Liver Disease

Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.

The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."

To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.

Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.

Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.

Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.

First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).

"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.

Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.

The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.

"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.

Next, the authors turned their attention to the PubMed cases.

"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.

Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.

Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.

Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."

Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.

The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).

"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.

"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."

"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.

The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.

Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.

The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."

To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.

Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.

Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.

Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.

First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).

"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.

Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.

The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.

"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.

Next, the authors turned their attention to the PubMed cases.

"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.

Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.

Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.

Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."

Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.

The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).

"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.

"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."

"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.

The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.

Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.

The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."

To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.

Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.

Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.

Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.

First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).

"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.

Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.

The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.

"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.

Next, the authors turned their attention to the PubMed cases.

"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.

Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.

Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.

Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."

Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.

The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).

"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.

"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."

"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.

The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.

The risk of sexually transmitting a chronic hepatitis C infection to a long-term monogamous heterosexual partner is very low, averaging just about 1% per year.

That risk level works out to a transmission rate of about one in every 190,000 sexual contacts, Dr. Norah Terrault and her colleagues reported in the April issue of Hepatology (2013;57:881-9).

The cross-sectional study also found that no one sexual practice – including anal intercourse or intercourse during menses – significantly increased the risk of transmission, wrote Dr. Terrault of the University of California, San Francisco. The findings can be used to provide "unambiguous and reassuring counseling messages," she and her coinvestigators noted.

Courtesy U.S. Dept of Veterans Affairs

The study included 500 subjects with chronic HCV infections, and their sexual partners. All couples reported longtime, monogamous relationships (median duration, 15 years); however, the relationship duration varied widely, spanning 2-52 years.

Each of the partners was interviewed separately about their sexual contacts and practices. At the time of interview, the index subjects were a median of 49 years old and the partners, a median of 48 years.

The HCV-positive subjects reported the highest incidence of past risk factors, including blood transfusions before 1992 (32%), injected illegal drugs (54%), and being stuck by a bloody sharp item in a hospital (4%). Nearly half (46%) reported having had at least 20 lifetime sexual partners, with 21% having had 50 or more.

However, partners also reported some risk factors: 11% had an early transfusion, 2% used illegal drugs, and 2% had a hospital sharps incident. Many (27%) also reported having had at least 20 sexual partners.

Among the 500 couples, 20 partners (4%) were coinfected with HCV. Of these, nine were concordantly infected, eight discordantly, and three were indeterminate.

Six of the concordant couples underwent phylogenetic typing. Three were infected with the same HCV isolate and three with different strains. The investigators estimated the time of transmission and any additional risk factor among the three couples with concordant strains.

For the first couple, with an 18-year relationship, transmission probably occurred after about 6.5 years. The female partner had a history of injected drug use, while the male had no identifiable risk factors.

The second couple had a 28-year relationship; transmission probably occurred at around 15 years, the investigators said. "The female partner had a history of injectable drug use and both partners reported more than 20 prior sexual partners, a history of sexual transmitted diseases, and a history of snorting of drugs."

For the third couple, who had been together for 10 years, transmission probably occurred at around year 6. "The male partner had a history of injectable drug use, of being stuck by a sharp bloody object while working in a hospital, and more than 20 prior sexual partners; both partners reported snorting drugs and sharing snorting equipment."

The investigators determined that these infections were probably sexually transmitted between the partners – a prevalence of about 1%. "The estimated risk per sexual contact ranged from 1/380,000 to 1/190, 000," they said.

However, they were unable to identify any behaviors that significantly increased the risk of transmission. Compared with couples without coinfection, coinfected couples were more likely to have vaginal intercourse during menses (100% vs. 66%), more likely to have anal intercourse (67% vs. 30%), and less likely to use condoms (0% vs. 30%), but none of these differences was statistically significant.

"HCV transmission by sex from chronically infected persons to their heterosexual partners in a long-term monogamous relationship likely occurs, but is a rare event," the authors concluded. "Our results provide a basis for specific counseling messages that clinicians can use with their patients... [that] support the current national recommendations that couples not change their sexual practices if they are in a monogamous heterosexual relationship."

None of the study authors reported any financial conflicts.

[email protected]

The risk of sexually transmitting a chronic hepatitis C infection to a long-term monogamous heterosexual partner is very low, averaging just about 1% per year.

That risk level works out to a transmission rate of about one in every 190,000 sexual contacts, Dr. Norah Terrault and her colleagues reported in the April issue of Hepatology (2013;57:881-9).

The cross-sectional study also found that no one sexual practice – including anal intercourse or intercourse during menses – significantly increased the risk of transmission, wrote Dr. Terrault of the University of California, San Francisco. The findings can be used to provide "unambiguous and reassuring counseling messages," she and her coinvestigators noted.

Courtesy U.S. Dept of Veterans Affairs

The study included 500 subjects with chronic HCV infections, and their sexual partners. All couples reported longtime, monogamous relationships (median duration, 15 years); however, the relationship duration varied widely, spanning 2-52 years.

Each of the partners was interviewed separately about their sexual contacts and practices. At the time of interview, the index subjects were a median of 49 years old and the partners, a median of 48 years.

The HCV-positive subjects reported the highest incidence of past risk factors, including blood transfusions before 1992 (32%), injected illegal drugs (54%), and being stuck by a bloody sharp item in a hospital (4%). Nearly half (46%) reported having had at least 20 lifetime sexual partners, with 21% having had 50 or more.

However, partners also reported some risk factors: 11% had an early transfusion, 2% used illegal drugs, and 2% had a hospital sharps incident. Many (27%) also reported having had at least 20 sexual partners.

Among the 500 couples, 20 partners (4%) were coinfected with HCV. Of these, nine were concordantly infected, eight discordantly, and three were indeterminate.

Six of the concordant couples underwent phylogenetic typing. Three were infected with the same HCV isolate and three with different strains. The investigators estimated the time of transmission and any additional risk factor among the three couples with concordant strains.

For the first couple, with an 18-year relationship, transmission probably occurred after about 6.5 years. The female partner had a history of injected drug use, while the male had no identifiable risk factors.

The second couple had a 28-year relationship; transmission probably occurred at around 15 years, the investigators said. "The female partner had a history of injectable drug use and both partners reported more than 20 prior sexual partners, a history of sexual transmitted diseases, and a history of snorting of drugs."

For the third couple, who had been together for 10 years, transmission probably occurred at around year 6. "The male partner had a history of injectable drug use, of being stuck by a sharp bloody object while working in a hospital, and more than 20 prior sexual partners; both partners reported snorting drugs and sharing snorting equipment."

The investigators determined that these infections were probably sexually transmitted between the partners – a prevalence of about 1%. "The estimated risk per sexual contact ranged from 1/380,000 to 1/190, 000," they said.

However, they were unable to identify any behaviors that significantly increased the risk of transmission. Compared with couples without coinfection, coinfected couples were more likely to have vaginal intercourse during menses (100% vs. 66%), more likely to have anal intercourse (67% vs. 30%), and less likely to use condoms (0% vs. 30%), but none of these differences was statistically significant.

"HCV transmission by sex from chronically infected persons to their heterosexual partners in a long-term monogamous relationship likely occurs, but is a rare event," the authors concluded. "Our results provide a basis for specific counseling messages that clinicians can use with their patients... [that] support the current national recommendations that couples not change their sexual practices if they are in a monogamous heterosexual relationship."

None of the study authors reported any financial conflicts.

[email protected]

The risk of sexually transmitting a chronic hepatitis C infection to a long-term monogamous heterosexual partner is very low, averaging just about 1% per year.

