Fatty Liver Disease: The Silent Epidemic

Nonalcoholic fatty liver disease is an "an underdiagnosed epidemic resulting from overnutrition," according to a leading researcher of the genetics and pathogenesis of NAFLD.

In grand rounds at the NIH Clinical Center, Dr. Yaron Rotman told clinicians that an increasing number of Americans have ultrasound evidence of NAFLD, which is defined as greater than 5.5% fat in liver that cannot be attributed to another cause, such as alcohol consumption.

A significant portion of patients with NAFLD, Dr. Rotman said, will develop nonalcoholic steatohepatitis (NASH), a more serious, related condition in which fat accumulation is accompanied by hepatic injury that can progress to liver cirrhosis. NASH can only be confirmed by biopsy: None of the noninvasive markers is reliable enough to be used in clinical practice. Moreover, there is no approved therapy for NAFLD and NASH, save for measures indicated in end-stage liver disease, said Dr. Rotman of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

"This is an epidemic with hard implications – people will die from this," he said. "We need prevention, more understanding of mechanisms, noninvasive diagnosis, and improved therapies."

The prevalence of NAFLD has increased with rising obesity rates, and is now the most common cause of elevated liver enzymes in the United States, although many NAFLD patients have normal enzymes.

Current estimates of NAFLD prevalence range from 20% to 30% in the general population and from 67% to 75% in obese individuals (Hepatology 2010;52:894-903). African Americans appear to have some protection from NAFLD and NASH compared with the population at large, likely due to genetic factors that have yet to be discovered (Hepatology 2004;40:1387-95). Children and nonobese people may also present with NAFLD and NASH, and genetic factors are suspected to play a role.

Symptoms of NAFLD and NASH can include vague right-upper quadrant abdominal discomfort and fatigue, but unless patients present with advanced liver disease, they tend to be discovered incidentally while being evaluated for something else, Dr. Rotman said in a separate interview. "The progression of disease doesn’t go hand in hand with progression of symptoms – this is not slope, it’s a cliff. Oftentimes, there are no symptoms until the liver disease is advanced."

Statins and fibrates have been found to be largely ineffective, and pioglitazone, an insulin sensitizer, has demonstrated benefit but has not led to improvement in fibrosis and carries potential side effects. Other treatments being tried include the antioxidant vitamin E, which has been shown to improve the histological features of NASH at 800 IU daily (N. Engl. J. Med. 2010;362:1675-85). Loss of 7%-10% of body weight has also been shown to procure histological improvement in patients with NASH (Hepatology 2010;51:121-9).

Dr. Rotman’s team at the NIDDK has been working to uncover the mechanisms of NAFLD and NASH, trying to unlock the mystery of why some patients will progress to NASH while others will not.

Dr. Rotman said that research is beginning to point to free fatty acids, not triglycerides, as the source of liver injury. The current theory of NASH pathogenesis, he said, is that "you have increased fatty acid delivery to the liver, some of which will be shunted to triglycerides, and the excess will spill over into toxic metabolites or reactive oxygen species, which will themselves cause liver damage. These can actually increase insulin resistance and enter into a vicious cycle."

The question of why some people appear to be protected – they have excess fat in their liver but never develop NASH – "we think is related to a strong genetic component," Dr. Rotman said.

Dr. Rotman’s team is working to find single nucleotide polymorphisms (SNPs), or genetic markers, of interest for NAFLD and NASH, looking for those with implications not just for disease but for severity of disease. In one study, 894 adults and 223 children with histologically confirmed NAFLD were genotyped for six SNPs associated with hepatic fat or liver enzymes in genomewide association studies.

In the adults, three SNPs, all on chromosome 22, showed associations with NASH. One SNP, PNPLA3, was associated with steatosis, inflammation, Mallory-Denk bodies, and fibrosis, and two others in the same region had similar associations.

In the children with NASH, there was no SNP associated with histological severity; however, the rs738409 G allele was seen associated with an earlier presentation of disease (Hepatology 2010;52:894-903).

