Chronic suppurative otitis media remains a global burden for children despite the declining incidence in industrialized countries and advances in diagnosis and management in developing countries. The World Health Organization cites chronic suppurative otitis media (CSOM) as a major cause of acquired hearing loss, primarily in developing countries and indigenous peoples.

CSOM is characterized by a persistent discharge from the middle ear lasting for a minimum of 2 weeks. In industrialized countries, the major risk factor is tympanostomy tube placement; in developing nations, the major risk factor is early bacterial colonization with Streptococcus pneumoniae and nontypable Haemophilus influenzae and early onset of acute bacterial otitis media with perforation. In both situations, biofilms are thought to underlie the pathogenesis with S. pneumoniae and nontypable H. influenzae found on mucosal biopsies using specific fluorescent in situ hybridization assays on specimens from children with chronic suppurative otitis media or recurrent acute otitis media (ROM). Dr. Ruth B. Thornton and her colleagues reported that 11 of 17 (65%) middle-ear mucosal biopsies from children with CSOM or ROM showed evidence of bacterial biofilm, and 12 (71%) demonstrated intracellular bacteria (Pediatrics 2011;11:94).

Microbiologic studies in children with otorrhea, through either a perforation or tympanostomy tube, demonstrate primarily Staphylococcus aureus, both methicillin sensitive and resistant isolates, and Pseudomonas aeruginosa. However, it is recognized that the early pathogens are S. pneumoniae and nontypable H. influenzae in these children recovered both from cultures of ear drainage and from molecular studies of middle-ear mucosal biopsies. Amanda J. Leach, Ph.D., and Peter S. Morris, Ph.D., reported that cultures from ear discharge in Aborigine children with acute perforations identified nontypable H. influenzae in 57%, S. pneumoniae in 34%, and both in 21% (Pediatr. Inf. Dis. J. 2007;26:S4-7).

The high rate of mixed infection has also been reported in Bedouin children with recurrent and persistent otitis. In children with otorrhea from a tympanostomy tube, a dichotomy in microbiology etiology was found. In young children, nasopharyngeal pathogens (S. pneumoniae and nontypable H. influenzae) dominated and in older children, external ear commensals (Staph. aureus and P. aeruginosa) predominated (Int. J. Pediatr. Otorhinolaryngol. 2003;67:1317-23).

In industrialized countries, successful treatment of young children with otorrhea through a tympanostomy tube has been reported with both oral amoxicillin/clavulanate and topical fluoroquinolones, reflecting the frequent role of S. pneumoniae and nontypable H. influenzae in young children. However, in older children, in those with foul-smelling discharge, and in those who fail amoxicillin/clavulanate, topical fluoroquinolone is the treatment of choice. Guidelines for the treatment of otorrhea through a tympanostomy tube have been published with a recommendation that topical therapy be used as the first choice when systemic signs of illness are not present (J. Otolaryngol. 2005;34[suppl. 2]:S60-3). Treatment failures are most often due to methicillin-resistant Staph. aureus (MRSA) and often require a combination of oral therapy with an agent active against MRSA such as trimethoprim/sulfamethoxazole and topical therapy with a fluoroquinolone; removal of the tympanostomy tube also may be necessary to achieve a cure.

The prevention of chronic suppurative otitis media has proven elusive. Studies of 7-valent pneumococcal conjugate (PCV7) vaccine in Dutch children with established ROM demonstrated no reduction in episodes. In fact, more episodes of AOM or otorrhea were observed in the vaccine group, despite good immunogenicity and a reduction in colonization with vaccine-type S. pneumoniae (Int. J. Pediatr. Otorhinolaryngol. 2006;70:275-85).

In studies of PCV7 administered at 2, 4, and 6 months of age to Aborigine infants, only a marginal benefit was observed when they were compared with a historical birth cohort. By 12 months of age, 89% of those vaccinated had experienced AOM; 34%, AOM with perforation; and 14%, CSOM. Although not statistically significant, this represented a 40% decrease in CSOM at 1 year of age (BMC Pediatr. 2009;9:14).

CSOM persists as an important cause of morbidity in indigenous children and in children in developing countries. It is a major cause of acquired hearing loss and impacts dramatically on the quality of life of affected children. We have made important advances in identifying the bacterial antecedents and understanding the pathogenesis of disease, yet morbidity remains substantial. Further research in the treatment and prevention of middle-ear biofilms is likely to be critical to reducing the burden of ear disease in children.

Dr. Pelton is chief of pediatric infectious disease and also is the coordinator of the maternal-child HIV program at Boston Medical Center. He disclosed that he has received honoraria and investigator-initiated research funding from Pfizer and Merck, and honoraria from GlaxoSmithKline related to pneumococcal vaccines. E-mail him at [email protected].  

Chronic suppurative otitis media remains a global burden for children despite the declining incidence in industrialized countries and advances in diagnosis and management in developing countries. The World Health Organization cites chronic suppurative otitis media (CSOM) as a major cause of acquired hearing loss, primarily in developing countries and indigenous peoples.

CSOM is characterized by a persistent discharge from the middle ear lasting for a minimum of 2 weeks. In industrialized countries, the major risk factor is tympanostomy tube placement; in developing nations, the major risk factor is early bacterial colonization with Streptococcus pneumoniae and nontypable Haemophilus influenzae and early onset of acute bacterial otitis media with perforation. In both situations, biofilms are thought to underlie the pathogenesis with S. pneumoniae and nontypable H. influenzae found on mucosal biopsies using specific fluorescent in situ hybridization assays on specimens from children with chronic suppurative otitis media or recurrent acute otitis media (ROM). Dr. Ruth B. Thornton and her colleagues reported that 11 of 17 (65%) middle-ear mucosal biopsies from children with CSOM or ROM showed evidence of bacterial biofilm, and 12 (71%) demonstrated intracellular bacteria (Pediatrics 2011;11:94).

Microbiologic studies in children with otorrhea, through either a perforation or tympanostomy tube, demonstrate primarily Staphylococcus aureus, both methicillin sensitive and resistant isolates, and Pseudomonas aeruginosa. However, it is recognized that the early pathogens are S. pneumoniae and nontypable H. influenzae in these children recovered both from cultures of ear drainage and from molecular studies of middle-ear mucosal biopsies. Amanda J. Leach, Ph.D., and Peter S. Morris, Ph.D., reported that cultures from ear discharge in Aborigine children with acute perforations identified nontypable H. influenzae in 57%, S. pneumoniae in 34%, and both in 21% (Pediatr. Inf. Dis. J. 2007;26:S4-7).

The high rate of mixed infection has also been reported in Bedouin children with recurrent and persistent otitis. In children with otorrhea from a tympanostomy tube, a dichotomy in microbiology etiology was found. In young children, nasopharyngeal pathogens (S. pneumoniae and nontypable H. influenzae) dominated and in older children, external ear commensals (Staph. aureus and P. aeruginosa) predominated (Int. J. Pediatr. Otorhinolaryngol. 2003;67:1317-23).

In industrialized countries, successful treatment of young children with otorrhea through a tympanostomy tube has been reported with both oral amoxicillin/clavulanate and topical fluoroquinolones, reflecting the frequent role of S. pneumoniae and nontypable H. influenzae in young children. However, in older children, in those with foul-smelling discharge, and in those who fail amoxicillin/clavulanate, topical fluoroquinolone is the treatment of choice. Guidelines for the treatment of otorrhea through a tympanostomy tube have been published with a recommendation that topical therapy be used as the first choice when systemic signs of illness are not present (J. Otolaryngol. 2005;34[suppl. 2]:S60-3). Treatment failures are most often due to methicillin-resistant Staph. aureus (MRSA) and often require a combination of oral therapy with an agent active against MRSA such as trimethoprim/sulfamethoxazole and topical therapy with a fluoroquinolone; removal of the tympanostomy tube also may be necessary to achieve a cure.

The prevention of chronic suppurative otitis media has proven elusive. Studies of 7-valent pneumococcal conjugate (PCV7) vaccine in Dutch children with established ROM demonstrated no reduction in episodes. In fact, more episodes of AOM or otorrhea were observed in the vaccine group, despite good immunogenicity and a reduction in colonization with vaccine-type S. pneumoniae (Int. J. Pediatr. Otorhinolaryngol. 2006;70:275-85).

In studies of PCV7 administered at 2, 4, and 6 months of age to Aborigine infants, only a marginal benefit was observed when they were compared with a historical birth cohort. By 12 months of age, 89% of those vaccinated had experienced AOM; 34%, AOM with perforation; and 14%, CSOM. Although not statistically significant, this represented a 40% decrease in CSOM at 1 year of age (BMC Pediatr. 2009;9:14).

CSOM persists as an important cause of morbidity in indigenous children and in children in developing countries. It is a major cause of acquired hearing loss and impacts dramatically on the quality of life of affected children. We have made important advances in identifying the bacterial antecedents and understanding the pathogenesis of disease, yet morbidity remains substantial. Further research in the treatment and prevention of middle-ear biofilms is likely to be critical to reducing the burden of ear disease in children.

Dr. Pelton is chief of pediatric infectious disease and also is the coordinator of the maternal-child HIV program at Boston Medical Center. He disclosed that he has received honoraria and investigator-initiated research funding from Pfizer and Merck, and honoraria from GlaxoSmithKline related to pneumococcal vaccines. E-mail him at [email protected].  

Chronic suppurative otitis media remains a global burden for children despite the declining incidence in industrialized countries and advances in diagnosis and management in developing countries. The World Health Organization cites chronic suppurative otitis media (CSOM) as a major cause of acquired hearing loss, primarily in developing countries and indigenous peoples.

CSOM is characterized by a persistent discharge from the middle ear lasting for a minimum of 2 weeks. In industrialized countries, the major risk factor is tympanostomy tube placement; in developing nations, the major risk factor is early bacterial colonization with Streptococcus pneumoniae and nontypable Haemophilus influenzae and early onset of acute bacterial otitis media with perforation. In both situations, biofilms are thought to underlie the pathogenesis with S. pneumoniae and nontypable H. influenzae found on mucosal biopsies using specific fluorescent in situ hybridization assays on specimens from children with chronic suppurative otitis media or recurrent acute otitis media (ROM). Dr. Ruth B. Thornton and her colleagues reported that 11 of 17 (65%) middle-ear mucosal biopsies from children with CSOM or ROM showed evidence of bacterial biofilm, and 12 (71%) demonstrated intracellular bacteria (Pediatrics 2011;11:94).

Microbiologic studies in children with otorrhea, through either a perforation or tympanostomy tube, demonstrate primarily Staphylococcus aureus, both methicillin sensitive and resistant isolates, and Pseudomonas aeruginosa. However, it is recognized that the early pathogens are S. pneumoniae and nontypable H. influenzae in these children recovered both from cultures of ear drainage and from molecular studies of middle-ear mucosal biopsies. Amanda J. Leach, Ph.D., and Peter S. Morris, Ph.D., reported that cultures from ear discharge in Aborigine children with acute perforations identified nontypable H. influenzae in 57%, S. pneumoniae in 34%, and both in 21% (Pediatr. Inf. Dis. J. 2007;26:S4-7).

The high rate of mixed infection has also been reported in Bedouin children with recurrent and persistent otitis. In children with otorrhea from a tympanostomy tube, a dichotomy in microbiology etiology was found. In young children, nasopharyngeal pathogens (S. pneumoniae and nontypable H. influenzae) dominated and in older children, external ear commensals (Staph. aureus and P. aeruginosa) predominated (Int. J. Pediatr. Otorhinolaryngol. 2003;67:1317-23).

In industrialized countries, successful treatment of young children with otorrhea through a tympanostomy tube has been reported with both oral amoxicillin/clavulanate and topical fluoroquinolones, reflecting the frequent role of S. pneumoniae and nontypable H. influenzae in young children. However, in older children, in those with foul-smelling discharge, and in those who fail amoxicillin/clavulanate, topical fluoroquinolone is the treatment of choice. Guidelines for the treatment of otorrhea through a tympanostomy tube have been published with a recommendation that topical therapy be used as the first choice when systemic signs of illness are not present (J. Otolaryngol. 2005;34[suppl. 2]:S60-3). Treatment failures are most often due to methicillin-resistant Staph. aureus (MRSA) and often require a combination of oral therapy with an agent active against MRSA such as trimethoprim/sulfamethoxazole and topical therapy with a fluoroquinolone; removal of the tympanostomy tube also may be necessary to achieve a cure.