That risk level works out to a transmission rate of about one in every 190,000 sexual contacts, Dr. Norah Terrault and her colleagues reported in the April issue of Hepatology (2013;57:881-9).

The cross-sectional study also found that no one sexual practice – including anal intercourse or intercourse during menses – significantly increased the risk of transmission, wrote Dr. Terrault of the University of California, San Francisco. The findings can be used to provide "unambiguous and reassuring counseling messages," she and her coinvestigators noted.

Courtesy U.S. Dept of Veterans Affairs

The study included 500 subjects with chronic HCV infections, and their sexual partners. All couples reported longtime, monogamous relationships (median duration, 15 years); however, the relationship duration varied widely, spanning 2-52 years.

Each of the partners was interviewed separately about their sexual contacts and practices. At the time of interview, the index subjects were a median of 49 years old and the partners, a median of 48 years.

The HCV-positive subjects reported the highest incidence of past risk factors, including blood transfusions before 1992 (32%), injected illegal drugs (54%), and being stuck by a bloody sharp item in a hospital (4%). Nearly half (46%) reported having had at least 20 lifetime sexual partners, with 21% having had 50 or more.

However, partners also reported some risk factors: 11% had an early transfusion, 2% used illegal drugs, and 2% had a hospital sharps incident. Many (27%) also reported having had at least 20 sexual partners.

Among the 500 couples, 20 partners (4%) were coinfected with HCV. Of these, nine were concordantly infected, eight discordantly, and three were indeterminate.

Six of the concordant couples underwent phylogenetic typing. Three were infected with the same HCV isolate and three with different strains. The investigators estimated the time of transmission and any additional risk factor among the three couples with concordant strains.

For the first couple, with an 18-year relationship, transmission probably occurred after about 6.5 years. The female partner had a history of injected drug use, while the male had no identifiable risk factors.

The second couple had a 28-year relationship; transmission probably occurred at around 15 years, the investigators said. "The female partner had a history of injectable drug use and both partners reported more than 20 prior sexual partners, a history of sexual transmitted diseases, and a history of snorting of drugs."

For the third couple, who had been together for 10 years, transmission probably occurred at around year 6. "The male partner had a history of injectable drug use, of being stuck by a sharp bloody object while working in a hospital, and more than 20 prior sexual partners; both partners reported snorting drugs and sharing snorting equipment."

The investigators determined that these infections were probably sexually transmitted between the partners – a prevalence of about 1%. "The estimated risk per sexual contact ranged from 1/380,000 to 1/190, 000," they said.

However, they were unable to identify any behaviors that significantly increased the risk of transmission. Compared with couples without coinfection, coinfected couples were more likely to have vaginal intercourse during menses (100% vs. 66%), more likely to have anal intercourse (67% vs. 30%), and less likely to use condoms (0% vs. 30%), but none of these differences was statistically significant.

"HCV transmission by sex from chronically infected persons to their heterosexual partners in a long-term monogamous relationship likely occurs, but is a rare event," the authors concluded. "Our results provide a basis for specific counseling messages that clinicians can use with their patients... [that] support the current national recommendations that couples not change their sexual practices if they are in a monogamous heterosexual relationship."

None of the study authors reported any financial conflicts.

[email protected]

Sofosbuvir resulted in a sustained virologic response in 90% of patients infected with hepatitis C virus genotype 1 or 4 at 12 weeks in a phase III trial.

Moreover, in a separate noninferiority analysis, patients with HCV genotypes 2 and 3 taking sofosbuvir had the same rates of sustained virologic response (SVR) as patients taking peginterferon, with fewer side effects, wrote Dr. Eric Lawitz in a report published online April 23 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214853).

In a report that is also to be presented at the International Liver Congress in Amsterdam, Dr. Lawitz analyzed more than 1,000 previously untreated HCV patients who received treatment with sofosbuvir in two multicenter studies. Sofosbuvir is an investigational nucleotide analogue HCV NS5B polymerase inhibitor.

The first study, the NEUTRINO trial, looked at a single group of 327 patients with genotypes 1, 4, 5, and 6 who received 12 weeks of open-label treatment with sofosbuvir (400 mg/day) plus peginterferon alfa-2a (180 mcg once per week) and ribavirin (given as a divided dose according to body weight, at 1,000 mg/day for patients less than 75 kg and 1,200 mg/day for heavier patients).

Most (89%) of these patients were genotype 1, with 9% having genotype 4, and the remainder having types 5 or 6, according to Dr. Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio.

At 12 weeks, SVR, defined by the lower limit of quantification of 25 IU/mL, occurred in 295 of these 327 patients (90%), with little difference in response rate according to genotype.

Having cirrhosis reduced the regimen’s SVR rate to 80%.

The second study assessed by Dr. Lawitz, the FISSION trial, involved 499 patients with HCV genotypes 2 or 3, who were randomized to open-label treatment with either sofosbuvir plus ribavirin for 12 weeks (n = 256) or peginterferon alfa-2a plus ribavirin for 24 weeks (n = 243).

Dosages in the sofosbuvir group were the same as in the NEUTRINO trial; in the peginterferon group, the ribavirin was given as 800 mg/day in two divided doses.

In this analysis, the researchers found that at 12 weeks, both treatment groups had an SVR of 67%.

Once again, the presence of cirrhosis reduced the likelihood of SVR. Genotype 3 also lowered the response, giving SVR rates of 56% in the sofosbuvir group and 63% in the peginterferon group.

In both NEUTRINO and FISSION, deep sequencing analysis of patients taking sofosbuvir who relapsed after having a virologic response showed no evidence of resistance-associated variants.

Discontinuation of sofosbuvir because of adverse events was uncommon in both trials: 2% in the NEUTRINO and 1% in the FISSION.

Indeed, "the influenza-like symptoms and fever that are characteristic of interferon treatment were reported in 16% and 18% of patients receiving peginterferon, respectively, but in only 3% of patients receiving sofosbuvir," Dr. Lawitz and his colleagues wrote.

"Depression, another common side effect of interferon therapy, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir."

Dr. Lawitz was an investigator in a second, unrelated study to be presented at the International Liver Congress and also reported in the New England Journal of Medicine. In that study, sofosbuvir was again proven to be effective in HCV genotype 2 and 3 patients for whom the traditional peginterferon-ribavirin regimen was not an option. Only the abstract of the study was available at press time (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMoa1214854]).

The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.

Sofosbuvir resulted in a sustained virologic response in 90% of patients infected with hepatitis C virus genotype 1 or 4 at 12 weeks in a phase III trial.

Moreover, in a separate noninferiority analysis, patients with HCV genotypes 2 and 3 taking sofosbuvir had the same rates of sustained virologic response (SVR) as patients taking peginterferon, with fewer side effects, wrote Dr. Eric Lawitz in a report published online April 23 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214853).

In a report that is also to be presented at the International Liver Congress in Amsterdam, Dr. Lawitz analyzed more than 1,000 previously untreated HCV patients who received treatment with sofosbuvir in two multicenter studies. Sofosbuvir is an investigational nucleotide analogue HCV NS5B polymerase inhibitor.

The first study, the NEUTRINO trial, looked at a single group of 327 patients with genotypes 1, 4, 5, and 6 who received 12 weeks of open-label treatment with sofosbuvir (400 mg/day) plus peginterferon alfa-2a (180 mcg once per week) and ribavirin (given as a divided dose according to body weight, at 1,000 mg/day for patients less than 75 kg and 1,200 mg/day for heavier patients).

