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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

Background : Treatment options for non-alcoholic steatohepatitis (NASH) are limited. Weight loss remains the most recommended therapy. Orlistat is an effective adjunct to dietary weight loss therapy.

Aim : To evaluate the efficacy of orlistat, given for 6 months to patients with obesity and biopsy confirmed NASH.

Methods : Ten obese patients with biopsy proven NASH were enrolled. Orlistat was given with meals for 6 months. Body Mass Index (BMI), liver enzymes, haemoglobin A1c, fasting lipids and glucose were assessed at baseline and at completion of the study. Paired liver histology was obtained.

Results : Six women and four men were enrolled. The mean weight loss was 22.7 lb and ranged from 0 to 24.3%. The following clinical values significantly improved: mean BMI: 43.4–39.8 (P = 0.007); mean haemoglobin A1c (%): 7.14–5.95 (P = 0.021); mean alanine aminotransferase (ALT) (U/L): 93 –54 (P = 0.009); and mean aspartate aminotransferase (AST) (U/L): 79–48 (P = 0.008). Steatosis improved in six patients, and fibrosis improved in three patients.

Conclusions : Orlistat therapy and dietary counselling were associated with significant decreases in body weight, haemoglobin A1c, ALT and AST. A 10% or greater reduction in weight improved steatosis and fibrosis as well as haemoglobin A1c levels in the majority of patients treated for 6 months. Controlled trials of longer duration are warranted to assess for histopathologic improvement as well as cost-efficacy in comparison to diet and exercise alone.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

The most recent National Health and Education Survey (NHANES) revealed that 30.5% of adult Americans are obese1 and the percentage continues to increase. As a result, the incidence of diabetes mellitus is also increasing.2, 3 Since non-alcoholic steatohepatitis (NASH) is strongly associated with obesity and diabetes,4 it is likely that the incidence of NASH is increasing as well. Natural history studies show that up to 16% of patients with NASH may progress to cirrhosis4 and some of these patients will develop end-stage liver disease and/or possibly hepatocellular carcinoma,5–7 necessitating liver transplant.8 Currently, therapeutic options are limited.9 Standard practice has been to advocate weight loss and exercise, but supporting data are limited to small trials with varied results.10–15

Orlistat, a reversible inhibitor of gastric and pancreatic lipases, blocks the absorption of approximately 30% of dietary triglycerides and was approved by the FDA in 1999 for the management of obesity. Data indicate that 38% of patients treated with orlistat and a low-fat diet for 1 year lose at least 5–10% of their baseline bodyweight.16 The effect of orlistat on NASH is unknown. Consequently, we designed a pilot trial of orlistat therapy for obese NASH patients. The aim of our study was to evaluate the efficacy of orlistat, given for 6 months to patients with obesity and histologically confirmed NASH.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

Ten obese patients with histologically confirmed NASH were randomly selected and enrolled from the outpatient Gastroenterology Clinic at Brooke Army Medical Center. The protocol was approved by the Institutional Review Board and all patients gave informed consent. Patients were excluded from the study if they had evidence of other causes of liver disease or severe liver disease defined as a serum albumin less than 3 g/dL, a platelet count less than 70 000/mm3 or clinical signs of decompensation (e.g. variceal bleeding, ascites, hepatic encephalopathy). Patients were excluded if they were less than 18 or greater than 75 years of age. All patients were placed on a 1400 cal/day diet, evaluated and counselled by a registered dietician, and joined a weight loss counselling program sponsored by the manufacturer of orlistat termed ‘Xenicare®’. All patients took orlistat 120 mg three times daily with meals for a total of 6 months. Laboratory data obtained at enrolment and at study completion included Body Mass Index (BMI), liver enzymes, fasting glucose, haemoglobin A1c and fasting lipids. Repeat, end of treatment, liver biopsies were performed on all patients and interpreted in a blinded fashion by a single pathologist (S.T.), using a previously published scoring system, with modification17 (Table 1).

Table 1.  Outline for grading and staging of liver biopsy specimens*
  1. * Modified from Brunt et al (17).

