Fatty Liver Disease Tied to Diabetes, Atherosclerosis

Medscape Medical News > Conference News

Miriam E. Tucker
April 11, 2014

LONDON, United Kingdom — Nonalcoholic fatty liver disease is an independent predictor of cardiometabolic risk, according to 2 new studies.

Taken together, these findings "contribute to a large body of evidence showing nonalcoholic fatty liver disease may pose a cardiovascular risk above and beyond that conferred by traditional risk factors," said Frank Lammert, MD, PhD, professor of internal medicine at the Saarlande University Medical Center in Homburg, Germany.

"I think the key message for clinical practice is that these diseases are closely correlated, and clinical practitioners should be aware of this," he told Medscape Medical News.

Dr. Lammert, who was not involved in either study, spoke during a press briefing here at European Association for the Study of the Liver International Liver Congress 2014, where results from the 2 studies were presented.

In the Japanese study, the presence of nonalcoholic fatty liver disease was associated with an increased risk for type 2 diabetes, and improvement in the disease over a 10-year follow-up period appeared to reduce the risk.

In the French study, nonalcoholic fatty liver disease was found to be a predictor of carotid atherosclerosis, independent of the classic cardiovascular risk factors. In patients with nonalcoholic fatty liver disease, carotid intima-media thickness (C-IMT), carotid plaques, and Framingham scores were greater.

Type 2 Diabetes

In the Japanese study, 3074 patients who did not have diabetes or hepatitis A or B and who did not consume excessive amounts of alcohol underwent 2 ultrasound health checks at least 10 years apart.

At baseline, 24% of the cohort was found to have nonalcoholic fatty liver disease, said Hajime Yamazaki, MD, from the Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan, who presented the results.

At a mean follow-up of 11.3 years, 16.1% of the 728 patients with nonalcoholic fatty liver disease at baseline had developed type 2 diabetes, compared with just 3.1% of the 2346 who did not. The crude odds ratio for the association was 6.05 (P < .001).

After multivariate analysis adjusted for a variety of confounders, including age, sex, body mass index, family history of diabetes, and dyslipidemia, the odds ratio remained significant, at 2.82 (P < .001).

Follow-up ultrasound showed improvement in 110 of the patients with nonalcoholic fatty liver disease at baseline; in the other 618, there was no improvement.

The reason for the improvement could not be determined from these data, but in most cases, it was likely the result of lifestyle changes, Dr. Yamazaki explained.

The incidence of type 2 diabetes lower in those whose condition improved than in those whose condition did not (6.4% vs 17.8%). The crude odds ratio for improvement in nonalcoholic fatty liver disease and type 2 diabetes was 0.31 (P = .004); on multivariate analysis, it was 0.30 (P = .003).

"The clinical message is that it is important to reduce fatty liver to prevent diabetes," he told Medscape Medical News.

This study is the largest and longest to show an association between nonalcoholic fatty liver disease and type 2 diabetes, and the first-ever to show a reduction in type 2 diabetes with improvement in fatty liver disease, he said.

This study was possible because ultrasound health checks are part of clinical practice in East Asian countries. It is unlikely that this type of study could be conducted elsewhere, but results would probably be similar in other populations, he explained.

Although cause and effect couldn't be assessed in this study, "for many of the patients — maybe for the majority — there is a causal link between liver disease and diabetes because the liver plays a central role in glucose homeostasis," Dr. Lammert pointed out.

Cardiovascular Disease

Results from the 2-part cross-sectional and longitudinal French study were presented by Raluca Pais, MD, PhD, from Université Pierre et Marie Curie and Hôpital de La Pitié-Salpêtrière in Paris.

The cross-sectional part involved 5671 patients 20 to 75 years of age who had 2 or more cardiovascular risk factors. All had undergone at least 1 carotid ultrasound to measure C-IMT and carotid plaques.

C-IMT was significantly higher in the 1871 subjects with nonalcoholic fatty liver disease than in the 3800 without the disease (0.64 vs 0.61 mm; P < .001), as were the prevalence of carotid plaques (44% vs 37%; P < 0.001) and Framingham risk scores (15 vs 8; P < 0.001). All were independent of age, sex, body mass index, hypertension, and tobacco use, Dr. Pais reported.

At 8-year follow-up in a subset of 1872 patients who had at least 2 C-IMT measurements, those with nonalcoholic fatty liver disease at baseline had a 34% increased risk for carotid plaques (P < .02).

These associations held true regardless of serum alanine aminotransferase levels, she said.