Most (89%) of these patients were genotype 1, with 9% having genotype 4, and the remainder having types 5 or 6, according to Dr. Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio.

At 12 weeks, SVR, defined by the lower limit of quantification of 25 IU/mL, occurred in 295 of these 327 patients (90%), with little difference in response rate according to genotype.

Having cirrhosis reduced the regimen’s SVR rate to 80%.

The second study assessed by Dr. Lawitz, the FISSION trial, involved 499 patients with HCV genotypes 2 or 3, who were randomized to open-label treatment with either sofosbuvir plus ribavirin for 12 weeks (n = 256) or peginterferon alfa-2a plus ribavirin for 24 weeks (n = 243).

Dosages in the sofosbuvir group were the same as in the NEUTRINO trial; in the peginterferon group, the ribavirin was given as 800 mg/day in two divided doses.

In this analysis, the researchers found that at 12 weeks, both treatment groups had an SVR of 67%.

Once again, the presence of cirrhosis reduced the likelihood of SVR. Genotype 3 also lowered the response, giving SVR rates of 56% in the sofosbuvir group and 63% in the peginterferon group.

In both NEUTRINO and FISSION, deep sequencing analysis of patients taking sofosbuvir who relapsed after having a virologic response showed no evidence of resistance-associated variants.

Discontinuation of sofosbuvir because of adverse events was uncommon in both trials: 2% in the NEUTRINO and 1% in the FISSION.

Indeed, "the influenza-like symptoms and fever that are characteristic of interferon treatment were reported in 16% and 18% of patients receiving peginterferon, respectively, but in only 3% of patients receiving sofosbuvir," Dr. Lawitz and his colleagues wrote.

"Depression, another common side effect of interferon therapy, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir."

Dr. Lawitz was an investigator in a second, unrelated study to be presented at the International Liver Congress and also reported in the New England Journal of Medicine. In that study, sofosbuvir was again proven to be effective in HCV genotype 2 and 3 patients for whom the traditional peginterferon-ribavirin regimen was not an option. Only the abstract of the study was available at press time (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMoa1214854]).

The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.

Sofosbuvir resulted in a sustained virologic response in 90% of patients infected with hepatitis C virus genotype 1 or 4 at 12 weeks in a phase III trial.

Moreover, in a separate noninferiority analysis, patients with HCV genotypes 2 and 3 taking sofosbuvir had the same rates of sustained virologic response (SVR) as patients taking peginterferon, with fewer side effects, wrote Dr. Eric Lawitz in a report published online April 23 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1214853).

In a report that is also to be presented at the International Liver Congress in Amsterdam, Dr. Lawitz analyzed more than 1,000 previously untreated HCV patients who received treatment with sofosbuvir in two multicenter studies. Sofosbuvir is an investigational nucleotide analogue HCV NS5B polymerase inhibitor.

The first study, the NEUTRINO trial, looked at a single group of 327 patients with genotypes 1, 4, 5, and 6 who received 12 weeks of open-label treatment with sofosbuvir (400 mg/day) plus peginterferon alfa-2a (180 mcg once per week) and ribavirin (given as a divided dose according to body weight, at 1,000 mg/day for patients less than 75 kg and 1,200 mg/day for heavier patients).

Most (89%) of these patients were genotype 1, with 9% having genotype 4, and the remainder having types 5 or 6, according to Dr. Lawitz of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio.

At 12 weeks, SVR, defined by the lower limit of quantification of 25 IU/mL, occurred in 295 of these 327 patients (90%), with little difference in response rate according to genotype.

Having cirrhosis reduced the regimen’s SVR rate to 80%.

The second study assessed by Dr. Lawitz, the FISSION trial, involved 499 patients with HCV genotypes 2 or 3, who were randomized to open-label treatment with either sofosbuvir plus ribavirin for 12 weeks (n = 256) or peginterferon alfa-2a plus ribavirin for 24 weeks (n = 243).

Dosages in the sofosbuvir group were the same as in the NEUTRINO trial; in the peginterferon group, the ribavirin was given as 800 mg/day in two divided doses.

In this analysis, the researchers found that at 12 weeks, both treatment groups had an SVR of 67%.

Once again, the presence of cirrhosis reduced the likelihood of SVR. Genotype 3 also lowered the response, giving SVR rates of 56% in the sofosbuvir group and 63% in the peginterferon group.

In both NEUTRINO and FISSION, deep sequencing analysis of patients taking sofosbuvir who relapsed after having a virologic response showed no evidence of resistance-associated variants.

Discontinuation of sofosbuvir because of adverse events was uncommon in both trials: 2% in the NEUTRINO and 1% in the FISSION.

Indeed, "the influenza-like symptoms and fever that are characteristic of interferon treatment were reported in 16% and 18% of patients receiving peginterferon, respectively, but in only 3% of patients receiving sofosbuvir," Dr. Lawitz and his colleagues wrote.

"Depression, another common side effect of interferon therapy, occurred in 14% of patients receiving peginterferon, as compared with 5% of patients receiving sofosbuvir."

Dr. Lawitz was an investigator in a second, unrelated study to be presented at the International Liver Congress and also reported in the New England Journal of Medicine. In that study, sofosbuvir was again proven to be effective in HCV genotype 2 and 3 patients for whom the traditional peginterferon-ribavirin regimen was not an option. Only the abstract of the study was available at press time (N. Engl. J. Med. 2013 April 23 [doi: 10.1056/NEJMoa1214854]).

The NEUTRINO and FISSION trials were sponsored by Gilead Sciences, maker of sofosbuvir. Dr. Lawitz disclosed financial relationships to Gilead and multiple other pharmaceutical companies. Several authors were employees of Gilead.

The microRNA inhibitor miravirsen induced a dose-dependent drop in hepatitis C virus RNA levels, according to a phase IIa clinical trial reported online March 28 in the New England Journal of Medicine.

The treatment reduced HCV RNA to undetectable levels in five patients. And there was no evidence of the virus developing resistance to miravirsen during the 18-week study, said Dr. Harry L. A. Janssen of Erasmus MC University Hospital, Rotterdam, the Netherlands, and his associates (N. Engl. J. Med. 2013 March 28 [doi:10.1056/NEJMoa1209026]).

MicroRNAs are small, endogenous RNA that are thought to regulate a wide variety of biologic processes, including cell growth and differentiation, apoptosis, and modulation of the host response to viral infection. Miravirsen inhibits microRNA-122, which is expressed at high levels in the liver "and is essential to the stability and propagation of HCV RNA," the investigators explained.

In primate studies, miravirsen induced long-lasting HCV suppression, with no evidence of viral mutations conferring resistance to the agent. In phase I human studies, no adverse events were reported in healthy volunteers who took miravirsen.

For the phase IIa study, 36 patients with treatment-naive, genotype 1chronic HCV infection were followed at seven international sites. They were randomly assigned in a double-blind fashion to receive 3-mg, 5-mg, or 7-mg/kg doses of miravirsen, or a matching placebo, injected subcutaneously in five weekly doses over 29 days.

The study patients were allowed to initiate therapy with pegylated interferon and ribavirin after completing the course of miravirsen, at the discretion of the study investigators. Twelve of the 36 patients did so.

At all three dosages, miravirsen induced declines in HCV RNA levels from baseline for the study’s 14 weeks beyond the initial 4-week treatment period.

The reduction was dose dependent: The mean maximum decrease in HCV RNA levels was 1.2 log for patients receiving 3 mg/kg, 2.9 log for those receiving 5 mg/kg, and 3.0 log for those receiving 7 mg/kg. In contrast, patients receiving placebo showed a decline of only 0.4 log.