In a separate study using the same cohort, the researchers found a different SNP, HSD17B13, associated with increased liver fat but decreased injury, inflammation, and fibrosis, as well as lower enzymes.

Dr. Rotman and his colleagues are also currently conducting a small study seeking the optimal dose of the antioxidant vitamin E in patients with NASH.

Gene studies, so far, account for only a fraction of fat in the liver, he noted. "They are polygenic disorders affected by many genes, with each gene making a small contribution," he said in an interview. "The bottom line is that as we learn more, we’ll find more of these genetic contributions – these are genes we don’t know anything about, and they’ll teach us much about normal physiology as well."

For clinicians treating patients with NAFLD, the question of whether and when to biopsy can be difficult, Dr. Rotman continued, not least because management strategy is largely the same whether or not there is histological evidence of NASH.

"In the research setting, biopsy is recommended because it’s the only way you can learn about the disease," he said. "In the clinical setting, the predominant reason I’ll send a patient to an invasive procedure is if it’s going to change management. Since there is no approved treatment for NAFLD and almost every patient with NAFLD will have to change their lifestyle – lose weight, exercise, and eat a healthy diet – it is not necessary to biopsy routinely."

However, he said, a biopsy "assures that you are not missing a completely different disorder, and there may be some benefit to be able to stage and give a prognosis. With some patients, a scary biopsy result can help them focus on changing their lifestyle."

Dr. Rotman disclosed no conflicts of interest.

Nonalcoholic fatty liver disease is an "an underdiagnosed epidemic resulting from overnutrition," according to a leading researcher of the genetics and pathogenesis of NAFLD.

In grand rounds at the NIH Clinical Center, Dr. Yaron Rotman told clinicians that an increasing number of Americans have ultrasound evidence of NAFLD, which is defined as greater than 5.5% fat in liver that cannot be attributed to another cause, such as alcohol consumption.

A significant portion of patients with NAFLD, Dr. Rotman said, will develop nonalcoholic steatohepatitis (NASH), a more serious, related condition in which fat accumulation is accompanied by hepatic injury that can progress to liver cirrhosis. NASH can only be confirmed by biopsy: None of the noninvasive markers is reliable enough to be used in clinical practice. Moreover, there is no approved therapy for NAFLD and NASH, save for measures indicated in end-stage liver disease, said Dr. Rotman of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

"This is an epidemic with hard implications – people will die from this," he said. "We need prevention, more understanding of mechanisms, noninvasive diagnosis, and improved therapies."

The prevalence of NAFLD has increased with rising obesity rates, and is now the most common cause of elevated liver enzymes in the United States, although many NAFLD patients have normal enzymes.

Current estimates of NAFLD prevalence range from 20% to 30% in the general population and from 67% to 75% in obese individuals (Hepatology 2010;52:894-903). African Americans appear to have some protection from NAFLD and NASH compared with the population at large, likely due to genetic factors that have yet to be discovered (Hepatology 2004;40:1387-95). Children and nonobese people may also present with NAFLD and NASH, and genetic factors are suspected to play a role.

Symptoms of NAFLD and NASH can include vague right-upper quadrant abdominal discomfort and fatigue, but unless patients present with advanced liver disease, they tend to be discovered incidentally while being evaluated for something else, Dr. Rotman said in a separate interview. "The progression of disease doesn’t go hand in hand with progression of symptoms – this is not slope, it’s a cliff. Oftentimes, there are no symptoms until the liver disease is advanced."

Statins and fibrates have been found to be largely ineffective, and pioglitazone, an insulin sensitizer, has demonstrated benefit but has not led to improvement in fibrosis and carries potential side effects. Other treatments being tried include the antioxidant vitamin E, which has been shown to improve the histological features of NASH at 800 IU daily (N. Engl. J. Med. 2010;362:1675-85). Loss of 7%-10% of body weight has also been shown to procure histological improvement in patients with NASH (Hepatology 2010;51:121-9).

Dr. Rotman’s team at the NIDDK has been working to uncover the mechanisms of NAFLD and NASH, trying to unlock the mystery of why some patients will progress to NASH while others will not.