The prevention of chronic suppurative otitis media has proven elusive. Studies of 7-valent pneumococcal conjugate (PCV7) vaccine in Dutch children with established ROM demonstrated no reduction in episodes. In fact, more episodes of AOM or otorrhea were observed in the vaccine group, despite good immunogenicity and a reduction in colonization with vaccine-type S. pneumoniae (Int. J. Pediatr. Otorhinolaryngol. 2006;70:275-85).

In studies of PCV7 administered at 2, 4, and 6 months of age to Aborigine infants, only a marginal benefit was observed when they were compared with a historical birth cohort. By 12 months of age, 89% of those vaccinated had experienced AOM; 34%, AOM with perforation; and 14%, CSOM. Although not statistically significant, this represented a 40% decrease in CSOM at 1 year of age (BMC Pediatr. 2009;9:14).

CSOM persists as an important cause of morbidity in indigenous children and in children in developing countries. It is a major cause of acquired hearing loss and impacts dramatically on the quality of life of affected children. We have made important advances in identifying the bacterial antecedents and understanding the pathogenesis of disease, yet morbidity remains substantial. Further research in the treatment and prevention of middle-ear biofilms is likely to be critical to reducing the burden of ear disease in children.

Dr. Pelton is chief of pediatric infectious disease and also is the coordinator of the maternal-child HIV program at Boston Medical Center. He disclosed that he has received honoraria and investigator-initiated research funding from Pfizer and Merck, and honoraria from GlaxoSmithKline related to pneumococcal vaccines. E-mail him at [email protected].  

Glycerol phenylbutyrate, a nitrogen-binding agent, has been approved for the chronic treatment of adults and children aged 2 years and older with urea cycle disorders, who cannot be managed with a protein-restricted diet or amino acid supplements alone, the Food and Drug Administration announced on Feb. 1.

The product, in a liquid formulation, helps eliminate excess ammonia that results from the accumulation of nitrogen in people with urea cycle disorders, which are inherited metabolic disorders. The drug is taken three times a day with a protein-restricted diet, according to the FDA statement announcing the approval. In some cases, it is used with dietary supplements, such as amino acids or arginine.

It will be marketed under the trade name Ravicti by Hyperion Therapeutics.

Approval was based on a study of 44 adults with urea cycle disorders, which found that glycerol phenylbutyrate was as effective as sodium phenylbutyrate (Buphenyl), in controlling ammonia levels, according to the FDA. In the study, patients were randomized to treatment with sodium phenylbutyrate, an approved treatment for urea cycle disorders, or glycerol phenylbutyrate for 2 weeks, then were switched to the other treatment for 2 weeks. Another three studies in children and adults "provided evidence supporting the long-term safety and effectiveness of Ravicti in patients 2 years and older," the FDA said.

Diarrhea, flatulence, and headache were the most common side effects associated with treatment, according to the FDA.

The manufacturer expects to launch the product by the end of April 2013 and will distribute it through two specialty pharmacies, according to a Hyperion statement.

[email protected]

Glycerol phenylbutyrate, a nitrogen-binding agent, has been approved for the chronic treatment of adults and children aged 2 years and older with urea cycle disorders, who cannot be managed with a protein-restricted diet or amino acid supplements alone, the Food and Drug Administration announced on Feb. 1.

The product, in a liquid formulation, helps eliminate excess ammonia that results from the accumulation of nitrogen in people with urea cycle disorders, which are inherited metabolic disorders. The drug is taken three times a day with a protein-restricted diet, according to the FDA statement announcing the approval. In some cases, it is used with dietary supplements, such as amino acids or arginine.

It will be marketed under the trade name Ravicti by Hyperion Therapeutics.

Approval was based on a study of 44 adults with urea cycle disorders, which found that glycerol phenylbutyrate was as effective as sodium phenylbutyrate (Buphenyl), in controlling ammonia levels, according to the FDA. In the study, patients were randomized to treatment with sodium phenylbutyrate, an approved treatment for urea cycle disorders, or glycerol phenylbutyrate for 2 weeks, then were switched to the other treatment for 2 weeks. Another three studies in children and adults "provided evidence supporting the long-term safety and effectiveness of Ravicti in patients 2 years and older," the FDA said.

Diarrhea, flatulence, and headache were the most common side effects associated with treatment, according to the FDA.

The manufacturer expects to launch the product by the end of April 2013 and will distribute it through two specialty pharmacies, according to a Hyperion statement.

[email protected]

Glycerol phenylbutyrate, a nitrogen-binding agent, has been approved for the chronic treatment of adults and children aged 2 years and older with urea cycle disorders, who cannot be managed with a protein-restricted diet or amino acid supplements alone, the Food and Drug Administration announced on Feb. 1.

The product, in a liquid formulation, helps eliminate excess ammonia that results from the accumulation of nitrogen in people with urea cycle disorders, which are inherited metabolic disorders. The drug is taken three times a day with a protein-restricted diet, according to the FDA statement announcing the approval. In some cases, it is used with dietary supplements, such as amino acids or arginine.

It will be marketed under the trade name Ravicti by Hyperion Therapeutics.

Approval was based on a study of 44 adults with urea cycle disorders, which found that glycerol phenylbutyrate was as effective as sodium phenylbutyrate (Buphenyl), in controlling ammonia levels, according to the FDA. In the study, patients were randomized to treatment with sodium phenylbutyrate, an approved treatment for urea cycle disorders, or glycerol phenylbutyrate for 2 weeks, then were switched to the other treatment for 2 weeks. Another three studies in children and adults "provided evidence supporting the long-term safety and effectiveness of Ravicti in patients 2 years and older," the FDA said.

Diarrhea, flatulence, and headache were the most common side effects associated with treatment, according to the FDA.

The manufacturer expects to launch the product by the end of April 2013 and will distribute it through two specialty pharmacies, according to a Hyperion statement.

[email protected]

A bill with bipartisan sponsors has been introduced in the U.S. House of Representatives to permanently repeal Medicare's Sustainable Growth Rate formula.

Rep. Joe Heck (R-Nev.) and Rep. Allyson Schwartz (D-Penn.) unveiled their proposal at a briefing with reporters on Feb. 6. They were surrounded by supporters, including representatives from the American College of Physicians, the American Academy of Family Physicians, the American College of Osteopathic Family Physicians, and the National Coalition on Health Care.

In addition to repealing the SGR, the bill also "stabilizes the current payment system for physicians, and it institutes measures to ensure access to primary care with increased updates for primary care physicians in the short term," said Rep. Schwartz, who added that it also "aggressively" tests new payment and delivery models and rewards high value, high quality health care. 

Rep. Schwartz and Rep. Heck, an osteopathic physician trained in emergency medicine, also introduced the bill in the last Congress. But both said that they think that legislators are primed to act, in part because of the struggle to reduce health care spending and the deficit. 

If the SGR is not replaced or repealed by the end of the year, physicians will see a 27% reduction in pay beginning in January 2014. Each year the cuts are delayed merely adds more on to the final tally for fixing the formula, noted Rep. Heck. The Congressional Budget Office estimated in its latest economic outlook released on Feb. 5 that it would cost about $138 billion to permanently repeal the SGR. That's less than the $245 billion in previous CBO estimates.

"The time right now is perfect to finally pass this legislation," said Rep. Heck. 

"I think the imminent process of sequestration may add a little urgency to reform because across the board cuts are not going to get us where we need to go," said John Rother, president and CEO of the National Coalition on Health Care, an umbrella group representing medical societies, businesses, unions, health care providers, religious associations, insurers, and consumers. "And the alternative here is smarter and much more oriented toward value, and it provides a very practical and beneficial alternative to the kind of meat-axe approaches in sequestration," Mr. Rother said.

Physician groups said they are hopeful that the proposal has legs this year.

The constant uncertainty about whether SGR cuts will occur, "undermines the family doctor's ability to continue to keep doors open and to invest in their practices," said Dr. Jeffrey Cain, president of the AAFP. He praised the Heck-Schwartz bill, which had not been officially introduced in the House at press time, saying that it would put an end to "the annual question of whether physicians can continue to afford to practice in Medicare," and that it also "stabilizes the Medicare cost system and provides solutions that are based on successful and proven methods that can improve quality and incent value."

Dr. Chuck Cutler, chair-elect of the ACP Board of Regents, said that "the stability that this bill brings to the marketplace and to our practice is particularly encouraging." He also said that the ACP was happy that the bill would maintain 2013 payment levels through the end of 2014 and then provide "positive and predictable updates" through 2019.

That is especially important as physicians test out new delivery and payment models, said Dr. Cutler.

From 2015 to 2018, the bill calls for annual increases of 2.5% for primary care, preventive, and care-coordination services. All other physicians would get a 0.5% increase for the 4-year period.

By 2019, physicians who continue to use a volume-drive fee-for-service model would get a smaller increase than would those who have transitioned to new models.

In addition to the groups who participated in the briefing, the bill also is supported by the American College of Obstetricians and Gynecologists, the Society of Hospital Medicine, the American College of Rheumatology, the American College of Cardiology, the American Academy of Neurology, and the American Academy of Pediatrics.

[email protected]

On Twitter @aliciaault

A bill with bipartisan sponsors has been introduced in the U.S. House of Representatives to permanently repeal Medicare's Sustainable Growth Rate formula.

Rep. Joe Heck (R-Nev.) and Rep. Allyson Schwartz (D-Penn.) unveiled their proposal at a briefing with reporters on Feb. 6. They were surrounded by supporters, including representatives from the American College of Physicians, the American Academy of Family Physicians, the American College of Osteopathic Family Physicians, and the National Coalition on Health Care.

In addition to repealing the SGR, the bill also "stabilizes the current payment system for physicians, and it institutes measures to ensure access to primary care with increased updates for primary care physicians in the short term," said Rep. Schwartz, who added that it also "aggressively" tests new payment and delivery models and rewards high value, high quality health care. 

Rep. Schwartz and Rep. Heck, an osteopathic physician trained in emergency medicine, also introduced the bill in the last Congress. But both said that they think that legislators are primed to act, in part because of the struggle to reduce health care spending and the deficit. 

If the SGR is not replaced or repealed by the end of the year, physicians will see a 27% reduction in pay beginning in January 2014. Each year the cuts are delayed merely adds more on to the final tally for fixing the formula, noted Rep. Heck. The Congressional Budget Office estimated in its latest economic outlook released on Feb. 5 that it would cost about $138 billion to permanently repeal the SGR. That's less than the $245 billion in previous CBO estimates.

"The time right now is perfect to finally pass this legislation," said Rep. Heck. 

"I think the imminent process of sequestration may add a little urgency to reform because across the board cuts are not going to get us where we need to go," said John Rother, president and CEO of the National Coalition on Health Care, an umbrella group representing medical societies, businesses, unions, health care providers, religious associations, insurers, and consumers. "And the alternative here is smarter and much more oriented toward value, and it provides a very practical and beneficial alternative to the kind of meat-axe approaches in sequestration," Mr. Rother said.

Physician groups said they are hopeful that the proposal has legs this year.

The constant uncertainty about whether SGR cuts will occur, "undermines the family doctor's ability to continue to keep doors open and to invest in their practices," said Dr. Jeffrey Cain, president of the AAFP. He praised the Heck-Schwartz bill, which had not been officially introduced in the House at press time, saying that it would put an end to "the annual question of whether physicians can continue to afford to practice in Medicare," and that it also "stabilizes the Medicare cost system and provides solutions that are based on successful and proven methods that can improve quality and incent value."

Dr. Chuck Cutler, chair-elect of the ACP Board of Regents, said that "the stability that this bill brings to the marketplace and to our practice is particularly encouraging." He also said that the ACP was happy that the bill would maintain 2013 payment levels through the end of 2014 and then provide "positive and predictable updates" through 2019.

That is especially important as physicians test out new delivery and payment models, said Dr. Cutler.

From 2015 to 2018, the bill calls for annual increases of 2.5% for primary care, preventive, and care-coordination services. All other physicians would get a 0.5% increase for the 4-year period.

By 2019, physicians who continue to use a volume-drive fee-for-service model would get a smaller increase than would those who have transitioned to new models.

In addition to the groups who participated in the briefing, the bill also is supported by the American College of Obstetricians and Gynecologists, the Society of Hospital Medicine, the American College of Rheumatology, the American College of Cardiology, the American Academy of Neurology, and the American Academy of Pediatrics.

[email protected]

On Twitter @aliciaault

A bill with bipartisan sponsors has been introduced in the U.S. House of Representatives to permanently repeal Medicare's Sustainable Growth Rate formula.