In five patients, miravirsen decreased HCV RNA to undetectable levels. That suggests that miravirsen eventually might be appropriate as monotherapy in some patients, Dr. Janssen and his colleagues said.

However, four of those five patients showed a rebound in viral levels at the conclusion of the study, which indicates that five weekly injections were not sufficient to induce a sustained virologic response.

"It is not clear whether regimens of miravirsen of longer duration could achieve a sustained virologic response; we are currently testing the effect of a 12-week regimen," the investigators noted.

Overall, HCV RNA levels rebounded after miravirsen was discontinued in nine patients who had not begun receiving interferon plus ribavirin. That included one patient given the 3-mg dose, five patients given the 5-mg dose, and three patients given the 7-mg dose of miravirsen.

The study subjects were assessed for resistance-associated mutations in HCV RNA at week 5 and at the time of viral rebound. No such mutations were found.

"There were no dose-limiting toxic effects or treatment discontinuations because of adverse events" or laboratory abnormalities, Dr. Janssen and his associates said.

No systemic allergic reactions occurred. Five patients given miravirsen and two patients given placebo reported transient, moderately severe adverse events that may not have been related to the study drug. Those included headache, otitis, flulike symptoms, and syncope.

There was one serious adverse event: One patient fell, lost consciousness, and injured a pelvic bone 9 weeks after receiving the last 7-mg dose of miravirsen.

Lab studies showed a sustained reduction in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase levels with miravirsen. There were no clinically significant changes in hemoglobin levels, total white-cell counts, prothrombin time, or activated partial thromboplastin time.

A "side benefit" of the treatment was a prolonged decrease in serum total cholesterol, which was expected because inhibition of microRNA-122 is known to disrupt cholesterol homeostasis.

The findings indicate that miravirsen should be considered a potential treatment for HCV infection, the study authors said. The injections can be given as infrequently as once a month, which encourages patient compliance. And unlike protease inhibitors, miravirsen "is not a substrate for cytochrome P-450 and is therefore not expected to have significant drug-drug interactions," the researchers said.

They added that antisense therapy "may also be relevant for diseases other than chronic HCV infection," including nonalcoholic fatty liver disease. Cancer, cardiovascular diseases, and autoimmune disorders also may respond to a strategy of inhibiting microRNAs that are associated with those diseases.

Santaris Pharma funded the study. Dr. Janssen and his associates reported ties to numerous industry sources.

The microRNA inhibitor miravirsen induced a dose-dependent drop in hepatitis C virus RNA levels, according to a phase IIa clinical trial reported online March 28 in the New England Journal of Medicine.

The treatment reduced HCV RNA to undetectable levels in five patients. And there was no evidence of the virus developing resistance to miravirsen during the 18-week study, said Dr. Harry L. A. Janssen of Erasmus MC University Hospital, Rotterdam, the Netherlands, and his associates (N. Engl. J. Med. 2013 March 28 [doi:10.1056/NEJMoa1209026]).

MicroRNAs are small, endogenous RNA that are thought to regulate a wide variety of biologic processes, including cell growth and differentiation, apoptosis, and modulation of the host response to viral infection. Miravirsen inhibits microRNA-122, which is expressed at high levels in the liver "and is essential to the stability and propagation of HCV RNA," the investigators explained.

In primate studies, miravirsen induced long-lasting HCV suppression, with no evidence of viral mutations conferring resistance to the agent. In phase I human studies, no adverse events were reported in healthy volunteers who took miravirsen.

For the phase IIa study, 36 patients with treatment-naive, genotype 1chronic HCV infection were followed at seven international sites. They were randomly assigned in a double-blind fashion to receive 3-mg, 5-mg, or 7-mg/kg doses of miravirsen, or a matching placebo, injected subcutaneously in five weekly doses over 29 days.

The study patients were allowed to initiate therapy with pegylated interferon and ribavirin after completing the course of miravirsen, at the discretion of the study investigators. Twelve of the 36 patients did so.

At all three dosages, miravirsen induced declines in HCV RNA levels from baseline for the study’s 14 weeks beyond the initial 4-week treatment period.

The reduction was dose dependent: The mean maximum decrease in HCV RNA levels was 1.2 log for patients receiving 3 mg/kg, 2.9 log for those receiving 5 mg/kg, and 3.0 log for those receiving 7 mg/kg. In contrast, patients receiving placebo showed a decline of only 0.4 log.

In five patients, miravirsen decreased HCV RNA to undetectable levels. That suggests that miravirsen eventually might be appropriate as monotherapy in some patients, Dr. Janssen and his colleagues said.

However, four of those five patients showed a rebound in viral levels at the conclusion of the study, which indicates that five weekly injections were not sufficient to induce a sustained virologic response.

"It is not clear whether regimens of miravirsen of longer duration could achieve a sustained virologic response; we are currently testing the effect of a 12-week regimen," the investigators noted.

Overall, HCV RNA levels rebounded after miravirsen was discontinued in nine patients who had not begun receiving interferon plus ribavirin. That included one patient given the 3-mg dose, five patients given the 5-mg dose, and three patients given the 7-mg dose of miravirsen.

The study subjects were assessed for resistance-associated mutations in HCV RNA at week 5 and at the time of viral rebound. No such mutations were found.

"There were no dose-limiting toxic effects or treatment discontinuations because of adverse events" or laboratory abnormalities, Dr. Janssen and his associates said.

No systemic allergic reactions occurred. Five patients given miravirsen and two patients given placebo reported transient, moderately severe adverse events that may not have been related to the study drug. Those included headache, otitis, flulike symptoms, and syncope.

There was one serious adverse event: One patient fell, lost consciousness, and injured a pelvic bone 9 weeks after receiving the last 7-mg dose of miravirsen.

Lab studies showed a sustained reduction in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase levels with miravirsen. There were no clinically significant changes in hemoglobin levels, total white-cell counts, prothrombin time, or activated partial thromboplastin time.

A "side benefit" of the treatment was a prolonged decrease in serum total cholesterol, which was expected because inhibition of microRNA-122 is known to disrupt cholesterol homeostasis.

The findings indicate that miravirsen should be considered a potential treatment for HCV infection, the study authors said. The injections can be given as infrequently as once a month, which encourages patient compliance. And unlike protease inhibitors, miravirsen "is not a substrate for cytochrome P-450 and is therefore not expected to have significant drug-drug interactions," the researchers said.

They added that antisense therapy "may also be relevant for diseases other than chronic HCV infection," including nonalcoholic fatty liver disease. Cancer, cardiovascular diseases, and autoimmune disorders also may respond to a strategy of inhibiting microRNAs that are associated with those diseases.

Santaris Pharma funded the study. Dr. Janssen and his associates reported ties to numerous industry sources.

The microRNA inhibitor miravirsen induced a dose-dependent drop in hepatitis C virus RNA levels, according to a phase IIa clinical trial reported online March 28 in the New England Journal of Medicine.

The treatment reduced HCV RNA to undetectable levels in five patients. And there was no evidence of the virus developing resistance to miravirsen during the 18-week study, said Dr. Harry L. A. Janssen of Erasmus MC University Hospital, Rotterdam, the Netherlands, and his associates (N. Engl. J. Med. 2013 March 28 [doi:10.1056/NEJMoa1209026]).