Dr. Rotman said that research is beginning to point to free fatty acids, not triglycerides, as the source of liver injury. The current theory of NASH pathogenesis, he said, is that "you have increased fatty acid delivery to the liver, some of which will be shunted to triglycerides, and the excess will spill over into toxic metabolites or reactive oxygen species, which will themselves cause liver damage. These can actually increase insulin resistance and enter into a vicious cycle."

The question of why some people appear to be protected – they have excess fat in their liver but never develop NASH – "we think is related to a strong genetic component," Dr. Rotman said.

Dr. Rotman’s team is working to find single nucleotide polymorphisms (SNPs), or genetic markers, of interest for NAFLD and NASH, looking for those with implications not just for disease but for severity of disease. In one study, 894 adults and 223 children with histologically confirmed NAFLD were genotyped for six SNPs associated with hepatic fat or liver enzymes in genomewide association studies.

In the adults, three SNPs, all on chromosome 22, showed associations with NASH. One SNP, PNPLA3, was associated with steatosis, inflammation, Mallory-Denk bodies, and fibrosis, and two others in the same region had similar associations.

In the children with NASH, there was no SNP associated with histological severity; however, the rs738409 G allele was seen associated with an earlier presentation of disease (Hepatology 2010;52:894-903).

In a separate study using the same cohort, the researchers found a different SNP, HSD17B13, associated with increased liver fat but decreased injury, inflammation, and fibrosis, as well as lower enzymes.

Dr. Rotman and his colleagues are also currently conducting a small study seeking the optimal dose of the antioxidant vitamin E in patients with NASH.

Gene studies, so far, account for only a fraction of fat in the liver, he noted. "They are polygenic disorders affected by many genes, with each gene making a small contribution," he said in an interview. "The bottom line is that as we learn more, we’ll find more of these genetic contributions – these are genes we don’t know anything about, and they’ll teach us much about normal physiology as well."

For clinicians treating patients with NAFLD, the question of whether and when to biopsy can be difficult, Dr. Rotman continued, not least because management strategy is largely the same whether or not there is histological evidence of NASH.

"In the research setting, biopsy is recommended because it’s the only way you can learn about the disease," he said. "In the clinical setting, the predominant reason I’ll send a patient to an invasive procedure is if it’s going to change management. Since there is no approved treatment for NAFLD and almost every patient with NAFLD will have to change their lifestyle – lose weight, exercise, and eat a healthy diet – it is not necessary to biopsy routinely."

However, he said, a biopsy "assures that you are not missing a completely different disorder, and there may be some benefit to be able to stage and give a prognosis. With some patients, a scary biopsy result can help them focus on changing their lifestyle."

Dr. Rotman disclosed no conflicts of interest.

Nonalcoholic fatty liver disease is an "an underdiagnosed epidemic resulting from overnutrition," according to a leading researcher of the genetics and pathogenesis of NAFLD.

In grand rounds at the NIH Clinical Center, Dr. Yaron Rotman told clinicians that an increasing number of Americans have ultrasound evidence of NAFLD, which is defined as greater than 5.5% fat in liver that cannot be attributed to another cause, such as alcohol consumption.

A significant portion of patients with NAFLD, Dr. Rotman said, will develop nonalcoholic steatohepatitis (NASH), a more serious, related condition in which fat accumulation is accompanied by hepatic injury that can progress to liver cirrhosis. NASH can only be confirmed by biopsy: None of the noninvasive markers is reliable enough to be used in clinical practice. Moreover, there is no approved therapy for NAFLD and NASH, save for measures indicated in end-stage liver disease, said Dr. Rotman of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

"This is an epidemic with hard implications – people will die from this," he said. "We need prevention, more understanding of mechanisms, noninvasive diagnosis, and improved therapies."

The prevalence of NAFLD has increased with rising obesity rates, and is now the most common cause of elevated liver enzymes in the United States, although many NAFLD patients have normal enzymes.