Rep. Joe Heck (R-Nev.) and Rep. Allyson Schwartz (D-Penn.) unveiled their proposal at a briefing with reporters on Feb. 6. They were surrounded by supporters, including representatives from the American College of Physicians, the American Academy of Family Physicians, the American College of Osteopathic Family Physicians, and the National Coalition on Health Care.

In addition to repealing the SGR, the bill also "stabilizes the current payment system for physicians, and it institutes measures to ensure access to primary care with increased updates for primary care physicians in the short term," said Rep. Schwartz, who added that it also "aggressively" tests new payment and delivery models and rewards high value, high quality health care. 

Rep. Schwartz and Rep. Heck, an osteopathic physician trained in emergency medicine, also introduced the bill in the last Congress. But both said that they think that legislators are primed to act, in part because of the struggle to reduce health care spending and the deficit. 

If the SGR is not replaced or repealed by the end of the year, physicians will see a 27% reduction in pay beginning in January 2014. Each year the cuts are delayed merely adds more on to the final tally for fixing the formula, noted Rep. Heck. The Congressional Budget Office estimated in its latest economic outlook released on Feb. 5 that it would cost about $138 billion to permanently repeal the SGR. That's less than the $245 billion in previous CBO estimates.

"The time right now is perfect to finally pass this legislation," said Rep. Heck. 

"I think the imminent process of sequestration may add a little urgency to reform because across the board cuts are not going to get us where we need to go," said John Rother, president and CEO of the National Coalition on Health Care, an umbrella group representing medical societies, businesses, unions, health care providers, religious associations, insurers, and consumers. "And the alternative here is smarter and much more oriented toward value, and it provides a very practical and beneficial alternative to the kind of meat-axe approaches in sequestration," Mr. Rother said.

Physician groups said they are hopeful that the proposal has legs this year.

The constant uncertainty about whether SGR cuts will occur, "undermines the family doctor's ability to continue to keep doors open and to invest in their practices," said Dr. Jeffrey Cain, president of the AAFP. He praised the Heck-Schwartz bill, which had not been officially introduced in the House at press time, saying that it would put an end to "the annual question of whether physicians can continue to afford to practice in Medicare," and that it also "stabilizes the Medicare cost system and provides solutions that are based on successful and proven methods that can improve quality and incent value."

Dr. Chuck Cutler, chair-elect of the ACP Board of Regents, said that "the stability that this bill brings to the marketplace and to our practice is particularly encouraging." He also said that the ACP was happy that the bill would maintain 2013 payment levels through the end of 2014 and then provide "positive and predictable updates" through 2019.

That is especially important as physicians test out new delivery and payment models, said Dr. Cutler.

From 2015 to 2018, the bill calls for annual increases of 2.5% for primary care, preventive, and care-coordination services. All other physicians would get a 0.5% increase for the 4-year period.

By 2019, physicians who continue to use a volume-drive fee-for-service model would get a smaller increase than would those who have transitioned to new models.

In addition to the groups who participated in the briefing, the bill also is supported by the American College of Obstetricians and Gynecologists, the Society of Hospital Medicine, the American College of Rheumatology, the American College of Cardiology, the American Academy of Neurology, and the American Academy of Pediatrics.

[email protected]

On Twitter @aliciaault

Hospitalists aren’t urban planners, but it doesn’t take a zoning expert to realize that when a community sees hundreds of new homes built, some of the residents of those homes will end up in the hospital. The same logic applies when a company moves thousands of jobs to an office building a few blocks away from a hospital.

HM group leaders might not normally think about such things when analyzing whether they need to add staff, but at least one practice consultant says they should.

Hospitals often have community data available, Hertz says, but group leaders don’t always think to access it. He suggests they view the information as a routine part of their strategic planning.

Of course, Hertz adds, it’s not the only information that goes into the expansion equation, but administrators often respect group leaders who come armed with data from inside and outside the hospital about why it is necessary to make a new hire.

“It’s about open, honest discussion,” he says. “It’s about looking at information both inside the four walls and outside in the community. It’s not easy, but it can be done. But you’ve got to plan.”

Hertz says HM group leaders should plan at least 12 to 18 months out for a hire, “which I know is hard these days,” he says. But, he adds, short-term forecasting makes it “very difficult” to know when and how best to grow your group. TH

Richard Quinn is a freelance writer in New Jersey.

Hospitalists aren’t urban planners, but it doesn’t take a zoning expert to realize that when a community sees hundreds of new homes built, some of the residents of those homes will end up in the hospital. The same logic applies when a company moves thousands of jobs to an office building a few blocks away from a hospital.

HM group leaders might not normally think about such things when analyzing whether they need to add staff, but at least one practice consultant says they should.

Hospitals often have community data available, Hertz says, but group leaders don’t always think to access it. He suggests they view the information as a routine part of their strategic planning.

Of course, Hertz adds, it’s not the only information that goes into the expansion equation, but administrators often respect group leaders who come armed with data from inside and outside the hospital about why it is necessary to make a new hire.

“It’s about open, honest discussion,” he says. “It’s about looking at information both inside the four walls and outside in the community. It’s not easy, but it can be done. But you’ve got to plan.”

Hertz says HM group leaders should plan at least 12 to 18 months out for a hire, “which I know is hard these days,” he says. But, he adds, short-term forecasting makes it “very difficult” to know when and how best to grow your group. TH

Richard Quinn is a freelance writer in New Jersey.

Hospitalists aren’t urban planners, but it doesn’t take a zoning expert to realize that when a community sees hundreds of new homes built, some of the residents of those homes will end up in the hospital. The same logic applies when a company moves thousands of jobs to an office building a few blocks away from a hospital.

HM group leaders might not normally think about such things when analyzing whether they need to add staff, but at least one practice consultant says they should.

Hospitals often have community data available, Hertz says, but group leaders don’t always think to access it. He suggests they view the information as a routine part of their strategic planning.

Of course, Hertz adds, it’s not the only information that goes into the expansion equation, but administrators often respect group leaders who come armed with data from inside and outside the hospital about why it is necessary to make a new hire.

“It’s about open, honest discussion,” he says. “It’s about looking at information both inside the four walls and outside in the community. It’s not easy, but it can be done. But you’ve got to plan.”

Hertz says HM group leaders should plan at least 12 to 18 months out for a hire, “which I know is hard these days,” he says. But, he adds, short-term forecasting makes it “very difficult” to know when and how best to grow your group. TH

Richard Quinn is a freelance writer in New Jersey.

The increased frequency in recent years of what has been termed "ad hoc" percutaneous coronary intervention is of concern to both interventional cardiologists and third-party payers.

The definition of ad hoc PCI that accompanied recent guidelines on that subject in a statement by the Society of Cardiovascular Angiography and Interventions (SCAI) is a "diagnostic catheterization followed in the same session or same sitting by PCI." Much of this increase has occurred in patients without symptoms and with minimal if any evidence of ischemia. Convenience and economics also play a role. As a result, cardiologists presume that they can do no harm without asking the question of whether they are doing any good.

A recent report on 144,737 nonacute PCIs using the National Cardiovascular Data Registry indicated that almost 30,000 PCIs (24.4%) were performed in patients without symptoms or class I angina and 30% were at low risk by noninvasive testing. In these nonacute patients, 67% were considered either inappropriate or uncertain (JAMA 2011;306:53-61). The rate of performing inappropriate PCI in hospitals varied between 6% and 16%. A number of hospitals had inappropriate rates exceeding 25%, and some had rates as high as 48%. The registry does not provide the number of ad hoc procedures performed, but one might presume that many of these patients would have fit the criteria for entry into the COURAGE trial (N. Engl. J. Med. 2007;356:1503-16), in which patients with stable coronary disease, 43% of whom had either no angina or class I angina, did as well with medical treatment as with PCI.

Angiographers have admitted having difficulty assessing the severity of stenosis, and therefore often proceeding to ad hoc PCI. The recent FAME study suggests that the measure of fractional flow reserve (FFR) is able to define coronary lesions that are clinically significant (N. Engl. J. Med. 2009;360;213-24). However, the conclusions of FAME have been challenged in regard to the clinical importance of FFR measurement.

Included in the recent SCAI guidelines is the requirement that before ad hoc PCI is performed, patients should be given information about the appropriateness, relative risk, and benefit of the procedure as well as therapeutic alternatives to PCI. For patients with ongoing symptoms and positive diagnostic tests for ischemia, this is easily obtained prior to intervention. But patients without symptoms and without evidence by stress testing may not be given the real story before the procedure. For these patients, SCAI advises that "time-out" be called and that they be given time to consider the alternatives for treatment of their disease (Catheter. Cardiovasc. Interv. 2012 Nov. 29 [doi: 10.1002/ccd.24701]).

Unfortunately for all of us, the federal government is also concerned about the issue of appropriateness. A recent whistleblower lawsuit in Ohio was resolved with a payment of fines of $3 million by the hospital and more than $500,000 by the physician group involved in the lawsuit. According to press reports, the physicians defended their "high rates as a result of their aggressive style of medicine." The physicians defended the medical care that they provided although they "might not have met the government’s guidelines of reimbursement" (New York Times, Jan. 5, 2013, sec. B1).

Unless we adhere to good practice guidelines, the federal government will force our adherence, whether we like it or not.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies. This column, "Heart of the Matter," appears regularly in Cardiology News.

The increased frequency in recent years of what has been termed "ad hoc" percutaneous coronary intervention is of concern to both interventional cardiologists and third-party payers.

The definition of ad hoc PCI that accompanied recent guidelines on that subject in a statement by the Society of Cardiovascular Angiography and Interventions (SCAI) is a "diagnostic catheterization followed in the same session or same sitting by PCI." Much of this increase has occurred in patients without symptoms and with minimal if any evidence of ischemia. Convenience and economics also play a role. As a result, cardiologists presume that they can do no harm without asking the question of whether they are doing any good.

A recent report on 144,737 nonacute PCIs using the National Cardiovascular Data Registry indicated that almost 30,000 PCIs (24.4%) were performed in patients without symptoms or class I angina and 30% were at low risk by noninvasive testing. In these nonacute patients, 67% were considered either inappropriate or uncertain (JAMA 2011;306:53-61). The rate of performing inappropriate PCI in hospitals varied between 6% and 16%. A number of hospitals had inappropriate rates exceeding 25%, and some had rates as high as 48%. The registry does not provide the number of ad hoc procedures performed, but one might presume that many of these patients would have fit the criteria for entry into the COURAGE trial (N. Engl. J. Med. 2007;356:1503-16), in which patients with stable coronary disease, 43% of whom had either no angina or class I angina, did as well with medical treatment as with PCI.

Angiographers have admitted having difficulty assessing the severity of stenosis, and therefore often proceeding to ad hoc PCI. The recent FAME study suggests that the measure of fractional flow reserve (FFR) is able to define coronary lesions that are clinically significant (N. Engl. J. Med. 2009;360;213-24). However, the conclusions of FAME have been challenged in regard to the clinical importance of FFR measurement.

Included in the recent SCAI guidelines is the requirement that before ad hoc PCI is performed, patients should be given information about the appropriateness, relative risk, and benefit of the procedure as well as therapeutic alternatives to PCI. For patients with ongoing symptoms and positive diagnostic tests for ischemia, this is easily obtained prior to intervention. But patients without symptoms and without evidence by stress testing may not be given the real story before the procedure. For these patients, SCAI advises that "time-out" be called and that they be given time to consider the alternatives for treatment of their disease (Catheter. Cardiovasc. Interv. 2012 Nov. 29 [doi: 10.1002/ccd.24701]).

Unfortunately for all of us, the federal government is also concerned about the issue of appropriateness. A recent whistleblower lawsuit in Ohio was resolved with a payment of fines of $3 million by the hospital and more than $500,000 by the physician group involved in the lawsuit. According to press reports, the physicians defended their "high rates as a result of their aggressive style of medicine." The physicians defended the medical care that they provided although they "might not have met the government’s guidelines of reimbursement" (New York Times, Jan. 5, 2013, sec. B1).

Unless we adhere to good practice guidelines, the federal government will force our adherence, whether we like it or not.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies. This column, "Heart of the Matter," appears regularly in Cardiology News.

The increased frequency in recent years of what has been termed "ad hoc" percutaneous coronary intervention is of concern to both interventional cardiologists and third-party payers.