MicroRNAs are small, endogenous RNA that are thought to regulate a wide variety of biologic processes, including cell growth and differentiation, apoptosis, and modulation of the host response to viral infection. Miravirsen inhibits microRNA-122, which is expressed at high levels in the liver "and is essential to the stability and propagation of HCV RNA," the investigators explained.

In primate studies, miravirsen induced long-lasting HCV suppression, with no evidence of viral mutations conferring resistance to the agent. In phase I human studies, no adverse events were reported in healthy volunteers who took miravirsen.

For the phase IIa study, 36 patients with treatment-naive, genotype 1chronic HCV infection were followed at seven international sites. They were randomly assigned in a double-blind fashion to receive 3-mg, 5-mg, or 7-mg/kg doses of miravirsen, or a matching placebo, injected subcutaneously in five weekly doses over 29 days.

The study patients were allowed to initiate therapy with pegylated interferon and ribavirin after completing the course of miravirsen, at the discretion of the study investigators. Twelve of the 36 patients did so.

At all three dosages, miravirsen induced declines in HCV RNA levels from baseline for the study’s 14 weeks beyond the initial 4-week treatment period.

The reduction was dose dependent: The mean maximum decrease in HCV RNA levels was 1.2 log for patients receiving 3 mg/kg, 2.9 log for those receiving 5 mg/kg, and 3.0 log for those receiving 7 mg/kg. In contrast, patients receiving placebo showed a decline of only 0.4 log.

In five patients, miravirsen decreased HCV RNA to undetectable levels. That suggests that miravirsen eventually might be appropriate as monotherapy in some patients, Dr. Janssen and his colleagues said.

However, four of those five patients showed a rebound in viral levels at the conclusion of the study, which indicates that five weekly injections were not sufficient to induce a sustained virologic response.

"It is not clear whether regimens of miravirsen of longer duration could achieve a sustained virologic response; we are currently testing the effect of a 12-week regimen," the investigators noted.

Overall, HCV RNA levels rebounded after miravirsen was discontinued in nine patients who had not begun receiving interferon plus ribavirin. That included one patient given the 3-mg dose, five patients given the 5-mg dose, and three patients given the 7-mg dose of miravirsen.

The study subjects were assessed for resistance-associated mutations in HCV RNA at week 5 and at the time of viral rebound. No such mutations were found.

"There were no dose-limiting toxic effects or treatment discontinuations because of adverse events" or laboratory abnormalities, Dr. Janssen and his associates said.

No systemic allergic reactions occurred. Five patients given miravirsen and two patients given placebo reported transient, moderately severe adverse events that may not have been related to the study drug. Those included headache, otitis, flulike symptoms, and syncope.

There was one serious adverse event: One patient fell, lost consciousness, and injured a pelvic bone 9 weeks after receiving the last 7-mg dose of miravirsen.

Lab studies showed a sustained reduction in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase levels with miravirsen. There were no clinically significant changes in hemoglobin levels, total white-cell counts, prothrombin time, or activated partial thromboplastin time.

A "side benefit" of the treatment was a prolonged decrease in serum total cholesterol, which was expected because inhibition of microRNA-122 is known to disrupt cholesterol homeostasis.

The findings indicate that miravirsen should be considered a potential treatment for HCV infection, the study authors said. The injections can be given as infrequently as once a month, which encourages patient compliance. And unlike protease inhibitors, miravirsen "is not a substrate for cytochrome P-450 and is therefore not expected to have significant drug-drug interactions," the researchers said.

They added that antisense therapy "may also be relevant for diseases other than chronic HCV infection," including nonalcoholic fatty liver disease. Cancer, cardiovascular diseases, and autoimmune disorders also may respond to a strategy of inhibiting microRNAs that are associated with those diseases.

Santaris Pharma funded the study. Dr. Janssen and his associates reported ties to numerous industry sources.

SAN FRANCISCO – Postmenopausal status is independently associated with a twofold increased risk of hepatic steatosis, the Dallas Heart Study has shown.

Among 1,018 women aged 30-65 years enrolled in the population-based study, 48% were postmenopausal. Their prevalence of hepatic steatosis as defined by greater than 5.5% hepatic fat content measured by magnetic resonance spectroscopy was 34%. In contrast, the prevalence was significantly less at 24% in the premenopausal women, Dr. Monika Sanghavi reported at the annual meeting of the American College of Cardiology.

The absolute hepatic triglyceride content in the postmenopausal cohort was 4.0%, significantly more than the 2.9% value in premenopausal women.

Of note, the prevalence of hepatic steatosis rose with greater time since the last menstrual period (LMP). The prevalence was 22% among women whose LMP was less than 2 months earlier, 31% in those whose LMP was 2-12 months earlier, and 35% in women whose LMP was more than 12 months prior, according to Dr. Sanghavi of the University of Texas Southwestern Medical Center, Dallas.

Women who were postmenopausal were, of course, substantially older on average than premenopausal women. However, they also had significantly higher average systolic blood pressure, 129 compared with 117 mm Hg; a greater prevalence of diabetes, 16% vs. 7%; a mean LDL cholesterol of 113 compared with 98 mg/dL, and an average serum triglyceride level of 107 mg/dL compared with 81 mg/dL in premenopausal women. In a multivariate analysis adjusted for these variables as well as smoking status, body mass index, and C-reactive protein level, being postmenopausal remained independently associated with a twofold increased likelihood of hepatic steatosis (odds ratio, 2.0).

Hepatic steatosis has come under increasing research scrutiny of late because it appears to be a marker of increased atherosclerotic risk. The liver abnormality is associated with the metabolic syndrome, but as the Dallas Heart Study data show, postmenopausal status confers an increased risk of hepatic steatosis through a mechanism independent of obesity, hyperlipidemia, and other conventional cardiovascular risk factors.

Dr. Sanghavi reported having no relevant financial conflicts.

SAN FRANCISCO – Postmenopausal status is independently associated with a twofold increased risk of hepatic steatosis, the Dallas Heart Study has shown.

Among 1,018 women aged 30-65 years enrolled in the population-based study, 48% were postmenopausal. Their prevalence of hepatic steatosis as defined by greater than 5.5% hepatic fat content measured by magnetic resonance spectroscopy was 34%. In contrast, the prevalence was significantly less at 24% in the premenopausal women, Dr. Monika Sanghavi reported at the annual meeting of the American College of Cardiology.

The absolute hepatic triglyceride content in the postmenopausal cohort was 4.0%, significantly more than the 2.9% value in premenopausal women.

Of note, the prevalence of hepatic steatosis rose with greater time since the last menstrual period (LMP). The prevalence was 22% among women whose LMP was less than 2 months earlier, 31% in those whose LMP was 2-12 months earlier, and 35% in women whose LMP was more than 12 months prior, according to Dr. Sanghavi of the University of Texas Southwestern Medical Center, Dallas.

Women who were postmenopausal were, of course, substantially older on average than premenopausal women. However, they also had significantly higher average systolic blood pressure, 129 compared with 117 mm Hg; a greater prevalence of diabetes, 16% vs. 7%; a mean LDL cholesterol of 113 compared with 98 mg/dL, and an average serum triglyceride level of 107 mg/dL compared with 81 mg/dL in premenopausal women. In a multivariate analysis adjusted for these variables as well as smoking status, body mass index, and C-reactive protein level, being postmenopausal remained independently associated with a twofold increased likelihood of hepatic steatosis (odds ratio, 2.0).

Hepatic steatosis has come under increasing research scrutiny of late because it appears to be a marker of increased atherosclerotic risk. The liver abnormality is associated with the metabolic syndrome, but as the Dallas Heart Study data show, postmenopausal status confers an increased risk of hepatic steatosis through a mechanism independent of obesity, hyperlipidemia, and other conventional cardiovascular risk factors.