Current estimates of NAFLD prevalence range from 20% to 30% in the general population and from 67% to 75% in obese individuals (Hepatology 2010;52:894-903). African Americans appear to have some protection from NAFLD and NASH compared with the population at large, likely due to genetic factors that have yet to be discovered (Hepatology 2004;40:1387-95). Children and nonobese people may also present with NAFLD and NASH, and genetic factors are suspected to play a role.

Symptoms of NAFLD and NASH can include vague right-upper quadrant abdominal discomfort and fatigue, but unless patients present with advanced liver disease, they tend to be discovered incidentally while being evaluated for something else, Dr. Rotman said in a separate interview. "The progression of disease doesn’t go hand in hand with progression of symptoms – this is not slope, it’s a cliff. Oftentimes, there are no symptoms until the liver disease is advanced."

Statins and fibrates have been found to be largely ineffective, and pioglitazone, an insulin sensitizer, has demonstrated benefit but has not led to improvement in fibrosis and carries potential side effects. Other treatments being tried include the antioxidant vitamin E, which has been shown to improve the histological features of NASH at 800 IU daily (N. Engl. J. Med. 2010;362:1675-85). Loss of 7%-10% of body weight has also been shown to procure histological improvement in patients with NASH (Hepatology 2010;51:121-9).

Dr. Rotman’s team at the NIDDK has been working to uncover the mechanisms of NAFLD and NASH, trying to unlock the mystery of why some patients will progress to NASH while others will not.

Dr. Rotman said that research is beginning to point to free fatty acids, not triglycerides, as the source of liver injury. The current theory of NASH pathogenesis, he said, is that "you have increased fatty acid delivery to the liver, some of which will be shunted to triglycerides, and the excess will spill over into toxic metabolites or reactive oxygen species, which will themselves cause liver damage. These can actually increase insulin resistance and enter into a vicious cycle."

The question of why some people appear to be protected – they have excess fat in their liver but never develop NASH – "we think is related to a strong genetic component," Dr. Rotman said.

Dr. Rotman’s team is working to find single nucleotide polymorphisms (SNPs), or genetic markers, of interest for NAFLD and NASH, looking for those with implications not just for disease but for severity of disease. In one study, 894 adults and 223 children with histologically confirmed NAFLD were genotyped for six SNPs associated with hepatic fat or liver enzymes in genomewide association studies.

In the adults, three SNPs, all on chromosome 22, showed associations with NASH. One SNP, PNPLA3, was associated with steatosis, inflammation, Mallory-Denk bodies, and fibrosis, and two others in the same region had similar associations.

In the children with NASH, there was no SNP associated with histological severity; however, the rs738409 G allele was seen associated with an earlier presentation of disease (Hepatology 2010;52:894-903).

In a separate study using the same cohort, the researchers found a different SNP, HSD17B13, associated with increased liver fat but decreased injury, inflammation, and fibrosis, as well as lower enzymes.

Dr. Rotman and his colleagues are also currently conducting a small study seeking the optimal dose of the antioxidant vitamin E in patients with NASH.

Gene studies, so far, account for only a fraction of fat in the liver, he noted. "They are polygenic disorders affected by many genes, with each gene making a small contribution," he said in an interview. "The bottom line is that as we learn more, we’ll find more of these genetic contributions – these are genes we don’t know anything about, and they’ll teach us much about normal physiology as well."

For clinicians treating patients with NAFLD, the question of whether and when to biopsy can be difficult, Dr. Rotman continued, not least because management strategy is largely the same whether or not there is histological evidence of NASH.

"In the research setting, biopsy is recommended because it’s the only way you can learn about the disease," he said. "In the clinical setting, the predominant reason I’ll send a patient to an invasive procedure is if it’s going to change management. Since there is no approved treatment for NAFLD and almost every patient with NAFLD will have to change their lifestyle – lose weight, exercise, and eat a healthy diet – it is not necessary to biopsy routinely."

However, he said, a biopsy "assures that you are not missing a completely different disorder, and there may be some benefit to be able to stage and give a prognosis. With some patients, a scary biopsy result can help them focus on changing their lifestyle."

Dr. Rotman disclosed no conflicts of interest.