The definition of ad hoc PCI that accompanied recent guidelines on that subject in a statement by the Society of Cardiovascular Angiography and Interventions (SCAI) is a "diagnostic catheterization followed in the same session or same sitting by PCI." Much of this increase has occurred in patients without symptoms and with minimal if any evidence of ischemia. Convenience and economics also play a role. As a result, cardiologists presume that they can do no harm without asking the question of whether they are doing any good.

A recent report on 144,737 nonacute PCIs using the National Cardiovascular Data Registry indicated that almost 30,000 PCIs (24.4%) were performed in patients without symptoms or class I angina and 30% were at low risk by noninvasive testing. In these nonacute patients, 67% were considered either inappropriate or uncertain (JAMA 2011;306:53-61). The rate of performing inappropriate PCI in hospitals varied between 6% and 16%. A number of hospitals had inappropriate rates exceeding 25%, and some had rates as high as 48%. The registry does not provide the number of ad hoc procedures performed, but one might presume that many of these patients would have fit the criteria for entry into the COURAGE trial (N. Engl. J. Med. 2007;356:1503-16), in which patients with stable coronary disease, 43% of whom had either no angina or class I angina, did as well with medical treatment as with PCI.

Angiographers have admitted having difficulty assessing the severity of stenosis, and therefore often proceeding to ad hoc PCI. The recent FAME study suggests that the measure of fractional flow reserve (FFR) is able to define coronary lesions that are clinically significant (N. Engl. J. Med. 2009;360;213-24). However, the conclusions of FAME have been challenged in regard to the clinical importance of FFR measurement.

Included in the recent SCAI guidelines is the requirement that before ad hoc PCI is performed, patients should be given information about the appropriateness, relative risk, and benefit of the procedure as well as therapeutic alternatives to PCI. For patients with ongoing symptoms and positive diagnostic tests for ischemia, this is easily obtained prior to intervention. But patients without symptoms and without evidence by stress testing may not be given the real story before the procedure. For these patients, SCAI advises that "time-out" be called and that they be given time to consider the alternatives for treatment of their disease (Catheter. Cardiovasc. Interv. 2012 Nov. 29 [doi: 10.1002/ccd.24701]).

Unfortunately for all of us, the federal government is also concerned about the issue of appropriateness. A recent whistleblower lawsuit in Ohio was resolved with a payment of fines of $3 million by the hospital and more than $500,000 by the physician group involved in the lawsuit. According to press reports, the physicians defended their "high rates as a result of their aggressive style of medicine." The physicians defended the medical care that they provided although they "might not have met the government’s guidelines of reimbursement" (New York Times, Jan. 5, 2013, sec. B1).

Unless we adhere to good practice guidelines, the federal government will force our adherence, whether we like it or not.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies. This column, "Heart of the Matter," appears regularly in Cardiology News.

The February 2013 issue of Health Affairs explores a surprisingly underutilized concept in health care that, until recently, has essentially been ignored – patient empowerment.

For some, this term may conjure up unpleasant memories of annoying encounters in which demanding patients (and family members) tried to dictate their own hospital course. Yet others may recall how some well-informed patients have helped them significantly expedite, as well as optimize, the care they provided.

In an article titled "What the Evidence Shows about Patient Activation: Better Health Outcomes and Care Experiences; Fewer Data on Costs," the authors define patient activation as "the skills and confidence that equip patients to become actively engaged in their health care." The authors note that patients who are less "activated" are three times as likely to have their medical needs go unmet and twice as likely to delay medical care, when compared to patients who are more engaged. On the other hand, highly activated patients were found to be at least twice as likely to prepare questions for their doctors and seek out health information, including the quality of health care providers.

In another article in the same issue, "Rx for the ‘Blockbuster Drug’ of Patient Engagement," Susan Denzter noted that evidence is emerging that patients who are actively involved in their medical care have better outcomes and lower medical bills compared with those who are not.

The medical community is finally embracing this crucial issue. We have always known that well-informed patients can bolster their own health care – and make our lives much easier as well. But it seems that in our historically paternalistic health care system, doctors tightly held onto the reins and patients, patients blindly complied (or so we thought).

In 2000, I published "Your Family Medical Record: An Interactive Guide to Getting the Best Care," a book designed to address the tremendous void between how patients think and how we, their doctors, think. At that time, Americans had not yet grasped the importance of patient engagement, and my book is no longer in print. I was a doctor desperately trying to introduce the concept of patient engagement to the American public. At the time, I had high hopes of bridging important gaps by teaching patients easy-to-understand concepts about keeping and understanding their own health records and expediting their own care through applying basic "patient skills," such as how to prepare for visits in advance and how to think through their symptoms in a methodical, concise manner. Thirteen years later, I am thrilled to see others succeeding where I did not, for this concept is far too important to sweep under the carpet.

In the burgeoning age of the Affordable Care Act, physicians are challenged to seek innovative cost-effective new means by which we can optimize the medical care we provide. If we teach our patients a patient skill or two when time allows, we can play an important role in this important paradigm shift in the American health care system that over time will, undoubtedly, help lower health care costs and improve patient care.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. This blog, "Teachable Moments," appears regularly in Hospitalist News.

The February 2013 issue of Health Affairs explores a surprisingly underutilized concept in health care that, until recently, has essentially been ignored – patient empowerment.

For some, this term may conjure up unpleasant memories of annoying encounters in which demanding patients (and family members) tried to dictate their own hospital course. Yet others may recall how some well-informed patients have helped them significantly expedite, as well as optimize, the care they provided.

In an article titled "What the Evidence Shows about Patient Activation: Better Health Outcomes and Care Experiences; Fewer Data on Costs," the authors define patient activation as "the skills and confidence that equip patients to become actively engaged in their health care." The authors note that patients who are less "activated" are three times as likely to have their medical needs go unmet and twice as likely to delay medical care, when compared to patients who are more engaged. On the other hand, highly activated patients were found to be at least twice as likely to prepare questions for their doctors and seek out health information, including the quality of health care providers.

In another article in the same issue, "Rx for the ‘Blockbuster Drug’ of Patient Engagement," Susan Denzter noted that evidence is emerging that patients who are actively involved in their medical care have better outcomes and lower medical bills compared with those who are not.

The medical community is finally embracing this crucial issue. We have always known that well-informed patients can bolster their own health care – and make our lives much easier as well. But it seems that in our historically paternalistic health care system, doctors tightly held onto the reins and patients, patients blindly complied (or so we thought).

In 2000, I published "Your Family Medical Record: An Interactive Guide to Getting the Best Care," a book designed to address the tremendous void between how patients think and how we, their doctors, think. At that time, Americans had not yet grasped the importance of patient engagement, and my book is no longer in print. I was a doctor desperately trying to introduce the concept of patient engagement to the American public. At the time, I had high hopes of bridging important gaps by teaching patients easy-to-understand concepts about keeping and understanding their own health records and expediting their own care through applying basic "patient skills," such as how to prepare for visits in advance and how to think through their symptoms in a methodical, concise manner. Thirteen years later, I am thrilled to see others succeeding where I did not, for this concept is far too important to sweep under the carpet.

In the burgeoning age of the Affordable Care Act, physicians are challenged to seek innovative cost-effective new means by which we can optimize the medical care we provide. If we teach our patients a patient skill or two when time allows, we can play an important role in this important paradigm shift in the American health care system that over time will, undoubtedly, help lower health care costs and improve patient care.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. This blog, "Teachable Moments," appears regularly in Hospitalist News.

The February 2013 issue of Health Affairs explores a surprisingly underutilized concept in health care that, until recently, has essentially been ignored – patient empowerment.

For some, this term may conjure up unpleasant memories of annoying encounters in which demanding patients (and family members) tried to dictate their own hospital course. Yet others may recall how some well-informed patients have helped them significantly expedite, as well as optimize, the care they provided.

In an article titled "What the Evidence Shows about Patient Activation: Better Health Outcomes and Care Experiences; Fewer Data on Costs," the authors define patient activation as "the skills and confidence that equip patients to become actively engaged in their health care." The authors note that patients who are less "activated" are three times as likely to have their medical needs go unmet and twice as likely to delay medical care, when compared to patients who are more engaged. On the other hand, highly activated patients were found to be at least twice as likely to prepare questions for their doctors and seek out health information, including the quality of health care providers.

In another article in the same issue, "Rx for the ‘Blockbuster Drug’ of Patient Engagement," Susan Denzter noted that evidence is emerging that patients who are actively involved in their medical care have better outcomes and lower medical bills compared with those who are not.

The medical community is finally embracing this crucial issue. We have always known that well-informed patients can bolster their own health care – and make our lives much easier as well. But it seems that in our historically paternalistic health care system, doctors tightly held onto the reins and patients, patients blindly complied (or so we thought).

In 2000, I published "Your Family Medical Record: An Interactive Guide to Getting the Best Care," a book designed to address the tremendous void between how patients think and how we, their doctors, think. At that time, Americans had not yet grasped the importance of patient engagement, and my book is no longer in print. I was a doctor desperately trying to introduce the concept of patient engagement to the American public. At the time, I had high hopes of bridging important gaps by teaching patients easy-to-understand concepts about keeping and understanding their own health records and expediting their own care through applying basic "patient skills," such as how to prepare for visits in advance and how to think through their symptoms in a methodical, concise manner. Thirteen years later, I am thrilled to see others succeeding where I did not, for this concept is far too important to sweep under the carpet.

In the burgeoning age of the Affordable Care Act, physicians are challenged to seek innovative cost-effective new means by which we can optimize the medical care we provide. If we teach our patients a patient skill or two when time allows, we can play an important role in this important paradigm shift in the American health care system that over time will, undoubtedly, help lower health care costs and improve patient care.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. This blog, "Teachable Moments," appears regularly in Hospitalist News.

Many physicians do not consider liver disease and liver cancer classic complications of obesity, type 2 diabetes, or metabolic syndrome, but they should.

Research findings over the past decade offer substantial evidence for links between obesity, diabetes, or metabolic syndrome and the earliest hepatic manifestation of these derangements: nonalcoholic fatty liver disease (NAFLD). Equally compelling links tie obesity, diabetes, and metabolic syndrome to more advanced liver pathology: nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer, especially hepatocellular carcinoma (HCC).

Courtesy UCLA Health System

Although the link between obesity, diabetes, or metabolic syndrome and NASH or liver cancer is not yet strong enough to justify major changes in disease surveillance or management, the link between these metabolic disorders and NAFLD is powerful and common enough to warrant routinely considering these patients as having NAFLD, say experts. And if NAFLD is found, the next step is deciding if a patient is the right candidate for NASH or cirrhosis assessment; and if those disorders develop, cancer screening follows.

A new dimension of obesity and diabetes morbidity

"For decades, attention to the patient with type 2 diabetes focused on the control of hyperglycemia and of risk factors associated with macrovascular disease. The epidemic of obesity now presents endocrinologists with new challenges. Among them is the need to identify early complications related to obesity in the setting of type 2 diabetes. NAFLD is a common complication of patients with type 2 diabetes that ... does not fit into the traditional realm of diabetic complications," Dr. Romina Lomonaco and Dr. Kenneth Cusi wrote in a recently published book chapter ("Evidence-based Management of Diabetes," chapter 21; TFM Publishing, 2012).

Not until recently has NAFLD been recognized as another common complication of patients with type 2 diabetes that requires special attention. NAFLD’s low profile as a complication of obesity and diabetes contrasts with its ubiquity. About 70% of patients with type 2 diabetes have NAFLD (compared with about 20% of all American adults), and perhaps up to 90% of morbidly obese patients have NAFLD. The prevalence of impaired fasting glucose and of newly diagnosed type 2 diabetes is about threefold higher in patients with NAFLD than in those without liver disease.

"Insulin resistance and obesity are probably the biggest factors" causing NAFLD, said Dr. Cusi, professor of medicine and chief of adult endocrinology, diabetes, and metabolism at the University of Florida in Gainesville. Moreover, "diabetes will worsen NAFLD, producing more fibrosis and an increased rate of cirrhosis," he said in an interview.

That’s significant because it is NAFLD progression that poses the biggest risk. NAFLD severity can range from mild, early-stage disease in an asymptomatic patient with normal liver enzyme levels to the development of inflammation –NASH – which can cause liver injury and fibrosis, lead to cirrhosis, and set up progression to organ failure or development of HCC or other liver cancer.