Grading for necroinflammatory activity (combined score of inflammation and hepatocyte degeneration and necrosis)
Inflammation
 0None
 1Scattered, rare intra-acinar neutrophils. Variable intra-acinar lymphocytes. Little to no portal inflammation
 2Intra-acinar neutrophils more prominent but without significant associated necrotic hepatocytes. Intra-acinar chronic inflammation also noted. Mild to moderate portal inflammation
 3Intra-acinar neutrophils prominent and associated with increased hepatocyte degeneration/necrosis. Intra-acinar chronic inflammation also noted. Mild to moderate portal inflammation
Hepatocyte degeneration/necrosis
 0None
 1Occasional ballooning degeneration of hepatocytes, limited to zone 3. No hepatocyte necrosis
 2Obvious ballooning degeneration of hepatocytes, most marked in zone 3. May have rare necrotic hepatocytes
 3Ballooning degeneration of hepatocytes with hepatocyte disarray. Degeneration may be pan-ancinar. Hepatocyte necrosis more prominent than in two with associated inflammatory cells
Staging for fibrosis
 1Zone 3 perisinusoidal/pericellular fibrosis; focally or extensively present
 2Zone 3 perisinusoidal/pericellular fibrosis with focal or extensive periportal fibrosis
 3Zone 3 perisinusoidal/pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis
 4Cirrhosis

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

Frequencies and descriptive statistics were performed on all clinical, histological and biochemical parameters. Because of the limited sample size of this pilot study, non-parametric statistical analyses were utilized. The Wilcoxin signed rank test was used to evaluate changes between the pre- and post-clinical and biochemical parameters after treatment with orlistat. A two-tailed alpha level of <0.05 was considered statistically significantly different. All evaluations were performed using the Statistical Package for the Social Sciences (spss) software, Chicago, IL.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

A total of 10 patients were enrolled. The mean age of our study cohort was 54.4 years (range: 46–64), with six women. The majority were Caucasian. There were six patients with hyperlipidemia, seven patients with diabetes mellitus and nine patients with documented hypertension. Four patients had all three conditions clinically associated with NASH.

All patients completed the 6-month study and had repeated liver biopsies. The mean weight loss was 22.7 lb with eight of 10 patients losing some weight (Figure 1). The mean BMI decreased significantly from 43.4 kg/m2 pre-treatment to 39.8 kg/m2 post-treatment (P = 0.007). Two patients did not lose weight, but they admitted to dietary and medication non-compliance. Of the patients who lost weight, the percent body weight lost ranged from 4.4 to 24.3%. Five patients lost at least 10% of their body weight.

image

Figure 1. Amount of weight loss (lb and %) in obese non-alcoholic steatohepatitis patients treated with orlistat.

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The clinical and biological responses to treatment are shown in (Table 2). Mean ALT (U/L) improved from 93 to 54 (P = 0.009); AST (U/L) improved from 79 to 48 (P = 0.008). Haemoglobin A1c levels improved from 7.14 to 5.95 (P = 0.021). A decrease in fasting mean glucose, total cholesterol or triglyceride levels was seen but did not reach statistical significance, (P > 0.05).

Table 2.  Comparison of the clinical and biochemical responses (mean ± s.d.) to treatment with orlistat in obese patients diagnosed with non-alcoholic steatohepatitis (n = 10 subjects)
 Pre-treatmentPost-treatmentP-value*
  1. * Pre- and post-treatment comparisons assessed using Wilcoxin signed rank test.

Body Mass Index (kg/m2)43.4 ± 6.039.8 ± 4.80.007
Total cholesterol (mg/dL)190 ± 36183 ± 330.092
Triglycerides (mg/dL)158 ± 86147 ± 530.575
HgbA1C (%)7.14 ± 1.95.95 ± 1.00.021
ALT (IU/L)93 ± 3954 ± 320.009
AST (IU/L)79 ± 3648 ± 230.008
Fasting glucose (mg/dL)145 ± 67110 ± 210.262

