة معدل و الخاصرالغرلي مستوى و الجلد وسمك الخاصر عند و نالمحيط والكولسترول بالدم المعدي

نقص متوسط كان حيث الكبد وإنزيمات والسكر البوليك وحمض الثالثية الدهونالجسم ٥٫٨٩± ٢٠٫٩٨الوزن كتلة معدل وفى انخفضت ٦بعد ٢٫٠٣± ٧٫٥٥كجم وقد أشهر

من أقل إلى الكبد . ١٫٥إنزيمات وانخفضت المرضى جميع فى الطبيعى المعدلالكبد ) فى ALT)إنزيمات الطبيعى بعد ٣٠إلى وفى ٦مريضا بعد ٦ ־٣بعد ٣٢أشهر من أشهر

( . الكبد إنزيمات وانخفضت البالون المرضى AST)إزالة جميع فى الطبيعى إلىبعد بعد ٦فقط اثنين ماعدا . ٦ ־٣أشهر النمط تحسن وقد البالون إزالة بعد من أشهر

االتجا فى إحصائية داللة ذو تحسنا وحجمه للكبد كل هالصوتى فى الطبيعىومقبولة. وفعالة متاحة وسيلة المعدة بالون أن البحث هذا من يستنتج المرضى

الوزن إنقاص استمرار أن ثبت كما الوزن إلنقاص استخدامها ويمكن آمنة أنها حيثالمدخل تعتبر الرياضة وممارسة الغذائية الحمية مع المعدة بالون بواسطة

فى بما الغذائى التمثيل لمتالزمة المصاحبة واألمراض الخاطر من للحد الرئيسىو الكبد إنزيمات ارتفاع مثل التشمعى الكبدى االلتهاب وعالمات أعراض ذلك

. الغرلي مستوى فى الداللة ذو االنخفاض وان الصوتى النمط وزيادة نتضخمهالتمثيل عوامل بعض تحسن و الشهية بتقليل عالقة له يكون قد بالدم المعدي

الغذائى.