Overall, about 40% of patients with NAFLD progress to NASH, but both obesity and diabetes ratchet up NAFLD progression, and so roughly half of all patients with diabetes have NASH. Patients with type 2 diabetes also have a two- to fourfold increased risk of developing advanced liver disease, cirrhosis, and HCC compared with people without diabetes. "About 15% of NASH patients develop cirrhosis, and a significant percent also develop cancer," Dr. Cusi said.

"NASH represents the hepatic manifestation of the metabolic syndrome, a constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia. It is projected that 25 million Americans will develop NASH by 2025, with 20% progressing to cirrhosis, hepatocellular carcinoma, or both, that may require liver transplantation," wrote Dr. Vatche G. Agopian and his associates from the Dumont-University of California, Los Angeles (UCLA), Transplant and Liver Cancer Center in a recent report (Ann. Surg. 2012;256:624-33).

From 2001 to 2009, the nationwide frequency of NASH as the primary indication for liver transplantation rose from 1% to 10%, with NASH becoming the third most common U.S. indication for liver transplantation (Gastroenterology 2011;141:1249-53). The UCLA surgeons reviewed their experience with 1,294 patients who underwent primary liver transplantation at their center between January 2002 and August 2011, and found 136 patients (11%) who met NASH criteria. But during the 10-year period studied, NASH as the trigger for liver transplant soared from 3% of transplants in 2002 to 19% in 2011, a jump that by 2011 made NASH the second most common cause for liver transplant at UCLA, trailing only hepatitis C virus. In fact, NASH "is poised to surpass hepatitis C as the leading indication in the next 10-20 years," wrote Dr. Agopian, a liver surgeon, and Dr. Busuttil, professor and chief of liver and pancreatic transplantation at UCLA, and their associates (Ann. Surg. 2012;256:624-33).

In their report, Dr. Agopian and Dr. Busuttil called the current surge in liver transplants for patients with NASH "the new epidemic."

"The future of [liver] transplantation is here with these patients who have nonalcoholic steatohepatitis and subsequent cirrhosis," commented Dr. John P. Roberts, professor and chief of transplant surgery at the University of California, San Francisco. "Currently, there are about 6,000 [liver] transplants [per year] in the United States. Half of those are done for hepatitis C. In the overall population of the United States, 1.3% have hepatitis C, and that provides about half of liver transplant patients. Twelve percent of the U.S. population have nonalcoholic steatohepatitis, a 10-fold increase over the percentage of the population with hepatitis C. Due to the kinetics of the hepatitis C epidemic, we are going to see a falloff in the number of patients with hepatitis C eligible for transplantation in the next 10 years. [Patients with NASH] are going to replace them, potentially by 10-fold," said Dr. Roberts, who commented on the report by Dr. Agopian and Dr. Busuttil on the UCLA experience during the 2012 annual meeting of the American Surgical Association in San Francisco.

The NAFLD, NASH, and HCC connections

"The link between obesity, NASH, cirrhosis, and HCC is very strong" said Dr. Stephen H. Caldwell, professor of medicine and director of hepatology at the University of Virginia in Charlottesville.

"What remains unknown is whether NASH and hepatic scar formation are essential to cause cancer, or can carcinomas arise in a noncirrhotic, non-NASH fatty liver? Scar formation itself is a carcinogenic process, especially when it progresses to stage 3 – bridging fibrosis – or to stage 4," when cirrhosis occurs.

"It’s difficult to justify screening all patients with a fatty liver; that would be a huge undertaking," Dr. Caldwell said in an interview. "The more important clinical message is to consider whether a patient has NASH, but that is hard to diagnose without a liver biopsy."

So far, no markers have been unquestionably accurate for diagnosing NASH. Any patient who is obese or has metabolic syndrome should be considered for NASH, said Dr. Caldwell. Signs of more advanced liver injury include cirrhosis or portal hypertension. Other, more subtle signs include spider angiomas, reddening of the palms, declining platelet counts, or a family history of liver disease. Any of these could be a reason to look for NASH, he said.

Last year, guidelines issued by the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology, and the American Gastroenterological Association recommended against routinely testing for NAFLD, even among patients in diabetes or obesity clinics. Evidence was lacking for routine screening, even of high-risk patients, the guidelines said, with no data on cost effectiveness and uncertainties about diagnostic tests and treatment options (Hepatology 2012;55:2005-32).

But the guidelines do call for targeted assessment of NAFLD, and targeting NASH workups for selected NAFLD patients. The guidelines recommend ruling out all other possible etiologies and establishing NAFLD by histology or imaging. When a patient is diagnosed with NAFLD, the guidelines say that "as the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its presence can be used to target patients for liver biopsy." The 2012 guidelines also highlighted the NAFLD Fibrosis Score (Hepatology 2007;45:846-54) as another useful tool to identify NAFLD patients at increased risk for NASH or cirrhosis. The guidelines called the plasma biomarker cytokeretin-18 "promising," but cautioned that it was "premature to recommend in routine clinical practice."

Major issues for patients who develop NASH are their risk for cirrhosis and liver failure, as well as that for liver cancer. Although the case already exists for obesity, diabetes, and metabolic syndrome as factors leading to NAFLD and NASH, evidence also links each of these three conditions to an increased rate of HCC and other liver cancer, such as cholangiocarcinoma.

"The evidence supports both an independent role for obesity, insulin resistance, and diabetes, as well as boosting the risk from other major risk factors such as hepatitis. The missing evidence is it has not been shown that treatment of diabetes or weight loss can reduce the risk of liver cancer," said Dr. Hashem B. El-Serag, professor and chief of gastroenterology and hepatology at the Baylor College of Medicine in Houston. "Screening for fatty liver by liver enzymes and ultrasound is probably a prudent first step" for obese or insulin-resistant patients, noted Dr. El-Serag. But surveillance for HCC by twice-annual ultrasound exams is only for patients with demonstrated advanced fibrosis or cirrhosis, he said in an interview.

"We currently recommend that anyone with NAFLD cirrhosis or cirrhosis of unknown etiology who is also obese or had diabetes should receive routine HCC surveillance," said Dr. György Baffy, chief of gastroenterology at the VA Boston Healthcare System. He predicts that "we may soon reach a general conclusion that people with morbid obesity (a body mass index of greater that 40 kg/m²) and poorly controlled diabetes should be considered for liver cancer surveillance even without clear evidence for cirrhosis," he said in an interview. But in general, "HCC occurrence in noncirrhotic liver is so low that surveillance would be rather inefficient."

Despite that, Dr. Baffy admits that the connection between diabetes and HCC may go beyond cirrhosis. "Up to half of all HCC may develop in noncirrhotic livers," he wrote in a recent editorial (Am. J. Gastroenterol. 2012;107:53-5). "It is more difficult to determine the need for HCC surveillance in diabetic patients with noncirrhotic liver or with no established liver disease."

To avoid missing a diagnosis of HCC, Dr. Baffy suggested awareness of the risk factors for advanced background liver disease and for HCC in patients with diabetes: male sex, older age, morbid obesity, poorly controlled and long-standing disease, and coexisting hepatitis C.

"For now, cirrhosis remains the primary indication for implementing HCC surveillance," but the new findings on liver cancer developing in liver disease associated with obesity and diabetes so far provide insufficient evidence to warrant any firm screening recommendations for these patients, Dr. Baffy wrote in another recent article along with Dr. Caldwell and Dr. Elizabeth M. Brunt (J. Hepatology 2012;56:1384-91). "The greater dilemma comes from new evidence that HCC may complicate NAFLD when fibrosis is mild or absent. Observations that diabetes may increase the risk of HCC regardless of the presence of cirrhosis remain a major concern for the 26 million Americans estimated to have diabetes or prediabetes," they wrote. "We may need to contemplate a paradigm shift in liver cancer surveillance, but for now at least, HCC appears to be a rare complication of NAFLD in the complete absence of fibrosis."

In addition, the value of regular cancer surveillance, even in patients with cirrhosis, remains uncertain, just as surveillance for breast cancer and prostate cancer has come under similar criticism. "It gets a little shaky when you look for evidence that [HCC] surveillance led to prolonged survival," said Dr. Caldwell. "You have all the same controversy as breast cancer, but surveillance is even less established for HCC."

Diabetes also linked to HCC spread

Once hepatocellular carcinoma forms in a patient with diabetes, the cancer may act more aggressively, according to studies from the University of Rochester (N.Y.).

A review of 265 consecutive patients treated for hepatocellular carcinoma (HCC) at Rochester’s Wilmot Cancer Center identified 91 (34%) with diabetes at the time of HCC diagnosis. Forty-seven of the 265 patients (18%) had distant metastases at the time of diagnosis. A multivariate analysis that controlled for age and etiologic risk factors showed that patients with diabetes were 10 times more likely to have distant metastases at the time of HCC diagnosis, compared with patients without diabetes, Dr. Aram F. Hezel and his associates reported last year (Cancer Investigation 2012;30:698-702). The analysis showed no statistically significant impact of diabetes on survival rate.

In a second analysis they found that patients with newly diagnosed HCC and diabetes were also significantly more likely to have macrovascular invasion by the HCC.

"We don’t treat patients with HCC differently if they have diabetes or obesity, but our findings show an association between diabetes and greater spread of HCC, more invasive cancer," said Dr. Hezel, an oncologist and director of hepatic and pancreatic cancer research at the Wilmot Cancer Center of the University of Rochester (N.Y.). "We don’t know whether we can treat the diabetes and change the behavior of the cancer by having patients under better control. Are cancers different in patients with diabetes or obesity? Do some metabolic states help push a cancer to more invasive behavior?" he asked in an interview.

"We use liver transplant to treat patients with liver cancer. In early stages of liver cancer the tumor is less likely to spread, so liver transplant can be curative. But if there are patients with a greater propensity for cancer spread at an earlier stage" then the efficacy of transplantation needs reassessment, Dr. Hezel said.

Few proven treatments for NAFLD, NASH, and to prevent HCC

Although diagnosing NAFLD is an important step in identifying patients at risk for NASH, cirrhosis, and liver cancer, interventions with proven benefits for NAFLD are limited. No approved drug treatments exist for NAFLD; lifestyle modification is the standard treatment to reduce steatosis and plasma levels of liver aminotransferases. Reductions in liver fat correlate closely with weight loss, Dr. Cusi, Dr. Lomonaco, and their associates said in a recently published analysis of NAFLD (Drugs 2013; Jan. 11 [Epub ahead of print]). A weight loss of 7%-10% has been linked with a roughly 50% drop in liver fat levels in NAFLD patients, they said. But long-term controlled studies are needed to better assess the impact of lifestyle changes on NAFLD and fatty livers.

Pioglitazone received endorsement from the AASLD panel for treating NASH in their 2012 NAFLD management recommendations. The recommendations cautioned that most NASH patients who received pioglitazone treatment in trials did not have diabetes, and that long-term safety and efficacy of pioglitazone in NASH patients are not established.

The AASLD guidelines also call for using vitamin E at a daily dosage of 800 IU, but only for patients with biopsy-proven NASH and no diabetes; the guidelines call it "first line" in this setting. But the guidelines also specifically caution against using vitamin E in patients with NASH and diabetes, patients with NAFLD who have not undergone a liver biopsy, patients with NASH and cirrhosis, and those with cryptogenic cirrhosis. The guidelines also caution against using metformin to treat NASH. No other drug intervention gets guideline endorsement for treating NASH.

"You can say diet and exercise minimize the risk of fatty liver, but beyond that drug therapy is unclear," said Dr. Caldwell. "I think as we see treatment evolve, we’ll see more interest [in treating NAFLD and NASH] by endocrinologists," he predicted.

The intervention picture changes when the goal is preventing liver cancer. "Effective treatment of insulin resistance and hyperinsulinemia may be critical to prevent hepatocarcinogenesis," wrote Dr. Baffy, Dr. Brunt, and Dr. Caldwell in their recent review (J. Hepatology 2012;56:1384-91). "Insulin sensitizing agents in diabetes may reduce the risk of HCC." They especially cited the epidemiologic evidence supporting a role for thiazolidinediones, which were linked to a 70% reduction in HCC incidence among patients with diabetes compared with patients treated with insulin or a sulfonylurea in a case-control study (Cancer 2010;116:1938-46). The same study also showed a similar, 70% reduction in HCC among patients treated with a biguanide like metformin.

"While current guidelines for the management of HCC have no specific recommendations for cases associated with NAFLD, obesity, and diabetes, the use of insulin-sensitizing drugs and avoidance of treatments that contribute to hyperinsulinemia are likely to enhance prevention and improve disease outcomes of HCC," said Dr. Baffy, Dr. Brunt, and Dr. Caldwell.

