Biochemical Markers in the Diagnosis of Nonalcoholic Fatty Liver Disease
Biochemical Markers in the Diagnosis of Nonalcoholic Fatty Liver Disease
Fatty liver is a common histologic finding in human liver biopsy specimens. It affects 10% to 24% of the general population and is believed to be a marker of risk of later chronic liver disease. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction, as determined by liver function testing, and it has been estimated that, with increasing levels of obesity in the United States, 20 million patients are affected.
NAFLD represents a spectrum of diseases, ranging from simple fatty liver (steatosis) to steatosis with inflammation and necrosis to cirrhosis that occurs in people who drink little or no alcohol. Nonalcoholic steatohepatitis (NASH) represents the more severe end of this spectrum and is associated with progressive liver disease, fibrosis, and cirrhosis. The major risk factors are obesity and insulin resistance, and the prevalence of these risk factors has increased rapidly throughout the world.
NAFLD is rapidly becoming an important problem. Undiagnosed, this condition may progress silently and result in cirrhosis, portal hypertension, and liver-related death in early adulthood. Mass screening for significant liver injury in patients with NAFLD will be an important medical challenge in the years to come because of the epidemics of obesity and diabetes. The inability of liver biopsy to meet this challenge makes the development of noninvasive, readily available, and easy-to-perform serum markers a high priority.
Recently, the increase or decrease in alanine aminotransferase (ALT) has been used as a marker to diagnose or monitor treatment for NASH. Serum ALT levels are often increased above the normal range in many patients, although the increase is less than that observed with alcoholic liver cirrhosis. Obesity is the condition most commonly associated with NAFLD, and, therefore, weight loss is frequently advocated, which may result in reductions in ALT in some patients. However the level of serum ALT can be misleading when assessing treatment efficacy and for predicting the outcome of NASH. Previously, treatment with ursodeoxycholic acid, vitamin E, and vitamin C decreased the serum ALT level but failed to show a parallel improvement in histologic features of disease. Treatment with vitamin E in obese and nonobese children for 3 to 6 months normalized the serum ALT level without significant improvement in the histologic features of NASH.
Serum γ-glutamyltransferase (GGT) was associated with several cardiovascular risk factors, and it was found to predict hypertension, diabetes, stroke, and coronary heart disease. In particular, there is strong evidence that the serum GGT level shows a dose-response relationship with incident diabetes, even within its normal range. The level of serum GGT is often increased above the normal range in many patients with NASH, although the increase is less than that observed with alcoholic cirrhosis.
The pathogenesis of NASH remains uncertain, but insulin resistance is involved in most cases that is not dependent on body mass index but is related to central obesity, which is common in people with NASH. Typically, the levels of nonesterified fatty acids (NEFAs) are elevated in persons with central abdominal obesity. NASH is often present in up to 30% of patients with type 2 diabetes or impaired glucose tolerance, and NASH may occasionally be a manifestation of diabetes mellitus. Increased fatty acid supply to the liver resulting from resistance to the antilypolytic action of insulin may be important. Furthermore, mobilization of fatty acids may also contribute to impaired glucose tolerance and type 2 diabetes. NASH has been noted in 34% to 75% of patients with an increased plasma glucose concentration. An autopsy study noted a trend toward a higher prevalence of NASH in patients with type 2 diabetes, whereas in contrast with type 2 diabetes, fatty liver is rare in subjects with type 1 diabetes mellitus. In 2 large separate studies of patients undergoing antiobesity surgery (551 patients by Marceau et al and 505 patients by Luyckx et al), the severity of NASH was closely related to impaired glycemia.
Haukeland et al concluded that abnormal glucose tolerance independently predicted NASH and fibrosis in 88 patients. Adams et al, in a study of 420 patients with NAFLD, showed that the overall death rate in patients with NAFLD was higher than expected, especially in patients with an impaired fasting glucose level or with diabetes.
The prevalence of diabetes for all age groups worldwide is estimated to be 4.4% in 2030, and the total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The ‘‘diabetes epidemic’’ will probably continue, even if levels of obesity remain constant. Adams et al reported that 22% of people were diagnosed with diabetes and 23% were reported to have hyperlipidemia.
In view of the increased mortality associated with an impaired fasting glucose level and with diabetes, it is important to screen for diabetes once a diagnosis of NAFLD is established. Interestingly, Holt et al, in a small study of 22 obese patients, proposed that the concentration of NEFAs is associated with fatty liver independent of classic measures of insulin resistance. Elevated NEFA levels have been associated with impaired glucose utilization, impaired suppression of glucose production, and impaired insulin secretion.
