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In a biopsy series, leaner Asian NASH patients were found to be less likely to have advanced fibrosis
and cirrhosis than Caucasians [6]. In a large Indian population-screening study using ultrasonography,
computed tomography and TE, 7% and 32% of the patients with BMI <25 kg/m2 and ≥25 kg/m2,
respectively, had fatty liver [3]. Seventy-five percent of the NAFLD patients had BMI <25 kg/m2. Among
a subgroup of NAFLD patients who underwent liver biopsy, 31% had NASH and 11% had cirrhosis.
Clinical outcome data of lean patients with NASH are limited. The incidence of HCC appears
to be slightly lower for NASH-related cirrhosis than hepatitis C-related cirrhosis in Caucasians but
remains significant at 1-2% per year. In less obese Asian populations, NASH-related HCC is relatively
uncommon. However, the difference may not be due to BMI alone. Like all chronic liver diseases, the
duration of disease determines the risk of cirrhosis and complications. In some developing countries
where nutritional abundance has only occurred recently, most NASH patients only have a short duration
of disease and have not had time to progress to cirrhosis and HCC.
This suggests that NASH and advanced fibrosis also occur in lean patients, albeit at a lower rate. Non-
invasive tests are thus preferred to exclude the small proportion of patients with significant disease.
What causes NAFLD in lean patients?
There are two possible explanations for the development of NAFLD in lean patients. First, this may
represent the milder end of the full spectrum of NAFLD/NASH. Second, patients may develop NAFLD
despite normal or low BMI because of other risk factors.
Genetics
Recent genome-wide association studies have identified a number of gene polymorphisms associated
with NAFLD/NASH. For example, the patatin-like phospholipase domain-containing protein 3
(PNPLA3) gene has been consistently shown to be associated with NAFLD and its histological severity.
PNPLA3 hydrolyses emulsified triglycerides in hepatocytes, and the I148M substitution abolishes the
enzymatic activity. As a result, the secretion of very low-density lipoproteins by hepatocytes is impaired.
Interestingly, the relative effect of PNPLA3 polymorphism on hepatic steatosis is more profound in
patients without MetS.
Similarly, apolipoprotein C3 (APOC3) gene variants have been shown to increase the risk of NAFLD in
Indians [7]. Carriers of the variant alleles have hypertriglyceridemia and reduction in plasma triglyceride
clearance. However, the effect of this gene variant is less apparent in subsequent validation studies in
Europeans.
Taken together, genetic predisposition to NAFLD has greater effects in patients with lower metabolic
burden. This partly contributes to the development of NAFLD in lean patients.
Weight gain
BMI and hepatic steatosis are both dynamic and subject to short-term changes. Among NAFLD
patients with normal BMI, recent weight gain is often observed. Healthy young people can quickly
develop increases in hepatic steatosis and aminotransferase levels through short-term excessive eating
and sedentary lifestyle [8]. In a study using paired proton-magnetic resonance spectroscopy to measure
hepatic steatosis in lean community subjects, increases in waist circumference and plasma triglycerides
were associated with incident fatty liver [9].
Central obesity
BMI is an imperfect measurement of adiposity. Patients with normal BMI can have central and visceral
obesity. As such, lean patients with NAFLD are often found to have greater waist circumference or
waist-to-hip ratio.
38 Postgraduate Course Syllabus • Metabolic Liver Disease
and cirrhosis than Caucasians [6]. In a large Indian population-screening study using ultrasonography,
computed tomography and TE, 7% and 32% of the patients with BMI <25 kg/m2 and ≥25 kg/m2,
respectively, had fatty liver [3]. Seventy-five percent of the NAFLD patients had BMI <25 kg/m2. Among
a subgroup of NAFLD patients who underwent liver biopsy, 31% had NASH and 11% had cirrhosis.
Clinical outcome data of lean patients with NASH are limited. The incidence of HCC appears
to be slightly lower for NASH-related cirrhosis than hepatitis C-related cirrhosis in Caucasians but
remains significant at 1-2% per year. In less obese Asian populations, NASH-related HCC is relatively
uncommon. However, the difference may not be due to BMI alone. Like all chronic liver diseases, the
duration of disease determines the risk of cirrhosis and complications. In some developing countries
where nutritional abundance has only occurred recently, most NASH patients only have a short duration
of disease and have not had time to progress to cirrhosis and HCC.
This suggests that NASH and advanced fibrosis also occur in lean patients, albeit at a lower rate. Non-
invasive tests are thus preferred to exclude the small proportion of patients with significant disease.
What causes NAFLD in lean patients?
There are two possible explanations for the development of NAFLD in lean patients. First, this may
represent the milder end of the full spectrum of NAFLD/NASH. Second, patients may develop NAFLD
despite normal or low BMI because of other risk factors.
Genetics
Recent genome-wide association studies have identified a number of gene polymorphisms associated
with NAFLD/NASH. For example, the patatin-like phospholipase domain-containing protein 3
(PNPLA3) gene has been consistently shown to be associated with NAFLD and its histological severity.
PNPLA3 hydrolyses emulsified triglycerides in hepatocytes, and the I148M substitution abolishes the
enzymatic activity. As a result, the secretion of very low-density lipoproteins by hepatocytes is impaired.
Interestingly, the relative effect of PNPLA3 polymorphism on hepatic steatosis is more profound in
patients without MetS.
Similarly, apolipoprotein C3 (APOC3) gene variants have been shown to increase the risk of NAFLD in
Indians [7]. Carriers of the variant alleles have hypertriglyceridemia and reduction in plasma triglyceride
clearance. However, the effect of this gene variant is less apparent in subsequent validation studies in
Europeans.
Taken together, genetic predisposition to NAFLD has greater effects in patients with lower metabolic
burden. This partly contributes to the development of NAFLD in lean patients.
Weight gain
BMI and hepatic steatosis are both dynamic and subject to short-term changes. Among NAFLD
patients with normal BMI, recent weight gain is often observed. Healthy young people can quickly
develop increases in hepatic steatosis and aminotransferase levels through short-term excessive eating
and sedentary lifestyle [8]. In a study using paired proton-magnetic resonance spectroscopy to measure
hepatic steatosis in lean community subjects, increases in waist circumference and plasma triglycerides
were associated with incident fatty liver [9].
Central obesity
BMI is an imperfect measurement of adiposity. Patients with normal BMI can have central and visceral
obesity. As such, lean patients with NAFLD are often found to have greater waist circumference or
waist-to-hip ratio.
38 Postgraduate Course Syllabus • Metabolic Liver Disease