Similar evidence recently came from other epidemiologic studies that suggest damping down of HCC development in patients treated with a thiazolidinedione or metformin. A report last year that analyzed health records of about 98,000 Taiwan residents found that treatment with a thiazolidinedione or with metformin reduced the rate of HCC in patients with diabetes by about 50% compared with other treatments (Am. J. Gastroenterol. 2012;107:46-52). More evidence supporting protection from metformin against formation of both HCC and a second, less common type of liver cancer, intrahepatic cholangiocarcinoma, came in two studies reported last May at the annual Digestive Disease Week in San Diego.

"Metformin has not proved useful in the therapy of NAFLD, but it is helpful in decreasing the risk of HCC in patients with obesity- or diabetes-associated liver disease. Metformin should be part of antidiabetic management whenever possible," Dr. Baffy said in an interview.

But other experts regard the evidence accumulated so far as too preliminary to guide management. "It is premature to recommend using [metformin or a thiazolidinedione] for the primary reason of HCC prevention," said Dr. El-Serag.

"I don’t think the evidence is convincing at this point" regarding preventing HCC, said Dr. Caldwell. "The thiazolidinediones seem to retard progression of NASH fibrosis, but they also have adverse effects and their popularity has decreased."

Early days for a complex pathology

It seems as if the links between obesity, diabetes, and metabolic syndrome and NAFLD, NASH, and liver cancer are so tangled that it will take more time to fully resolve the etiologic relationships and the implications for diagnosis and management. The bottom line today is that a growing segment of American adults face risks for significant liver disease because of obesity, type 2 diabetes, and other elements of the metabolic syndrome.

"We see more and more patients over the last decade with liver cancer who didn’t have hepatitis or alcohol use but have diabetes and obesity. It’s a changing demographic," said Dr. Hezel. "We increasingly see liver cancer in patients without one of the classic risk factors. There are two possible mechanisms. Fibrosis and inflammation" caused by NAFLD and NASH trigger cancer formation and growth, "or it could be a more direct effect of high insulin levels or other hormonal effects. This is an emerging area; it follows on the epidemic of obesity and diabetes."

Dr. Cusi, Dr. Caldwell, Dr. Baffy, Dr. El-Serag, Dr. Busuttil, and Dr. Hezel all said that they had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

Many physicians do not consider liver disease and liver cancer classic complications of obesity, type 2 diabetes, or metabolic syndrome, but they should.

Research findings over the past decade offer substantial evidence for links between obesity, diabetes, or metabolic syndrome and the earliest hepatic manifestation of these derangements: nonalcoholic fatty liver disease (NAFLD). Equally compelling links tie obesity, diabetes, and metabolic syndrome to more advanced liver pathology: nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer, especially hepatocellular carcinoma (HCC).

Courtesy UCLA Health System

Although the link between obesity, diabetes, or metabolic syndrome and NASH or liver cancer is not yet strong enough to justify major changes in disease surveillance or management, the link between these metabolic disorders and NAFLD is powerful and common enough to warrant routinely considering these patients as having NAFLD, say experts. And if NAFLD is found, the next step is deciding if a patient is the right candidate for NASH or cirrhosis assessment; and if those disorders develop, cancer screening follows.

A new dimension of obesity and diabetes morbidity

"For decades, attention to the patient with type 2 diabetes focused on the control of hyperglycemia and of risk factors associated with macrovascular disease. The epidemic of obesity now presents endocrinologists with new challenges. Among them is the need to identify early complications related to obesity in the setting of type 2 diabetes. NAFLD is a common complication of patients with type 2 diabetes that ... does not fit into the traditional realm of diabetic complications," Dr. Romina Lomonaco and Dr. Kenneth Cusi wrote in a recently published book chapter ("Evidence-based Management of Diabetes," chapter 21; TFM Publishing, 2012).

Not until recently has NAFLD been recognized as another common complication of patients with type 2 diabetes that requires special attention. NAFLD’s low profile as a complication of obesity and diabetes contrasts with its ubiquity. About 70% of patients with type 2 diabetes have NAFLD (compared with about 20% of all American adults), and perhaps up to 90% of morbidly obese patients have NAFLD. The prevalence of impaired fasting glucose and of newly diagnosed type 2 diabetes is about threefold higher in patients with NAFLD than in those without liver disease.

"Insulin resistance and obesity are probably the biggest factors" causing NAFLD, said Dr. Cusi, professor of medicine and chief of adult endocrinology, diabetes, and metabolism at the University of Florida in Gainesville. Moreover, "diabetes will worsen NAFLD, producing more fibrosis and an increased rate of cirrhosis," he said in an interview.

That’s significant because it is NAFLD progression that poses the biggest risk. NAFLD severity can range from mild, early-stage disease in an asymptomatic patient with normal liver enzyme levels to the development of inflammation –NASH – which can cause liver injury and fibrosis, lead to cirrhosis, and set up progression to organ failure or development of HCC or other liver cancer.

Overall, about 40% of patients with NAFLD progress to NASH, but both obesity and diabetes ratchet up NAFLD progression, and so roughly half of all patients with diabetes have NASH. Patients with type 2 diabetes also have a two- to fourfold increased risk of developing advanced liver disease, cirrhosis, and HCC compared with people without diabetes. "About 15% of NASH patients develop cirrhosis, and a significant percent also develop cancer," Dr. Cusi said.

"NASH represents the hepatic manifestation of the metabolic syndrome, a constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia. It is projected that 25 million Americans will develop NASH by 2025, with 20% progressing to cirrhosis, hepatocellular carcinoma, or both, that may require liver transplantation," wrote Dr. Vatche G. Agopian and his associates from the Dumont-University of California, Los Angeles (UCLA), Transplant and Liver Cancer Center in a recent report (Ann. Surg. 2012;256:624-33).

From 2001 to 2009, the nationwide frequency of NASH as the primary indication for liver transplantation rose from 1% to 10%, with NASH becoming the third most common U.S. indication for liver transplantation (Gastroenterology 2011;141:1249-53). The UCLA surgeons reviewed their experience with 1,294 patients who underwent primary liver transplantation at their center between January 2002 and August 2011, and found 136 patients (11%) who met NASH criteria. But during the 10-year period studied, NASH as the trigger for liver transplant soared from 3% of transplants in 2002 to 19% in 2011, a jump that by 2011 made NASH the second most common cause for liver transplant at UCLA, trailing only hepatitis C virus. In fact, NASH "is poised to surpass hepatitis C as the leading indication in the next 10-20 years," wrote Dr. Agopian, a liver surgeon, and Dr. Busuttil, professor and chief of liver and pancreatic transplantation at UCLA, and their associates (Ann. Surg. 2012;256:624-33).

In their report, Dr. Agopian and Dr. Busuttil called the current surge in liver transplants for patients with NASH "the new epidemic."

"The future of [liver] transplantation is here with these patients who have nonalcoholic steatohepatitis and subsequent cirrhosis," commented Dr. John P. Roberts, professor and chief of transplant surgery at the University of California, San Francisco. "Currently, there are about 6,000 [liver] transplants [per year] in the United States. Half of those are done for hepatitis C. In the overall population of the United States, 1.3% have hepatitis C, and that provides about half of liver transplant patients. Twelve percent of the U.S. population have nonalcoholic steatohepatitis, a 10-fold increase over the percentage of the population with hepatitis C. Due to the kinetics of the hepatitis C epidemic, we are going to see a falloff in the number of patients with hepatitis C eligible for transplantation in the next 10 years. [Patients with NASH] are going to replace them, potentially by 10-fold," said Dr. Roberts, who commented on the report by Dr. Agopian and Dr. Busuttil on the UCLA experience during the 2012 annual meeting of the American Surgical Association in San Francisco.

The NAFLD, NASH, and HCC connections

"The link between obesity, NASH, cirrhosis, and HCC is very strong" said Dr. Stephen H. Caldwell, professor of medicine and director of hepatology at the University of Virginia in Charlottesville.

"What remains unknown is whether NASH and hepatic scar formation are essential to cause cancer, or can carcinomas arise in a noncirrhotic, non-NASH fatty liver? Scar formation itself is a carcinogenic process, especially when it progresses to stage 3 – bridging fibrosis – or to stage 4," when cirrhosis occurs.

"It’s difficult to justify screening all patients with a fatty liver; that would be a huge undertaking," Dr. Caldwell said in an interview. "The more important clinical message is to consider whether a patient has NASH, but that is hard to diagnose without a liver biopsy."

So far, no markers have been unquestionably accurate for diagnosing NASH. Any patient who is obese or has metabolic syndrome should be considered for NASH, said Dr. Caldwell. Signs of more advanced liver injury include cirrhosis or portal hypertension. Other, more subtle signs include spider angiomas, reddening of the palms, declining platelet counts, or a family history of liver disease. Any of these could be a reason to look for NASH, he said.

Last year, guidelines issued by the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology, and the American Gastroenterological Association recommended against routinely testing for NAFLD, even among patients in diabetes or obesity clinics. Evidence was lacking for routine screening, even of high-risk patients, the guidelines said, with no data on cost effectiveness and uncertainties about diagnostic tests and treatment options (Hepatology 2012;55:2005-32).

But the guidelines do call for targeted assessment of NAFLD, and targeting NASH workups for selected NAFLD patients. The guidelines recommend ruling out all other possible etiologies and establishing NAFLD by histology or imaging. When a patient is diagnosed with NAFLD, the guidelines say that "as the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its presence can be used to target patients for liver biopsy." The 2012 guidelines also highlighted the NAFLD Fibrosis Score (Hepatology 2007;45:846-54) as another useful tool to identify NAFLD patients at increased risk for NASH or cirrhosis. The guidelines called the plasma biomarker cytokeretin-18 "promising," but cautioned that it was "premature to recommend in routine clinical practice."

Major issues for patients who develop NASH are their risk for cirrhosis and liver failure, as well as that for liver cancer. Although the case already exists for obesity, diabetes, and metabolic syndrome as factors leading to NAFLD and NASH, evidence also links each of these three conditions to an increased rate of HCC and other liver cancer, such as cholangiocarcinoma.

"The evidence supports both an independent role for obesity, insulin resistance, and diabetes, as well as boosting the risk from other major risk factors such as hepatitis. The missing evidence is it has not been shown that treatment of diabetes or weight loss can reduce the risk of liver cancer," said Dr. Hashem B. El-Serag, professor and chief of gastroenterology and hepatology at the Baylor College of Medicine in Houston. "Screening for fatty liver by liver enzymes and ultrasound is probably a prudent first step" for obese or insulin-resistant patients, noted Dr. El-Serag. But surveillance for HCC by twice-annual ultrasound exams is only for patients with demonstrated advanced fibrosis or cirrhosis, he said in an interview.

"We currently recommend that anyone with NAFLD cirrhosis or cirrhosis of unknown etiology who is also obese or had diabetes should receive routine HCC surveillance," said Dr. György Baffy, chief of gastroenterology at the VA Boston Healthcare System. He predicts that "we may soon reach a general conclusion that people with morbid obesity (a body mass index of greater that 40 kg/m²) and poorly controlled diabetes should be considered for liver cancer surveillance even without clear evidence for cirrhosis," he said in an interview. But in general, "HCC occurrence in noncirrhotic liver is so low that surveillance would be rather inefficient."

Despite that, Dr. Baffy admits that the connection between diabetes and HCC may go beyond cirrhosis. "Up to half of all HCC may develop in noncirrhotic livers," he wrote in a recent editorial (Am. J. Gastroenterol. 2012;107:53-5). "It is more difficult to determine the need for HCC surveillance in diabetic patients with noncirrhotic liver or with no established liver disease."

To avoid missing a diagnosis of HCC, Dr. Baffy suggested awareness of the risk factors for advanced background liver disease and for HCC in patients with diabetes: male sex, older age, morbid obesity, poorly controlled and long-standing disease, and coexisting hepatitis C.

"For now, cirrhosis remains the primary indication for implementing HCC surveillance," but the new findings on liver cancer developing in liver disease associated with obesity and diabetes so far provide insufficient evidence to warrant any firm screening recommendations for these patients, Dr. Baffy wrote in another recent article along with Dr. Caldwell and Dr. Elizabeth M. Brunt (J. Hepatology 2012;56:1384-91). "The greater dilemma comes from new evidence that HCC may complicate NAFLD when fibrosis is mild or absent. Observations that diabetes may increase the risk of HCC regardless of the presence of cirrhosis remain a major concern for the 26 million Americans estimated to have diabetes or prediabetes," they wrote. "We may need to contemplate a paradigm shift in liver cancer surveillance, but for now at least, HCC appears to be a rare complication of NAFLD in the complete absence of fibrosis."