Because NEFAs are increasingly portrayed as villains in a web of metabolic disturbances that link these different conditions in metabolic syndrome and, in particular, insulin resistance, it is reasonable to propose that NEFAs and abnormal glucose tolerance are independent predictors of NASH. However, there are problems in using NEFAs as a risk factor for diabetes or cardiovascular disease. Only in the Quebec cardiovascular study were elevated NEFA concentrations found to be markers for future ischemic heart disease, but in a majority of other studies, they have been found to be less sensitive markers for future cardiovascular disease. In addition the day-to-day coefficient of variation of NEFAs is about 43%, which means, statistically, that they are not good markers for epidemiology.
Consistent with insulin resistance, low adiponectin levels in patients with NAFLD were reported and may represent a pathogenic mechanism leading to altered hepatocyte lipid metabolism and fat accumulation. In fact, high adiponectin levels have been reported to protect against alcoholic and nonalcoholic fatty liver disease in mice by reducing fatty acid synthesis through inhibition of acyl-CoA carboxylase and fatty acid synthase expression and activity. Further studies are needed before adiponectin can be used as a sensitive and specific biochemical marker.
Histologic examination helps to distinguish hepatic steatosis from NASH, identifies features of fibrosis, and facilitates estimation of long-term prognosis. However, it has been concluded that there was significant sampling variability in routine liver biopsies in patients with NAFLD. The sampling variability has the potential to alter significantly the diagnosis and staging of NAFLD and, thus, the pharmacologic therapies for NASH. In addition, there are several drawbacks in using liver biopsy because this procedure is invasive, costly, and prone to complications, some minor, such as pain, and others more severe, with a recorded risk of death of 0.01%. Most important, the number of patients at risk for NAFLD is high enough that liver biopsy is not a practical and efficient tool for identifying people at risk of advanced fibrosis in large cohorts of people. Indeed, an estimated 15% to 20% of the Western European population has steatosis, and more than half of Americans are overweight or obese.
There is no biochemical marker for fatty liver or NASH. (There are many biochemical markers for hepatic fibrosis.) Several biomarkers have been evaluated for sensitivity and specificity for hepatic fibrosis (apolipoprotein A1, haptoglobin, α2-macroglobulin, hyaluronic acid, and procollagen peptides such as types I, III, and VI), but none is being tested on a similar scale for NAFLD or NASH. One difficulty that remains is establishing biochemical markers that differentiate between alcoholic and nonalcoholic steatohepatitis. Recently, Ohtsuka et al suggested that carbohydrate-deficient transferrin could be used to differentiate between NASH and alcoholic hepatitis. The issue of whether NEFAs, abnormal glucose tolerance test results, adiponectin, and carbohydrate-deficient transferrin are markers or predictors of fatty liver or NASH will remain controversial; this can be established through further research.
Fatty liver is a common histologic finding in human liver biopsy specimens. It affects 10% to 24% of the general population and is believed to be a marker of risk of later chronic liver disease. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction, as determined by liver function testing, and it has been estimated that, with increasing levels of obesity in the United States, 20 million patients are affected.
NAFLD represents a spectrum of diseases, ranging from simple fatty liver (steatosis) to steatosis with inflammation and necrosis to cirrhosis that occurs in people who drink little or no alcohol. Nonalcoholic steatohepatitis (NASH) represents the more severe end of this spectrum and is associated with progressive liver disease, fibrosis, and cirrhosis. The major risk factors are obesity and insulin resistance, and the prevalence of these risk factors has increased rapidly throughout the world.
NAFLD is rapidly becoming an important problem. Undiagnosed, this condition may progress silently and result in cirrhosis, portal hypertension, and liver-related death in early adulthood. Mass screening for significant liver injury in patients with NAFLD will be an important medical challenge in the years to come because of the epidemics of obesity and diabetes. The inability of liver biopsy to meet this challenge makes the development of noninvasive, readily available, and easy-to-perform serum markers a high priority.
Recently, the increase or decrease in alanine aminotransferase (ALT) has been used as a marker to diagnose or monitor treatment for NASH. Serum ALT levels are often increased above the normal range in many patients, although the increase is less than that observed with alcoholic liver cirrhosis. Obesity is the condition most commonly associated with NAFLD, and, therefore, weight loss is frequently advocated, which may result in reductions in ALT in some patients. However the level of serum ALT can be misleading when assessing treatment efficacy and for predicting the outcome of NASH. Previously, treatment with ursodeoxycholic acid, vitamin E, and vitamin C decreased the serum ALT level but failed to show a parallel improvement in histologic features of disease. Treatment with vitamin E in obese and nonobese children for 3 to 6 months normalized the serum ALT level without significant improvement in the histologic features of NASH.
Serum γ-glutamyltransferase (GGT) was associated with several cardiovascular risk factors, and it was found to predict hypertension, diabetes, stroke, and coronary heart disease. In particular, there is strong evidence that the serum GGT level shows a dose-response relationship with incident diabetes, even within its normal range. The level of serum GGT is often increased above the normal range in many patients with NASH, although the increase is less than that observed with alcoholic cirrhosis.