"Patients at risk for CVD should probably be screened for fatty liver, regardless of the transaminase levels, because nonalcoholic fatty liver disease is an independent predictor of cardiovascular risk, beyond traditional risk factors like metabolic syndrome," she told Medscape Medical News. "We don't know if nonalcoholic fatty liver disease is a marker or actively involved in the pathogenesis and progression of cardiovascular disease. It's at least a marker; for the rest, we don't yet have the answer."

Clinical Implications

During the briefing, Dr. Lammert advised that patients who enter a liver unit be assessed for cardiovascular risk and that those seen in cardiology settings be evaluated by a liver specialist.

"We should stratify the risk and define the subgroup of patients who would benefit from being treated by both a cardiologist and a hepatologist. It shouldn't happen by chance," he said.

He also advised that liver specialists focus on patients who present with nonalcoholic fatty liver disease without traditional cardiovascular risk factors, noting that at least 1 such genetic subgroup has been identified. "We need to define this better," said Dr. Lammert.

Dr. Yamazaki, Dr. Pais, and Dr. Lammert have disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) International Liver Congress 2014: Abstracts 23 and 26. Presented April 10, 2014.

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Fibrosis and fatty liver disease increase risk of early atherosclerosis

Public release date: 24-Apr-2012

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell 

Italian researchers report that severe fibrosis increases the early atherosclerosis risk in patients with genotype 1 chronic hepatitis C virus (HCV) infection. A second study found that fatty liver disease also increases risk of developing atherosclerosis at an earlier period. Both studies appear in the May issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

In the first study, researchers led by Dr. Salvatore Petta from the Di.Bi.M.I.S. University of Palermo in Italy evaluated 174 patients with chronic HCV (genotype 1) along with 174 controls from an outpatient cardiology unit for signs of atherosclerosis. Ultrasonography was used to measure thickening of the carotid artery. Severity of fibrosis was determined for all HCV patients.

The team found carotid plaques in 42% of HCV patients compared to 23% of patients in the control group. Older age and severe liver fibrosis were independently associated with the presence of carotid plaque according to the authors. In patients 55 years or younger who had less sever fibrosis (stage F0-F2) only 22% had plaques in their artery compared to 52% with more sever fibrosis (stage F3-F4). Patients older the 55 years of age had similar prevalence of carotid lesions for those with or without severe fibrosis at 58% and 51% respectively.

"Our findings suggest that severe liver fibrosis places chronic HCV patients at higher risk of early atherosclerosis," said Dr. Petta. "This patient group should be carefully monitored to prevent progression of cardiovascular disease that is independent of their metabolic profile." The authors also caution that a majority of the European study participants were overweight, which should be considered in applying results to other patient populations.

A second study by Dr. Michaela Kozakova and colleagues from the University of Pisa further explored whether the association between fatty liver disease and early atherosclerosis is a consequence of shared conventional risk factors or is it determined by a specific circulating factor originating from liver or adipose tissue. For this purpose the researches investigated the association between the presence of early carotid plaques and the fatty liver index (FLI), which is an established surrogate marker for fatty liver disease based on body mass index (BMI), waist circumference, triglycerides and gamma glutamyltransferase (GGT), in subjects who were part of the multicenter European RISC (Relationship between Insulin Sensitivity and Cardiovascular risk) study group. For the present study, a subgroup of 1.012 RISC subjects who were free of hypertension, diabetes, cardiovascular diseases, chronic hepatic, inflammatory and neoplastic diseases, abnormal lipid levels, and metabolic syndrome were included.

In such a healthy population, only about 5% of subjects had small carotid plaques, and these subjects were older, had a FLI of 60 or more, and had higher blood pressure, LDL cholesterol, glucose, GGT and C-reactive protein than participants without plaques. In logistic regression model, after adjustment for conventional cardiovascular risk factors, family history, liver transaminase and alcohol consumption, the independent predictors of plaque presence were age, FLI of 60 or more and smoking habit. However, when FLI in the model was replaced by variables used in its equation the predictors of early atherosclerosis were age, GGT and smoking.

"Our cross-sectional study indicates that GGT may represent a link between fatty liver disease and development of early atherosclerosis," concludes Dr. Kozakova. On the basis of these results the authors suggest the GGT levels in the blood could be used as a biomarker of atherosclerosis.

###

Full Citations:Carotid Atherosclerosis and Chronic Hepatitis C: A Prospective Study of Risk Associations." Salvatore Petta, Daniele Torres, Giovanni Fazio, Calogero Cammà, Daniela Cabibi, Vito Di Marco, Anna Licata, Giulio Marchesini, Alessandra Mazzola,Gaspare Parrinello, Salvatore Novo, Giuseppe Licata and Antonio Craxì. Hepatology; April 4, 2012 (DOI: 10.1002/hep.25508); Print Issue Date: May 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.25508/abstract.