Repeat liver biopsies were performed in all patients and compared with pre-treatment histology. The average length of the biopsy specimen was 1.78 cm. The results are divided into three categories: inflammation/necrosis grade; fibrosis stage; and steatosis percentage. Inflammatory activity was essentially unchanged in our small study group, improving by one grade in two patients. No worsening in inflammation was noted in any patient. Fibrosis improved by 1 point in three patients, and one patient had a one-stage worsening in fibrosis (Figure 2). Steatosis improved in six patients, ranging from a 10 to 30% improvement (Figure 3). Two patients had no change in steatosis and two patients had slight worsening. Three of the five patients who lost at least 10% of their body weight had a one-stage improvement in fibrosis. Additionally, the majority of patients tolerated therapy without serious side effects. However, the two patients who did not adhere to the recommended diet complained of increased flatus, oily discharge and increased stool frequency, symptoms that discouraged them from taking the drug as prescribed.

image

Figure 2. Fibrosis stage for each patient before and after treatment with orlistat.

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image

Figure 3. Percent steatosis in each patient before and after treatment with orlistat.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

While much has been learned in recent years about NASH, therapeutic modalities to treat this disease remain limited. In clinical practice, patients are often told to lose weight and exercise, but specific guidance on the amount of weight loss or the type and duration of exercise is not available. The effect of weight loss in patients with NASH has been evaluated in a few small, non-randomised trials.10–14 These studies have yielded mixed results. Total or near total starvation diets appear to improve liver enzymes and steatosis, but may worsen underlying inflammation and fibrosis.10,14 Steady weight loss, especially those achieving at least a 10% reduction in weight, appears to improve both liver enzymes and histology.11–13

Orlistat, a reversible inhibitor of gastric and pancreatic lipases, has been approved by the FDA for weight loss. It is not absorbed into the circulation and is mainly excreted unchanged in the faeces. Data suggest that when combined with dietary counselling, approximately 40% of patients treated for 1 year were able to lose up to 10% of their body weight.

Published data with the use of orlistat in NASH patients is limited. A case series of three obese patients with biopsy proven NASH showed improvement in steatosis, inflammation and fibrosis when treated for at least 6 months. All patients lost at least 20 lb. Liver enzymes normalized in all three patients and follow-up histology revealed significant improvement in steatosis, inflammation and fibrosis.18

This current study demonstrates that Orlistat, along with dietary counselling, is effective in reducing body weight in the majority of patients, and appears to be well tolerated. Weight loss significantly improved aminotransferase levels and haemoglobin A1c levels. Fasting serum glucose and lipid profiles showed trends towards improvement, although these changes did not reach statistical significance.

Three patients who were able to lose at least 10% of their body weight had improvement in fibrosis, and three patients improved both fibrosis and steatosis. This seems to corroborate previously published work11, 13 demonstrating that steady weight loss improves aminotransferase levels, hepatic steatosis and in some patients, hepatic fibrosis. Furthermore, haemoglobin A1c and fasting glucose levels improved in these patients, suggesting that improved insulin utilization coincided with improved histopathologic activity. This is consistent with previous data demonstrating that histopathologic improvement in NASH patients is associated with improved insulin utilisation.19

Several limitations to this trial exist. First, in this pilot trial there is no parallel control group. Previously published trials in NASH have demonstrated that the control group can have histopathologic improvement as well.20, 21 However, concomitant improvement in aminotransferases and surrogate markers of insulin resistance argue for histologic improvement arising from orlistat induced weight loss. Additionally, the treatment interval was only 6 months, which may be too short of a follow-up period to demonstrate large changes in histopathology with therapy.

In conclusion, our pilot trial agrees with previously published data suggesting that weight loss amounting to at least a 10% reduction in body weight improves both biochemical and histological profiles in the majority of obese NASH patients. Orlistat may be an effective adjunct to dietary counselling in this subgroup of obese patients. Consequently, controlled trials of longer duration are warranted to assess for histopathologic improvement as well as cost-efficacy in comparison to diet and exercise alone.

Disclaimer statement

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References

The opinion of ascertains contained herein are the private views of the authors and are not to be construed as official or reflecting the view of the Department of the Army or the Department of Defense.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. Disclaimer statement
  10. References
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