In addition, the value of regular cancer surveillance, even in patients with cirrhosis, remains uncertain, just as surveillance for breast cancer and prostate cancer has come under similar criticism. "It gets a little shaky when you look for evidence that [HCC] surveillance led to prolonged survival," said Dr. Caldwell. "You have all the same controversy as breast cancer, but surveillance is even less established for HCC."

Diabetes also linked to HCC spread

Once hepatocellular carcinoma forms in a patient with diabetes, the cancer may act more aggressively, according to studies from the University of Rochester (N.Y.).

A review of 265 consecutive patients treated for hepatocellular carcinoma (HCC) at Rochester’s Wilmot Cancer Center identified 91 (34%) with diabetes at the time of HCC diagnosis. Forty-seven of the 265 patients (18%) had distant metastases at the time of diagnosis. A multivariate analysis that controlled for age and etiologic risk factors showed that patients with diabetes were 10 times more likely to have distant metastases at the time of HCC diagnosis, compared with patients without diabetes, Dr. Aram F. Hezel and his associates reported last year (Cancer Investigation 2012;30:698-702). The analysis showed no statistically significant impact of diabetes on survival rate.

In a second analysis they found that patients with newly diagnosed HCC and diabetes were also significantly more likely to have macrovascular invasion by the HCC.

"We don’t treat patients with HCC differently if they have diabetes or obesity, but our findings show an association between diabetes and greater spread of HCC, more invasive cancer," said Dr. Hezel, an oncologist and director of hepatic and pancreatic cancer research at the Wilmot Cancer Center of the University of Rochester (N.Y.). "We don’t know whether we can treat the diabetes and change the behavior of the cancer by having patients under better control. Are cancers different in patients with diabetes or obesity? Do some metabolic states help push a cancer to more invasive behavior?" he asked in an interview.

"We use liver transplant to treat patients with liver cancer. In early stages of liver cancer the tumor is less likely to spread, so liver transplant can be curative. But if there are patients with a greater propensity for cancer spread at an earlier stage" then the efficacy of transplantation needs reassessment, Dr. Hezel said.

Few proven treatments for NAFLD, NASH, and to prevent HCC

Although diagnosing NAFLD is an important step in identifying patients at risk for NASH, cirrhosis, and liver cancer, interventions with proven benefits for NAFLD are limited. No approved drug treatments exist for NAFLD; lifestyle modification is the standard treatment to reduce steatosis and plasma levels of liver aminotransferases. Reductions in liver fat correlate closely with weight loss, Dr. Cusi, Dr. Lomonaco, and their associates said in a recently published analysis of NAFLD (Drugs 2013; Jan. 11 [Epub ahead of print]). A weight loss of 7%-10% has been linked with a roughly 50% drop in liver fat levels in NAFLD patients, they said. But long-term controlled studies are needed to better assess the impact of lifestyle changes on NAFLD and fatty livers.

Pioglitazone received endorsement from the AASLD panel for treating NASH in their 2012 NAFLD management recommendations. The recommendations cautioned that most NASH patients who received pioglitazone treatment in trials did not have diabetes, and that long-term safety and efficacy of pioglitazone in NASH patients are not established.

The AASLD guidelines also call for using vitamin E at a daily dosage of 800 IU, but only for patients with biopsy-proven NASH and no diabetes; the guidelines call it "first line" in this setting. But the guidelines also specifically caution against using vitamin E in patients with NASH and diabetes, patients with NAFLD who have not undergone a liver biopsy, patients with NASH and cirrhosis, and those with cryptogenic cirrhosis. The guidelines also caution against using metformin to treat NASH. No other drug intervention gets guideline endorsement for treating NASH.

"You can say diet and exercise minimize the risk of fatty liver, but beyond that drug therapy is unclear," said Dr. Caldwell. "I think as we see treatment evolve, we’ll see more interest [in treating NAFLD and NASH] by endocrinologists," he predicted.

The intervention picture changes when the goal is preventing liver cancer. "Effective treatment of insulin resistance and hyperinsulinemia may be critical to prevent hepatocarcinogenesis," wrote Dr. Baffy, Dr. Brunt, and Dr. Caldwell in their recent review (J. Hepatology 2012;56:1384-91). "Insulin sensitizing agents in diabetes may reduce the risk of HCC." They especially cited the epidemiologic evidence supporting a role for thiazolidinediones, which were linked to a 70% reduction in HCC incidence among patients with diabetes compared with patients treated with insulin or a sulfonylurea in a case-control study (Cancer 2010;116:1938-46). The same study also showed a similar, 70% reduction in HCC among patients treated with a biguanide like metformin.

"While current guidelines for the management of HCC have no specific recommendations for cases associated with NAFLD, obesity, and diabetes, the use of insulin-sensitizing drugs and avoidance of treatments that contribute to hyperinsulinemia are likely to enhance prevention and improve disease outcomes of HCC," said Dr. Baffy, Dr. Brunt, and Dr. Caldwell.

Similar evidence recently came from other epidemiologic studies that suggest damping down of HCC development in patients treated with a thiazolidinedione or metformin. A report last year that analyzed health records of about 98,000 Taiwan residents found that treatment with a thiazolidinedione or with metformin reduced the rate of HCC in patients with diabetes by about 50% compared with other treatments (Am. J. Gastroenterol. 2012;107:46-52). More evidence supporting protection from metformin against formation of both HCC and a second, less common type of liver cancer, intrahepatic cholangiocarcinoma, came in two studies reported last May at the annual Digestive Disease Week in San Diego.

"Metformin has not proved useful in the therapy of NAFLD, but it is helpful in decreasing the risk of HCC in patients with obesity- or diabetes-associated liver disease. Metformin should be part of antidiabetic management whenever possible," Dr. Baffy said in an interview.

But other experts regard the evidence accumulated so far as too preliminary to guide management. "It is premature to recommend using [metformin or a thiazolidinedione] for the primary reason of HCC prevention," said Dr. El-Serag.

"I don’t think the evidence is convincing at this point" regarding preventing HCC, said Dr. Caldwell. "The thiazolidinediones seem to retard progression of NASH fibrosis, but they also have adverse effects and their popularity has decreased."

Early days for a complex pathology

It seems as if the links between obesity, diabetes, and metabolic syndrome and NAFLD, NASH, and liver cancer are so tangled that it will take more time to fully resolve the etiologic relationships and the implications for diagnosis and management. The bottom line today is that a growing segment of American adults face risks for significant liver disease because of obesity, type 2 diabetes, and other elements of the metabolic syndrome.

"We see more and more patients over the last decade with liver cancer who didn’t have hepatitis or alcohol use but have diabetes and obesity. It’s a changing demographic," said Dr. Hezel. "We increasingly see liver cancer in patients without one of the classic risk factors. There are two possible mechanisms. Fibrosis and inflammation" caused by NAFLD and NASH trigger cancer formation and growth, "or it could be a more direct effect of high insulin levels or other hormonal effects. This is an emerging area; it follows on the epidemic of obesity and diabetes."

Dr. Cusi, Dr. Caldwell, Dr. Baffy, Dr. El-Serag, Dr. Busuttil, and Dr. Hezel all said that they had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

Many physicians do not consider liver disease and liver cancer classic complications of obesity, type 2 diabetes, or metabolic syndrome, but they should.

Research findings over the past decade offer substantial evidence for links between obesity, diabetes, or metabolic syndrome and the earliest hepatic manifestation of these derangements: nonalcoholic fatty liver disease (NAFLD). Equally compelling links tie obesity, diabetes, and metabolic syndrome to more advanced liver pathology: nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer, especially hepatocellular carcinoma (HCC).

Courtesy UCLA Health System

Although the link between obesity, diabetes, or metabolic syndrome and NASH or liver cancer is not yet strong enough to justify major changes in disease surveillance or management, the link between these metabolic disorders and NAFLD is powerful and common enough to warrant routinely considering these patients as having NAFLD, say experts. And if NAFLD is found, the next step is deciding if a patient is the right candidate for NASH or cirrhosis assessment; and if those disorders develop, cancer screening follows.

A new dimension of obesity and diabetes morbidity

"For decades, attention to the patient with type 2 diabetes focused on the control of hyperglycemia and of risk factors associated with macrovascular disease. The epidemic of obesity now presents endocrinologists with new challenges. Among them is the need to identify early complications related to obesity in the setting of type 2 diabetes. NAFLD is a common complication of patients with type 2 diabetes that ... does not fit into the traditional realm of diabetic complications," Dr. Romina Lomonaco and Dr. Kenneth Cusi wrote in a recently published book chapter ("Evidence-based Management of Diabetes," chapter 21; TFM Publishing, 2012).

Not until recently has NAFLD been recognized as another common complication of patients with type 2 diabetes that requires special attention. NAFLD’s low profile as a complication of obesity and diabetes contrasts with its ubiquity. About 70% of patients with type 2 diabetes have NAFLD (compared with about 20% of all American adults), and perhaps up to 90% of morbidly obese patients have NAFLD. The prevalence of impaired fasting glucose and of newly diagnosed type 2 diabetes is about threefold higher in patients with NAFLD than in those without liver disease.

"Insulin resistance and obesity are probably the biggest factors" causing NAFLD, said Dr. Cusi, professor of medicine and chief of adult endocrinology, diabetes, and metabolism at the University of Florida in Gainesville. Moreover, "diabetes will worsen NAFLD, producing more fibrosis and an increased rate of cirrhosis," he said in an interview.

That’s significant because it is NAFLD progression that poses the biggest risk. NAFLD severity can range from mild, early-stage disease in an asymptomatic patient with normal liver enzyme levels to the development of inflammation –NASH – which can cause liver injury and fibrosis, lead to cirrhosis, and set up progression to organ failure or development of HCC or other liver cancer.

Overall, about 40% of patients with NAFLD progress to NASH, but both obesity and diabetes ratchet up NAFLD progression, and so roughly half of all patients with diabetes have NASH. Patients with type 2 diabetes also have a two- to fourfold increased risk of developing advanced liver disease, cirrhosis, and HCC compared with people without diabetes. "About 15% of NASH patients develop cirrhosis, and a significant percent also develop cancer," Dr. Cusi said.

"NASH represents the hepatic manifestation of the metabolic syndrome, a constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia. It is projected that 25 million Americans will develop NASH by 2025, with 20% progressing to cirrhosis, hepatocellular carcinoma, or both, that may require liver transplantation," wrote Dr. Vatche G. Agopian and his associates from the Dumont-University of California, Los Angeles (UCLA), Transplant and Liver Cancer Center in a recent report (Ann. Surg. 2012;256:624-33).

From 2001 to 2009, the nationwide frequency of NASH as the primary indication for liver transplantation rose from 1% to 10%, with NASH becoming the third most common U.S. indication for liver transplantation (Gastroenterology 2011;141:1249-53). The UCLA surgeons reviewed their experience with 1,294 patients who underwent primary liver transplantation at their center between January 2002 and August 2011, and found 136 patients (11%) who met NASH criteria. But during the 10-year period studied, NASH as the trigger for liver transplant soared from 3% of transplants in 2002 to 19% in 2011, a jump that by 2011 made NASH the second most common cause for liver transplant at UCLA, trailing only hepatitis C virus. In fact, NASH "is poised to surpass hepatitis C as the leading indication in the next 10-20 years," wrote Dr. Agopian, a liver surgeon, and Dr. Busuttil, professor and chief of liver and pancreatic transplantation at UCLA, and their associates (Ann. Surg. 2012;256:624-33).

In their report, Dr. Agopian and Dr. Busuttil called the current surge in liver transplants for patients with NASH "the new epidemic."

"The future of [liver] transplantation is here with these patients who have nonalcoholic steatohepatitis and subsequent cirrhosis," commented Dr. John P. Roberts, professor and chief of transplant surgery at the University of California, San Francisco. "Currently, there are about 6,000 [liver] transplants [per year] in the United States. Half of those are done for hepatitis C. In the overall population of the United States, 1.3% have hepatitis C, and that provides about half of liver transplant patients. Twelve percent of the U.S. population have nonalcoholic steatohepatitis, a 10-fold increase over the percentage of the population with hepatitis C. Due to the kinetics of the hepatitis C epidemic, we are going to see a falloff in the number of patients with hepatitis C eligible for transplantation in the next 10 years. [Patients with NASH] are going to replace them, potentially by 10-fold," said Dr. Roberts, who commented on the report by Dr. Agopian and Dr. Busuttil on the UCLA experience during the 2012 annual meeting of the American Surgical Association in San Francisco.