"Fatty Liver Index, Gamma-glutamyltransferase and Early Carotid Plaques." Michaela Kozakova, Carlo Palombo, Marco Paterni Eng, Jacqueline Dekker, Allan Flyvbjerg, Asimina Mitrakou, Amalia Gastaldelli, Ele Ferrannini and the RISC Investigators. Hepatology; Published Online: April 19, 2012 (DOI: 10.1002/hep.25555); Print Issue Date: May 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.25555/abstract.

Author Contact: Media representative at the University of Pisa is Dr. Roberta Filidei who can be reached at R.Filidei@adm.unipi.it. or 804-827-0890 begin_of_the_skype_highlighting 804-827-0890 end_of_the_skype_highlighting. Contacts at the University Hospital are Dr. Del Mauro and Dr. Zanotto who can be reached at ufficio.stampa@ao-pisa.toscana.it.

These studies are published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com or our new online platform, Wiley Online Library (http://www.wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

Source

Chronic Hepatitis C Virus Infection Is Associated with Early Atherosclerosis

SUMMARY: People with chronic hepatitis C are more likely than those never infected to have diabetes and visceral fat accumulation, but have lower levels of LDL "bad" cholesterol, according to a study described in the June 28, 2010 advance online issue of Gut. After HCV clearance, LDL levels rose to match those of never-infected individuals, but glucose levels and abdominal fat remained similar. After adjusting for other risk factors, chronic hepatitis C patients had greater carotid intima-media thickness, an indicator of the early stages of atherosclerosis.

By Liz Highleyman

Previous research has found that people with chronic hepatitis C virus (HCV) infection have an elevated risk for cardiovascular disease. While HCV has been linked to insulin resistance or diabetes -- known risk factors for heart disease -- it is also typically characterized by favorable blood lipid levels.

In the present study, Aya Mostafa from AinShams University in Cairo and colleagues looked at the effect of this paradoxical risk profile on metabolism and atherosclerosis (hardening of the arteries and build-up of plaque) in the setting of HCV infection and clearance.

This cross-sectional analysis included more than 1200 participants in Egypt aged 35 years or older. Within this study population, 329 had chronic hepatitis C, 173 had cleared HCV infection, and 795 were never infected with HCV; a subset of 192, 115, and 187 participants, respectively, from the 3 groups underwent ultrasound imaging.

The investigators evaluated presence of diabetes, fasting blood glucose, lipid levels, and body fat deposition using ultrasound. Carotid intima-media thickness (IMT), or width of the inner lining of the carotid arteries supplying the brain, was used as a measure of atherosclerosis.

Results

• Diabetes was more common among participants with chronic hepatitis C and cleared HCV infection (both with a prevalence of 10.1%) than among those who never had HCV (6.6%; P = 0.04 for chronic, 0.08 for cleared).
• The amount of mesenteric or visceral fat was greater in people with chronic hepatitis C (36.4 mm) and cleared infection (37.8 mm) relative to those never infected (32.7 mm; P = 0.004 for chronic, < 0.0001 for cleared).
• Low-density lipoprotein (LDL) cholesterol levels were lower in the chronic hepatitis C group (2.69 mmol/L; P < 0.001), but similar in those with cleared infection (3.56 mmol/L; P = 0.4) and those never infected (3.45 mmol/L).
• Carotid IMT did not differ significantly according to HCV infection status, at 0.73, 0.71, and 0.71 mm, respectively.
• After adjustmenting for traditional cardiovascular risk factors, however, IMT was greater in peoplewith chronic infection (0.76 mm) compared with never infected individuals (0.70 mm; P = 0.02).

Based on these findings, the researchers proposed, "Hepatic function normalization with HCV clearance may account for reversal of favorable lipids observed with HCV infection." However, they added, glucose levels and visceral fat accumulation "appear less amenable to HCV resolution."

"These different cardiovascular risk patterns may determine equivalent atherosclerosis risk by infection status," they suggested. "However, once these factors were accounted for, those with chronic infection had raised IMT, suggesting a direct effect of infection."

Department of Community Medicine, Faculty of Medicine, AinShams University, Cairo, Egypt; Department of Tropical Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt; Viral Hepatitis Reference Laboratory, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt; Institut Pasteur, Paris, France; Department of Metabolic Medicine, Imperial College NHS Healthcare Trust, London, UK; International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College NHS Healthcare Trust, London, UK; Faculty of Medicine, Minia University, Minia, Egypt.

7/30/10

Reference

A Mostafa, MK Mohamed, M Saeed, and others. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut (Abstract). June 28, 2010 (Epub ahead of print).

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