Dr. Sanghavi reported having no relevant financial conflicts.

SAN FRANCISCO – Postmenopausal status is independently associated with a twofold increased risk of hepatic steatosis, the Dallas Heart Study has shown.

Among 1,018 women aged 30-65 years enrolled in the population-based study, 48% were postmenopausal. Their prevalence of hepatic steatosis as defined by greater than 5.5% hepatic fat content measured by magnetic resonance spectroscopy was 34%. In contrast, the prevalence was significantly less at 24% in the premenopausal women, Dr. Monika Sanghavi reported at the annual meeting of the American College of Cardiology.

The absolute hepatic triglyceride content in the postmenopausal cohort was 4.0%, significantly more than the 2.9% value in premenopausal women.

Of note, the prevalence of hepatic steatosis rose with greater time since the last menstrual period (LMP). The prevalence was 22% among women whose LMP was less than 2 months earlier, 31% in those whose LMP was 2-12 months earlier, and 35% in women whose LMP was more than 12 months prior, according to Dr. Sanghavi of the University of Texas Southwestern Medical Center, Dallas.

Women who were postmenopausal were, of course, substantially older on average than premenopausal women. However, they also had significantly higher average systolic blood pressure, 129 compared with 117 mm Hg; a greater prevalence of diabetes, 16% vs. 7%; a mean LDL cholesterol of 113 compared with 98 mg/dL, and an average serum triglyceride level of 107 mg/dL compared with 81 mg/dL in premenopausal women. In a multivariate analysis adjusted for these variables as well as smoking status, body mass index, and C-reactive protein level, being postmenopausal remained independently associated with a twofold increased likelihood of hepatic steatosis (odds ratio, 2.0).

Hepatic steatosis has come under increasing research scrutiny of late because it appears to be a marker of increased atherosclerotic risk. The liver abnormality is associated with the metabolic syndrome, but as the Dallas Heart Study data show, postmenopausal status confers an increased risk of hepatic steatosis through a mechanism independent of obesity, hyperlipidemia, and other conventional cardiovascular risk factors.

Dr. Sanghavi reported having no relevant financial conflicts.

The analysis of volatile organic compounds in exhaled breath may provide a noninvasive and accurate test for diagnosing nonalcoholic steatohepatitis, according to results from a pilot study published in March.

This test could reduce the number of unnecessary liver biopsies and missed diagnoses associated with assessing plasma transaminase levels, reported Dr. Froukje J. Verdam of Maastricht (the Netherlands) University Medical Center and her associates (J. Hepatol. 2013;58:543-8).

Researchers evaluated breath samples with gas chromatography–mass spectrometry from 65 consecutive overweight or obese patients before they underwent laparoscopic abdominal surgery, between October 2007 and May 2011. These results were compared with histologic analysis of liver biopsies taken intraoperatively and assessments of plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Overall, liver biopsies showed that 39 patients (60%) had nonalcoholic steatohepatitis (NASH), defined as "showing signs of steatosis and inflammation." Additionally, ALT and AST levels were significantly higher in patients with the disease than without. However, "parameters such as gender, age, BMI, and HbA_1c did not differ significantly," reported the study authors.

The analysis of three volatile organic compounds (VOCs) – n-tridecane, 3-methylbutanonitrile, and 1-propanol – enabled investigators to distinguish between patients with and without NASH, with a sensitivity of 90%, a specificity of 69%, and an area under the receiver operating characteristic (ROC) curve of 0.77 plus or minus 0.07. The positive predictive value of using VOC analysis for NASH was 81%, while the negative predictive value was 82%.

In comparison, in 61 patients from whom plasma was available, the sensitivity of measuring ALT was 19%, while the specificity was 96%. The positive and negative predictive values of ALT were 88% and 43%, respectively.

Further evaluation of the AST/ALT ratio found that it was 32% sensitive and 79% specific, while positive and negative predictive values were 70% and 43%, respectively.

"It can be concluded that the diagnostic value of VOC is much higher than that of plasma transaminases, resulting in less misdiagnosed patients," wrote the study authors. Prediction of NASH using VOC, ALT, and the AST/ALT ratio did not reflect liver biopsy results in 18%, 51%, and 49% of subjects, respectively.

Using VOC evaluation rather than histologic testing has several other advantages, according to the researchers. "The analysis of exhaled breath can identify NASH presence at an early stage, and early identification in a mild stage is pivotal to enhance the chances of cure," they wrote. "Furthermore, whereas a small part of the liver is considered in the evaluation of biopsies, the breath test used in this study noninvasively reflects total liver function."

Funding for this pilot study was provided by grants from the Dutch SenterNovem Innovation Oriented Research Program on Genomics and the Transnational University Limburg, Belgium. The study authors reported no conflicts of interest.

The analysis of volatile organic compounds in exhaled breath may provide a noninvasive and accurate test for diagnosing nonalcoholic steatohepatitis, according to results from a pilot study published in March.

This test could reduce the number of unnecessary liver biopsies and missed diagnoses associated with assessing plasma transaminase levels, reported Dr. Froukje J. Verdam of Maastricht (the Netherlands) University Medical Center and her associates (J. Hepatol. 2013;58:543-8).

Researchers evaluated breath samples with gas chromatography–mass spectrometry from 65 consecutive overweight or obese patients before they underwent laparoscopic abdominal surgery, between October 2007 and May 2011. These results were compared with histologic analysis of liver biopsies taken intraoperatively and assessments of plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Overall, liver biopsies showed that 39 patients (60%) had nonalcoholic steatohepatitis (NASH), defined as "showing signs of steatosis and inflammation." Additionally, ALT and AST levels were significantly higher in patients with the disease than without. However, "parameters such as gender, age, BMI, and HbA_1c did not differ significantly," reported the study authors.

The analysis of three volatile organic compounds (VOCs) – n-tridecane, 3-methylbutanonitrile, and 1-propanol – enabled investigators to distinguish between patients with and without NASH, with a sensitivity of 90%, a specificity of 69%, and an area under the receiver operating characteristic (ROC) curve of 0.77 plus or minus 0.07. The positive predictive value of using VOC analysis for NASH was 81%, while the negative predictive value was 82%.

In comparison, in 61 patients from whom plasma was available, the sensitivity of measuring ALT was 19%, while the specificity was 96%. The positive and negative predictive values of ALT were 88% and 43%, respectively.

Further evaluation of the AST/ALT ratio found that it was 32% sensitive and 79% specific, while positive and negative predictive values were 70% and 43%, respectively.

"It can be concluded that the diagnostic value of VOC is much higher than that of plasma transaminases, resulting in less misdiagnosed patients," wrote the study authors. Prediction of NASH using VOC, ALT, and the AST/ALT ratio did not reflect liver biopsy results in 18%, 51%, and 49% of subjects, respectively.

Using VOC evaluation rather than histologic testing has several other advantages, according to the researchers. "The analysis of exhaled breath can identify NASH presence at an early stage, and early identification in a mild stage is pivotal to enhance the chances of cure," they wrote. "Furthermore, whereas a small part of the liver is considered in the evaluation of biopsies, the breath test used in this study noninvasively reflects total liver function."

Funding for this pilot study was provided by grants from the Dutch SenterNovem Innovation Oriented Research Program on Genomics and the Transnational University Limburg, Belgium. The study authors reported no conflicts of interest.

