Weight loss induced by orlistat reverses fatty infiltration and improves hepatic fibrosis in obese patients with non‐alcoholic steatohepatitis

Non‐alcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis and cirrhosis.¹,² To date, treatment has been restricted to diet and weight loss, but without compelling results. Orlistat (Xenical) is a natural lipase inhibitor, which reduces the absorption of dietary fat by 30%³ and improves insulin resistance and lipid profile.⁴,⁵ Whether or not orlistat reverses hepatic fibrosis and inflammation in obese patients with NASH has not been assessed.

A total of 14 obese patients with NASH underwent liver biopsy before and after 6 months treatment with orlistat (120 mg thrice daily). Patients were also provided a moderate calorie‐restricted diet with a median daily intake of 25 kcal/kg body weight/day. Parameters of oxidative stress, insulin resistance, lipids and liver histology were measured. All patients signed informed consent. Of 22 recruited patients, 14 (10 women and 4 men, mean (SD) age of 42 (3) years, and body mass index of 31.5 kg.m²) completed the study. In all, four patients had mixed hyperlipidaemia, five had diabetes mellitus type 2 and five had obesity alone.

Orlistat reduced fatty infiltration in 10 patients (70%, p<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. A total of 5 (35%) patients returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in 3 (21%) patients and by 1 grade in 7 (50%) patients. There was no change in 4 (28%) patients. The mean (SD) weight decreased from 94.1 (15.5; median 93.5) kg pretreatment to 89 (15.1; median 87.0) kg post treatment (–5.3% change). One patient did not lose weight. Of the patients who lost weight, the percentage of body weight lost ranged from (–2.3% to –16.3%, median –5%, mean (SD) 5.4 (4.3)%). Seven patients lost at least 6% of their body weight. The weight loss correlated only with the extension of fat (r = 0.5), but not with the changes in fibrosis or in inflammation. A significant improvement in serum levels of alanine aminotransferase, aspartate aminotransferase and lipids occurred at the end of treatment with orlistat (alanine aminotransferase 84 (10) IU/l vs 43 (5) IU/l, p<0.001; aspartate aminotransferase 72 (11) IU/l vs 32 (4) IU/l, p<0.001; total cholesterol 229 (12) mg/dl vs 194 (13) mg/dl, p<0.001), triglycerides 238 (23) mg/dl vs 163 (10) mg/dl, p<0.001) and LDL 143 (11) mg/dl vs 120 (5) mg/dl, p<0.003). Similarly, insulin resistance index and malondialdehyde (MDA) levels improved significantly after orlistat treatment, whereas HbAıc remained unchanged (homeostatic model assessment index, normal 0.8–5.4; 6.5 (2.5) vs 3.3 (1.2), p<0.05; MDA normal <0.3 nmol/ml; 0.47 (0.03) nmol/ml vs 0.37 (0.02) nmol/ml; p<0.01), and (HbAıc normal 3.8–6.4%, 7.1 (3.1)% vs 7.5 (2.6)%, p>0.05).

The mechanism underlying the effect of orlistat remains unknown. Orlistat reduces the absorption of dietary fat and modulate insulin action by changing not only the amount of fat delivered to the liver, but also by changing the type of fat. Saturated fatty acids increase insulin resistance, whereas unsaturated fat, particularly monounsaturated fat, improves insulin sensitivity.⁶ Patients with hypertriglyceridaemia have raised tumour necrosis factor‐α, which induces systemic inflammation.⁷ Whether the reduced levels of postprandial triglycerides induced by orlistat lowers the inflammatory component associated with NASH remains to be determined. MDA may reflect the process of lipid peroxidation occurring in the liver.⁸ However, it could be an expression of an enhanced production of free radicals in the circulation as documented in obese patients and patients with diabetes.⁹ In our patients, MDA levels were reduced with orlistat treatment, which may be due to the lowering of plasma low density lipopritein (LDL) levels, which may increase cellular LDL receptors synthesis. This will shorten the time of residence of LDL in the plasma, and thereby reduces its exposure to free radicals and preserves LDL antioxidant content, which make it more resistant to oxidation.

One limitation of our clinical study is absence of a placebo group. Thus, all the changes observed could be nonspecific and do not necessarily reflect any unique property of orlistat. Therefore, trials comparing orlistat‐induced weight loss against the effect of similar weight loss induced by dieting or exercise are needed before any claim that orlistat has a specific benefit can be substantiated.

Table 1 Baseline histological features and changes after 6 months of treatment with orlistat.

Patient	Fat extension before treatment	Fat extension after treatment	Inflammation before treatment	Inflammation after treatment	Fibrosis before treatment	Fibrosis after treatment	Weight change (%)
1	Severe	Severe	A2	A0	F2	F0	−2.9
2	Severe	Mild	A2	A1	F2	F1	−4.5
3	Mild	Normal	A4	A2	F2	F3	−8.4
4	Mild	Normal	A2	A2	F1	F1	−2.4
5	Severe	Mild	A2	A0	F2	F0	−8.2
6	Severe	Severe	A2	A1	F2	F1	−2.3
7	Moderate	ild	A1	A1	F1	F0	−5.5
8	Severe	Severe	A2	A1	F2	F1	+3
9	Severe	Mild	A2	A1	F1	F0	−16.3
10	Severe	Moderate	A2	A2	F2	F1	−3.3
11	Severe	Severe	A3	A2	F3	F1	−7.3
12	Mild	Normal	A1	A0	F1	F1	−6.3
13	Moderate	Mild	A1	A0	F1	F0	−4.1
14	Severe	Mild	A2	A0	F2	F2	−6.9

Fat extension: normal  =  <10%, mild  =  <30%, moderate  =  30–60%, severe  =  >60%. Fibrosis scale: 0  =  none, F1 =  portal, F2  =  portal +septa, F3  =  bridging, F4  =  cirrhosis. Portal & periportal inflammatory activity (A): 0 = normal, 1 = mild, 2 = moderate, 3 = severe.