The NAFLD, NASH, and HCC connections

"The link between obesity, NASH, cirrhosis, and HCC is very strong" said Dr. Stephen H. Caldwell, professor of medicine and director of hepatology at the University of Virginia in Charlottesville.

"What remains unknown is whether NASH and hepatic scar formation are essential to cause cancer, or can carcinomas arise in a noncirrhotic, non-NASH fatty liver? Scar formation itself is a carcinogenic process, especially when it progresses to stage 3 – bridging fibrosis – or to stage 4," when cirrhosis occurs.

"It’s difficult to justify screening all patients with a fatty liver; that would be a huge undertaking," Dr. Caldwell said in an interview. "The more important clinical message is to consider whether a patient has NASH, but that is hard to diagnose without a liver biopsy."

So far, no markers have been unquestionably accurate for diagnosing NASH. Any patient who is obese or has metabolic syndrome should be considered for NASH, said Dr. Caldwell. Signs of more advanced liver injury include cirrhosis or portal hypertension. Other, more subtle signs include spider angiomas, reddening of the palms, declining platelet counts, or a family history of liver disease. Any of these could be a reason to look for NASH, he said.

Last year, guidelines issued by the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology, and the American Gastroenterological Association recommended against routinely testing for NAFLD, even among patients in diabetes or obesity clinics. Evidence was lacking for routine screening, even of high-risk patients, the guidelines said, with no data on cost effectiveness and uncertainties about diagnostic tests and treatment options (Hepatology 2012;55:2005-32).

But the guidelines do call for targeted assessment of NAFLD, and targeting NASH workups for selected NAFLD patients. The guidelines recommend ruling out all other possible etiologies and establishing NAFLD by histology or imaging. When a patient is diagnosed with NAFLD, the guidelines say that "as the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its presence can be used to target patients for liver biopsy." The 2012 guidelines also highlighted the NAFLD Fibrosis Score (Hepatology 2007;45:846-54) as another useful tool to identify NAFLD patients at increased risk for NASH or cirrhosis. The guidelines called the plasma biomarker cytokeretin-18 "promising," but cautioned that it was "premature to recommend in routine clinical practice."

Major issues for patients who develop NASH are their risk for cirrhosis and liver failure, as well as that for liver cancer. Although the case already exists for obesity, diabetes, and metabolic syndrome as factors leading to NAFLD and NASH, evidence also links each of these three conditions to an increased rate of HCC and other liver cancer, such as cholangiocarcinoma.

"The evidence supports both an independent role for obesity, insulin resistance, and diabetes, as well as boosting the risk from other major risk factors such as hepatitis. The missing evidence is it has not been shown that treatment of diabetes or weight loss can reduce the risk of liver cancer," said Dr. Hashem B. El-Serag, professor and chief of gastroenterology and hepatology at the Baylor College of Medicine in Houston. "Screening for fatty liver by liver enzymes and ultrasound is probably a prudent first step" for obese or insulin-resistant patients, noted Dr. El-Serag. But surveillance for HCC by twice-annual ultrasound exams is only for patients with demonstrated advanced fibrosis or cirrhosis, he said in an interview.

"We currently recommend that anyone with NAFLD cirrhosis or cirrhosis of unknown etiology who is also obese or had diabetes should receive routine HCC surveillance," said Dr. György Baffy, chief of gastroenterology at the VA Boston Healthcare System. He predicts that "we may soon reach a general conclusion that people with morbid obesity (a body mass index of greater that 40 kg/m²) and poorly controlled diabetes should be considered for liver cancer surveillance even without clear evidence for cirrhosis," he said in an interview. But in general, "HCC occurrence in noncirrhotic liver is so low that surveillance would be rather inefficient."

Despite that, Dr. Baffy admits that the connection between diabetes and HCC may go beyond cirrhosis. "Up to half of all HCC may develop in noncirrhotic livers," he wrote in a recent editorial (Am. J. Gastroenterol. 2012;107:53-5). "It is more difficult to determine the need for HCC surveillance in diabetic patients with noncirrhotic liver or with no established liver disease."

To avoid missing a diagnosis of HCC, Dr. Baffy suggested awareness of the risk factors for advanced background liver disease and for HCC in patients with diabetes: male sex, older age, morbid obesity, poorly controlled and long-standing disease, and coexisting hepatitis C.

"For now, cirrhosis remains the primary indication for implementing HCC surveillance," but the new findings on liver cancer developing in liver disease associated with obesity and diabetes so far provide insufficient evidence to warrant any firm screening recommendations for these patients, Dr. Baffy wrote in another recent article along with Dr. Caldwell and Dr. Elizabeth M. Brunt (J. Hepatology 2012;56:1384-91). "The greater dilemma comes from new evidence that HCC may complicate NAFLD when fibrosis is mild or absent. Observations that diabetes may increase the risk of HCC regardless of the presence of cirrhosis remain a major concern for the 26 million Americans estimated to have diabetes or prediabetes," they wrote. "We may need to contemplate a paradigm shift in liver cancer surveillance, but for now at least, HCC appears to be a rare complication of NAFLD in the complete absence of fibrosis."

In addition, the value of regular cancer surveillance, even in patients with cirrhosis, remains uncertain, just as surveillance for breast cancer and prostate cancer has come under similar criticism. "It gets a little shaky when you look for evidence that [HCC] surveillance led to prolonged survival," said Dr. Caldwell. "You have all the same controversy as breast cancer, but surveillance is even less established for HCC."

Diabetes also linked to HCC spread

Once hepatocellular carcinoma forms in a patient with diabetes, the cancer may act more aggressively, according to studies from the University of Rochester (N.Y.).

A review of 265 consecutive patients treated for hepatocellular carcinoma (HCC) at Rochester’s Wilmot Cancer Center identified 91 (34%) with diabetes at the time of HCC diagnosis. Forty-seven of the 265 patients (18%) had distant metastases at the time of diagnosis. A multivariate analysis that controlled for age and etiologic risk factors showed that patients with diabetes were 10 times more likely to have distant metastases at the time of HCC diagnosis, compared with patients without diabetes, Dr. Aram F. Hezel and his associates reported last year (Cancer Investigation 2012;30:698-702). The analysis showed no statistically significant impact of diabetes on survival rate.

In a second analysis they found that patients with newly diagnosed HCC and diabetes were also significantly more likely to have macrovascular invasion by the HCC.

"We don’t treat patients with HCC differently if they have diabetes or obesity, but our findings show an association between diabetes and greater spread of HCC, more invasive cancer," said Dr. Hezel, an oncologist and director of hepatic and pancreatic cancer research at the Wilmot Cancer Center of the University of Rochester (N.Y.). "We don’t know whether we can treat the diabetes and change the behavior of the cancer by having patients under better control. Are cancers different in patients with diabetes or obesity? Do some metabolic states help push a cancer to more invasive behavior?" he asked in an interview.

"We use liver transplant to treat patients with liver cancer. In early stages of liver cancer the tumor is less likely to spread, so liver transplant can be curative. But if there are patients with a greater propensity for cancer spread at an earlier stage" then the efficacy of transplantation needs reassessment, Dr. Hezel said.

Few proven treatments for NAFLD, NASH, and to prevent HCC

Although diagnosing NAFLD is an important step in identifying patients at risk for NASH, cirrhosis, and liver cancer, interventions with proven benefits for NAFLD are limited. No approved drug treatments exist for NAFLD; lifestyle modification is the standard treatment to reduce steatosis and plasma levels of liver aminotransferases. Reductions in liver fat correlate closely with weight loss, Dr. Cusi, Dr. Lomonaco, and their associates said in a recently published analysis of NAFLD (Drugs 2013; Jan. 11 [Epub ahead of print]). A weight loss of 7%-10% has been linked with a roughly 50% drop in liver fat levels in NAFLD patients, they said. But long-term controlled studies are needed to better assess the impact of lifestyle changes on NAFLD and fatty livers.

Pioglitazone received endorsement from the AASLD panel for treating NASH in their 2012 NAFLD management recommendations. The recommendations cautioned that most NASH patients who received pioglitazone treatment in trials did not have diabetes, and that long-term safety and efficacy of pioglitazone in NASH patients are not established.

The AASLD guidelines also call for using vitamin E at a daily dosage of 800 IU, but only for patients with biopsy-proven NASH and no diabetes; the guidelines call it "first line" in this setting. But the guidelines also specifically caution against using vitamin E in patients with NASH and diabetes, patients with NAFLD who have not undergone a liver biopsy, patients with NASH and cirrhosis, and those with cryptogenic cirrhosis. The guidelines also caution against using metformin to treat NASH. No other drug intervention gets guideline endorsement for treating NASH.

"You can say diet and exercise minimize the risk of fatty liver, but beyond that drug therapy is unclear," said Dr. Caldwell. "I think as we see treatment evolve, we’ll see more interest [in treating NAFLD and NASH] by endocrinologists," he predicted.

The intervention picture changes when the goal is preventing liver cancer. "Effective treatment of insulin resistance and hyperinsulinemia may be critical to prevent hepatocarcinogenesis," wrote Dr. Baffy, Dr. Brunt, and Dr. Caldwell in their recent review (J. Hepatology 2012;56:1384-91). "Insulin sensitizing agents in diabetes may reduce the risk of HCC." They especially cited the epidemiologic evidence supporting a role for thiazolidinediones, which were linked to a 70% reduction in HCC incidence among patients with diabetes compared with patients treated with insulin or a sulfonylurea in a case-control study (Cancer 2010;116:1938-46). The same study also showed a similar, 70% reduction in HCC among patients treated with a biguanide like metformin.

"While current guidelines for the management of HCC have no specific recommendations for cases associated with NAFLD, obesity, and diabetes, the use of insulin-sensitizing drugs and avoidance of treatments that contribute to hyperinsulinemia are likely to enhance prevention and improve disease outcomes of HCC," said Dr. Baffy, Dr. Brunt, and Dr. Caldwell.

Similar evidence recently came from other epidemiologic studies that suggest damping down of HCC development in patients treated with a thiazolidinedione or metformin. A report last year that analyzed health records of about 98,000 Taiwan residents found that treatment with a thiazolidinedione or with metformin reduced the rate of HCC in patients with diabetes by about 50% compared with other treatments (Am. J. Gastroenterol. 2012;107:46-52). More evidence supporting protection from metformin against formation of both HCC and a second, less common type of liver cancer, intrahepatic cholangiocarcinoma, came in two studies reported last May at the annual Digestive Disease Week in San Diego.

"Metformin has not proved useful in the therapy of NAFLD, but it is helpful in decreasing the risk of HCC in patients with obesity- or diabetes-associated liver disease. Metformin should be part of antidiabetic management whenever possible," Dr. Baffy said in an interview.

But other experts regard the evidence accumulated so far as too preliminary to guide management. "It is premature to recommend using [metformin or a thiazolidinedione] for the primary reason of HCC prevention," said Dr. El-Serag.

"I don’t think the evidence is convincing at this point" regarding preventing HCC, said Dr. Caldwell. "The thiazolidinediones seem to retard progression of NASH fibrosis, but they also have adverse effects and their popularity has decreased."

Early days for a complex pathology

It seems as if the links between obesity, diabetes, and metabolic syndrome and NAFLD, NASH, and liver cancer are so tangled that it will take more time to fully resolve the etiologic relationships and the implications for diagnosis and management. The bottom line today is that a growing segment of American adults face risks for significant liver disease because of obesity, type 2 diabetes, and other elements of the metabolic syndrome.

"We see more and more patients over the last decade with liver cancer who didn’t have hepatitis or alcohol use but have diabetes and obesity. It’s a changing demographic," said Dr. Hezel. "We increasingly see liver cancer in patients without one of the classic risk factors. There are two possible mechanisms. Fibrosis and inflammation" caused by NAFLD and NASH trigger cancer formation and growth, "or it could be a more direct effect of high insulin levels or other hormonal effects. This is an emerging area; it follows on the epidemic of obesity and diabetes."

Dr. Cusi, Dr. Caldwell, Dr. Baffy, Dr. El-Serag, Dr. Busuttil, and Dr. Hezel all said that they had no relevant disclosures.

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