The analysis of volatile organic compounds in exhaled breath may provide a noninvasive and accurate test for diagnosing nonalcoholic steatohepatitis, according to results from a pilot study published in March.

This test could reduce the number of unnecessary liver biopsies and missed diagnoses associated with assessing plasma transaminase levels, reported Dr. Froukje J. Verdam of Maastricht (the Netherlands) University Medical Center and her associates (J. Hepatol. 2013;58:543-8).

Researchers evaluated breath samples with gas chromatography–mass spectrometry from 65 consecutive overweight or obese patients before they underwent laparoscopic abdominal surgery, between October 2007 and May 2011. These results were compared with histologic analysis of liver biopsies taken intraoperatively and assessments of plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Overall, liver biopsies showed that 39 patients (60%) had nonalcoholic steatohepatitis (NASH), defined as "showing signs of steatosis and inflammation." Additionally, ALT and AST levels were significantly higher in patients with the disease than without. However, "parameters such as gender, age, BMI, and HbA_1c did not differ significantly," reported the study authors.

The analysis of three volatile organic compounds (VOCs) – n-tridecane, 3-methylbutanonitrile, and 1-propanol – enabled investigators to distinguish between patients with and without NASH, with a sensitivity of 90%, a specificity of 69%, and an area under the receiver operating characteristic (ROC) curve of 0.77 plus or minus 0.07. The positive predictive value of using VOC analysis for NASH was 81%, while the negative predictive value was 82%.

In comparison, in 61 patients from whom plasma was available, the sensitivity of measuring ALT was 19%, while the specificity was 96%. The positive and negative predictive values of ALT were 88% and 43%, respectively.

Further evaluation of the AST/ALT ratio found that it was 32% sensitive and 79% specific, while positive and negative predictive values were 70% and 43%, respectively.

"It can be concluded that the diagnostic value of VOC is much higher than that of plasma transaminases, resulting in less misdiagnosed patients," wrote the study authors. Prediction of NASH using VOC, ALT, and the AST/ALT ratio did not reflect liver biopsy results in 18%, 51%, and 49% of subjects, respectively.

Using VOC evaluation rather than histologic testing has several other advantages, according to the researchers. "The analysis of exhaled breath can identify NASH presence at an early stage, and early identification in a mild stage is pivotal to enhance the chances of cure," they wrote. "Furthermore, whereas a small part of the liver is considered in the evaluation of biopsies, the breath test used in this study noninvasively reflects total liver function."

Funding for this pilot study was provided by grants from the Dutch SenterNovem Innovation Oriented Research Program on Genomics and the Transnational University Limburg, Belgium. The study authors reported no conflicts of interest.

ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.

"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.

Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.

Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.

The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.

At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.

In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.

The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log₁₀ IU/mL and 6.9 log₁₀ IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.

Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.

No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.

Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.

The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.

Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.

Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.

ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.

ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.

"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.

Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.

Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.

The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.

At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.

In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.

The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log₁₀ IU/mL and 6.9 log₁₀ IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.

Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.

No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.

Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.

The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.

Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.

Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.

ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.

ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.

"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.

Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.

Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.

The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.

At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.

In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.

The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log₁₀ IU/mL and 6.9 log₁₀ IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.

Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.

No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.

Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.

The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.

Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.

Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.

ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.

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.

[email protected]

On Twitter @mitchelzoler

Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.

Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.

Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).

Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.

However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.

Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.

Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.

Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.

When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).

The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).

Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.

In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.

Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).

But these surrogate outcome improvements did not translate to better clinical outcomes. "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse)," the researchers wrote.

The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).

Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.

Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.

Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).

Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.

However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.

Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.

Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.

Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.

When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).

The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).

Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.

In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.

Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).

But these surrogate outcome improvements did not translate to better clinical outcomes. "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse)," the researchers wrote.

The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).

Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.

Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.

Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).

Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.

However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.

Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.

Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.

Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.

When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).

The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).

Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.

In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.

Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).

But these surrogate outcome improvements did not translate to better clinical outcomes. "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse)," the researchers wrote.

The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).

Statin therapy taken to prevent cardiovascular events also appears to protect against hepatocellular carcinoma, reducing the overall risk for the cancer by 37%, according to the results of a systematic review and meta-analysis.

In a meta-analysis of all the studies in the literature that have examined statins’ effect on HCC risk, use of the drugs was associated with a pronounced and consistent risk reduction (48%) in Asian populations, as well as a still-significant reduction (33%) in Western populations, reported Dr. Siddharth Singh and his associates at the Mayo Clinic, Rochester, Minn.

Video source: American Gastroenterological Association's YouTube page

At present, "it does not seem prudent to prescribe statins for chemoprevention" of HCC in the general population, mainly because of the high number of people who would need to be treated to prevent a single case of HCC. "However, in patients with multiple risk factors, such as East Asian men who have chronic HBV [hepatitis B virus] infection, statins may have a clinically relevant chemoprotective effect against HCC, the investigators said (Gastroenterology 2012 Oct. 15 [doi: 10.1053/j.gastro.2012.10.005]).

Prospective cohort studies or randomized clinical trials of the issue are warranted in populations at high risk for HCC, they noted.

The results of preclinical studies have suggested that statins may decrease the risk of cancers, perhaps because their antiproliferative, proapoptotic, antiangiogenic, immunomodulatory, and anti-infective effects may prevent cancer growth. But clinical studies have produced conflicting results.

Dr. Singh and his colleagues performed a systematic review of the literature for studies that clearly defined statin exposure, reported HCC risk, and either reported relative risks or odds ratios for the development of HCC or provided the data so those risks could be calculated. They then performed a meta-analysis of 10 studies: 7 observational studies and 3 that reported pooled data from 26 randomized clinical trials.

Most of the studies were considered to be of high quality. Most of them accounted for various potential confounders such as patient age; sex; medication use; and the presence of viral hepatitis, cirrhosis, diabetes, or alcoholic liver disease. The likelihood of selection bias and of publication bias in the included studies was judged to be very low.

Altogether the 10 studies included 1,459,417 subjects and 4,298 cases of HCC.

In an initial analysis of the data, the use of statins was associated with a significant 41% reduction in the rate of HCC. After the data were adjusted to account for several potential confounders, the risk reduction was altered slightly, but a robust 37% reduction in HCC rate remained.

The investigators also performed an analysis of the data based on the location of the studies, because the epidemiology of HCC is so different between Western and Asian populations. They found that statin use correlated with a 48% reduction in the rate of HCC in Asian populations, where viral hepatitis is the primary risk factor for the disease, and a 33% reduction in the rate of HCC in Western populations, where the metabolic syndrome, nonalcoholic fatty liver disease, and alcohol-related cirrhosis are the primary risk factors.

The researchers also performed sensitivity analyses according to the studies’ design (cohort vs. case control) and quality (high vs. low). Both cohort and case-control studies confirmed a protective effect of statins against the development of HCC, as did both high-quality and low-quality studies.

In a final sensitivity analysis, each study was serially excluded from the meta-analysis to determine whether any one study was having a dominant effect on the odds ratios. None of the studies was found to markedly affect the outcomes of the analyses.

The study design didn’t permit separate analyses of the protective effects of statins by drug type or by dose or duration of therapy.

The studies included in this meta-analysis were too heterogeneous to allow the investigators to calculate an overall number needed to treat. But the studies restricted to Asian patients were homogeneous and did allow this calculation for men of Asian ethnicity.

Dr. Singh and his associates determined that 5,209 East Asian men would need to be treated with statins to prevent 1 case of HCC per year. For very-high-risk Asian men with chronic HBV-associated cirrhosis, the number needed to treat with statins to prevent 1 case of HCC per year would be 57.