The pathogenesis of NASH remains uncertain, but insulin resistance is involved in most cases that is not dependent on body mass index but is related to central obesity, which is common in people with NASH. Typically, the levels of nonesterified fatty acids (NEFAs) are elevated in persons with central abdominal obesity. NASH is often present in up to 30% of patients with type 2 diabetes or impaired glucose tolerance, and NASH may occasionally be a manifestation of diabetes mellitus. Increased fatty acid supply to the liver resulting from resistance to the antilypolytic action of insulin may be important. Furthermore, mobilization of fatty acids may also contribute to impaired glucose tolerance and type 2 diabetes. NASH has been noted in 34% to 75% of patients with an increased plasma glucose concentration. An autopsy study noted a trend toward a higher prevalence of NASH in patients with type 2 diabetes, whereas in contrast with type 2 diabetes, fatty liver is rare in subjects with type 1 diabetes mellitus. In 2 large separate studies of patients undergoing antiobesity surgery (551 patients by Marceau et al and 505 patients by Luyckx et al), the severity of NASH was closely related to impaired glycemia.
Haukeland et al concluded that abnormal glucose tolerance independently predicted NASH and fibrosis in 88 patients. Adams et al, in a study of 420 patients with NAFLD, showed that the overall death rate in patients with NAFLD was higher than expected, especially in patients with an impaired fasting glucose level or with diabetes.
The prevalence of diabetes for all age groups worldwide is estimated to be 4.4% in 2030, and the total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The ‘‘diabetes epidemic’’ will probably continue, even if levels of obesity remain constant. Adams et al reported that 22% of people were diagnosed with diabetes and 23% were reported to have hyperlipidemia.
In view of the increased mortality associated with an impaired fasting glucose level and with diabetes, it is important to screen for diabetes once a diagnosis of NAFLD is established. Interestingly, Holt et al, in a small study of 22 obese patients, proposed that the concentration of NEFAs is associated with fatty liver independent of classic measures of insulin resistance. Elevated NEFA levels have been associated with impaired glucose utilization, impaired suppression of glucose production, and impaired insulin secretion.
Because NEFAs are increasingly portrayed as villains in a web of metabolic disturbances that link these different conditions in metabolic syndrome and, in particular, insulin resistance, it is reasonable to propose that NEFAs and abnormal glucose tolerance are independent predictors of NASH. However, there are problems in using NEFAs as a risk factor for diabetes or cardiovascular disease. Only in the Quebec cardiovascular study were elevated NEFA concentrations found to be markers for future ischemic heart disease, but in a majority of other studies, they have been found to be less sensitive markers for future cardiovascular disease. In addition the day-to-day coefficient of variation of NEFAs is about 43%, which means, statistically, that they are not good markers for epidemiology.
Consistent with insulin resistance, low adiponectin levels in patients with NAFLD were reported and may represent a pathogenic mechanism leading to altered hepatocyte lipid metabolism and fat accumulation. In fact, high adiponectin levels have been reported to protect against alcoholic and nonalcoholic fatty liver disease in mice by reducing fatty acid synthesis through inhibition of acyl-CoA carboxylase and fatty acid synthase expression and activity. Further studies are needed before adiponectin can be used as a sensitive and specific biochemical marker.
Histologic examination helps to distinguish hepatic steatosis from NASH, identifies features of fibrosis, and facilitates estimation of long-term prognosis. However, it has been concluded that there was significant sampling variability in routine liver biopsies in patients with NAFLD. The sampling variability has the potential to alter significantly the diagnosis and staging of NAFLD and, thus, the pharmacologic therapies for NASH. In addition, there are several drawbacks in using liver biopsy because this procedure is invasive, costly, and prone to complications, some minor, such as pain, and others more severe, with a recorded risk of death of 0.01%. Most important, the number of patients at risk for NAFLD is high enough that liver biopsy is not a practical and efficient tool for identifying people at risk of advanced fibrosis in large cohorts of people. Indeed, an estimated 15% to 20% of the Western European population has steatosis, and more than half of Americans are overweight or obese.
There is no biochemical marker for fatty liver or NASH. (There are many biochemical markers for hepatic fibrosis.) Several biomarkers have been evaluated for sensitivity and specificity for hepatic fibrosis (apolipoprotein A1, haptoglobin, α2-macroglobulin, hyaluronic acid, and procollagen peptides such as types I, III, and VI), but none is being tested on a similar scale for NAFLD or NASH. One difficulty that remains is establishing biochemical markers that differentiate between alcoholic and nonalcoholic steatohepatitis. Recently, Ohtsuka et al suggested that carbohydrate-deficient transferrin could be used to differentiate between NASH and alcoholic hepatitis. The issue of whether NEFAs, abnormal glucose tolerance test results, adiponectin, and carbohydrate-deficient transferrin are markers or predictors of fatty liver or NASH will remain controversial; this can be established through further research.
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