No financial conflicts of interest were reported.

Statin therapy taken to prevent cardiovascular events also appears to protect against hepatocellular carcinoma, reducing the overall risk for the cancer by 37%, according to the results of a systematic review and meta-analysis.

In a meta-analysis of all the studies in the literature that have examined statins’ effect on HCC risk, use of the drugs was associated with a pronounced and consistent risk reduction (48%) in Asian populations, as well as a still-significant reduction (33%) in Western populations, reported Dr. Siddharth Singh and his associates at the Mayo Clinic, Rochester, Minn.

Video source: American Gastroenterological Association's YouTube page

At present, "it does not seem prudent to prescribe statins for chemoprevention" of HCC in the general population, mainly because of the high number of people who would need to be treated to prevent a single case of HCC. "However, in patients with multiple risk factors, such as East Asian men who have chronic HBV [hepatitis B virus] infection, statins may have a clinically relevant chemoprotective effect against HCC, the investigators said (Gastroenterology 2012 Oct. 15 [doi: 10.1053/j.gastro.2012.10.005]).

Prospective cohort studies or randomized clinical trials of the issue are warranted in populations at high risk for HCC, they noted.

The results of preclinical studies have suggested that statins may decrease the risk of cancers, perhaps because their antiproliferative, proapoptotic, antiangiogenic, immunomodulatory, and anti-infective effects may prevent cancer growth. But clinical studies have produced conflicting results.

Dr. Singh and his colleagues performed a systematic review of the literature for studies that clearly defined statin exposure, reported HCC risk, and either reported relative risks or odds ratios for the development of HCC or provided the data so those risks could be calculated. They then performed a meta-analysis of 10 studies: 7 observational studies and 3 that reported pooled data from 26 randomized clinical trials.

Most of the studies were considered to be of high quality. Most of them accounted for various potential confounders such as patient age; sex; medication use; and the presence of viral hepatitis, cirrhosis, diabetes, or alcoholic liver disease. The likelihood of selection bias and of publication bias in the included studies was judged to be very low.

Altogether the 10 studies included 1,459,417 subjects and 4,298 cases of HCC.

In an initial analysis of the data, the use of statins was associated with a significant 41% reduction in the rate of HCC. After the data were adjusted to account for several potential confounders, the risk reduction was altered slightly, but a robust 37% reduction in HCC rate remained.

The investigators also performed an analysis of the data based on the location of the studies, because the epidemiology of HCC is so different between Western and Asian populations. They found that statin use correlated with a 48% reduction in the rate of HCC in Asian populations, where viral hepatitis is the primary risk factor for the disease, and a 33% reduction in the rate of HCC in Western populations, where the metabolic syndrome, nonalcoholic fatty liver disease, and alcohol-related cirrhosis are the primary risk factors.

The researchers also performed sensitivity analyses according to the studies’ design (cohort vs. case control) and quality (high vs. low). Both cohort and case-control studies confirmed a protective effect of statins against the development of HCC, as did both high-quality and low-quality studies.

In a final sensitivity analysis, each study was serially excluded from the meta-analysis to determine whether any one study was having a dominant effect on the odds ratios. None of the studies was found to markedly affect the outcomes of the analyses.

The study design didn’t permit separate analyses of the protective effects of statins by drug type or by dose or duration of therapy.

The studies included in this meta-analysis were too heterogeneous to allow the investigators to calculate an overall number needed to treat. But the studies restricted to Asian patients were homogeneous and did allow this calculation for men of Asian ethnicity.

Dr. Singh and his associates determined that 5,209 East Asian men would need to be treated with statins to prevent 1 case of HCC per year. For very-high-risk Asian men with chronic HBV-associated cirrhosis, the number needed to treat with statins to prevent 1 case of HCC per year would be 57.

No financial conflicts of interest were reported.

Statin therapy taken to prevent cardiovascular events also appears to protect against hepatocellular carcinoma, reducing the overall risk for the cancer by 37%, according to the results of a systematic review and meta-analysis.

In a meta-analysis of all the studies in the literature that have examined statins’ effect on HCC risk, use of the drugs was associated with a pronounced and consistent risk reduction (48%) in Asian populations, as well as a still-significant reduction (33%) in Western populations, reported Dr. Siddharth Singh and his associates at the Mayo Clinic, Rochester, Minn.

Video source: American Gastroenterological Association's YouTube page

At present, "it does not seem prudent to prescribe statins for chemoprevention" of HCC in the general population, mainly because of the high number of people who would need to be treated to prevent a single case of HCC. "However, in patients with multiple risk factors, such as East Asian men who have chronic HBV [hepatitis B virus] infection, statins may have a clinically relevant chemoprotective effect against HCC, the investigators said (Gastroenterology 2012 Oct. 15 [doi: 10.1053/j.gastro.2012.10.005]).

Prospective cohort studies or randomized clinical trials of the issue are warranted in populations at high risk for HCC, they noted.

The results of preclinical studies have suggested that statins may decrease the risk of cancers, perhaps because their antiproliferative, proapoptotic, antiangiogenic, immunomodulatory, and anti-infective effects may prevent cancer growth. But clinical studies have produced conflicting results.

Dr. Singh and his colleagues performed a systematic review of the literature for studies that clearly defined statin exposure, reported HCC risk, and either reported relative risks or odds ratios for the development of HCC or provided the data so those risks could be calculated. They then performed a meta-analysis of 10 studies: 7 observational studies and 3 that reported pooled data from 26 randomized clinical trials.

Most of the studies were considered to be of high quality. Most of them accounted for various potential confounders such as patient age; sex; medication use; and the presence of viral hepatitis, cirrhosis, diabetes, or alcoholic liver disease. The likelihood of selection bias and of publication bias in the included studies was judged to be very low.

Altogether the 10 studies included 1,459,417 subjects and 4,298 cases of HCC.

In an initial analysis of the data, the use of statins was associated with a significant 41% reduction in the rate of HCC. After the data were adjusted to account for several potential confounders, the risk reduction was altered slightly, but a robust 37% reduction in HCC rate remained.

The investigators also performed an analysis of the data based on the location of the studies, because the epidemiology of HCC is so different between Western and Asian populations. They found that statin use correlated with a 48% reduction in the rate of HCC in Asian populations, where viral hepatitis is the primary risk factor for the disease, and a 33% reduction in the rate of HCC in Western populations, where the metabolic syndrome, nonalcoholic fatty liver disease, and alcohol-related cirrhosis are the primary risk factors.

The researchers also performed sensitivity analyses according to the studies’ design (cohort vs. case control) and quality (high vs. low). Both cohort and case-control studies confirmed a protective effect of statins against the development of HCC, as did both high-quality and low-quality studies.

In a final sensitivity analysis, each study was serially excluded from the meta-analysis to determine whether any one study was having a dominant effect on the odds ratios. None of the studies was found to markedly affect the outcomes of the analyses.

The study design didn’t permit separate analyses of the protective effects of statins by drug type or by dose or duration of therapy.

The studies included in this meta-analysis were too heterogeneous to allow the investigators to calculate an overall number needed to treat. But the studies restricted to Asian patients were homogeneous and did allow this calculation for men of Asian ethnicity.

Dr. Singh and his associates determined that 5,209 East Asian men would need to be treated with statins to prevent 1 case of HCC per year. For very-high-risk Asian men with chronic HBV-associated cirrhosis, the number needed to treat with statins to prevent 1 case of HCC per year would be 57.

No financial conflicts of interest were reported.