Elsevier

Atherosclerosis

Volume 232, Issue 1, January 2014, Pages 99-109
Atherosclerosis

Review
Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology

https://doi.org/10.1016/j.atherosclerosis.2013.10.030Get rights and content

Abstract

Background

Liver regulates lipid metabolism in health and disease states. Nevertheless, the entity of cardiovascular risk (CVR) resulting from dysregulation of lipid metabolism secondary to liver disease is poorly characterized.

Aim and methods

To review, based on a PubMed literature search, the features and the determinants of serum lipid phenotype and its correlation with hepatic steatosis, insulin resistance (IR) and CVR across the wide spectrum of the most common chronic liver diseases due to different etiologies.

Results

Alcoholic liver disease (ALD) is associated with steatosis, IR and a typical lipid profile. The relationship between alcohol intake, incident type 2 diabetes (T2D) and CVR describes a J-shaped curve. Non-alcoholic fatty liver disease (NAFLD), and probably nonalcoholic steatohepatitis (NASH) in particular, is associated with IR, atherogenic dyslipidemia and increased CVR independent of traditional risk factors. Moreover, NASH-cirrhosis and T2D contribute to increasing CVR in liver transplant recipients. HBV infection is generally free from IR, steatosis and CVR. HCV-associated dysmetabolic syndrome, featuring steatosis, hypocholesterolemia and IR, appears to be associated with substantially increased CVR. Hyperlipidemia is an almost universal finding in primary biliary cirrhosis, a condition typically spared from steatosis and associated with neither subclinical atherosclerosis nor excess CVR. Finally, little is known on CVR in patients with hepatocellular carcinoma.

Conclusions

CVR is increased in ALD, NAFLD and chronic HCV infection, all conditions featuring IR and steatosis. Therefore, irrespective of serum lipid phenotype, hepatic steatosis and IR may be major shared determinants in amplifying CVR in common liver disease due to varying etiology.

Section snippets

Background and aims

Liver, a major regulator of lipid metabolism through the synthesis of apoprotein and lipoprotein and de novo lipogenesis [1], is also a chief modifier of cardiovascular risk (CVR). This occurs through the synthesis of atherogenic apoprotein-B (Apo-B), and the remodeling of HDL and apoB containing lipoproteins by action of Cholesterol Ester Transfer Protein (CETP) and liver-X receptor (LXR) [2], [3]. The activation of CETP gene expression by LXR is deemed to be pro-atherogenic [3], and certain

Alcoholic liver disease

Excess alcohol intake is a common cause of non-familial hyperlipidemia [12], [13]. Alcoholic hyperlipidemia, which follows binge drinking and is often associated with alcoholic fatty liver (AFL) and steatohepatitis (ASH), rarely occurs in established cirrhosis and is characterized by elevated plasma TG resulting from VLDL accumulation or, rarely, by superimposed (fasting) hyperchylomicronemia [14], [15], [16]. Such a VLDL increase depends on the amount of ingested alcohol and patient features

NAFLD

NAFLD displays a powerful atherogenic lipoprotein profile; serum TG, LDL-CH, and Apo-B are increased, while HDL-CH and LDL buoyancy are decreased [52], [53], [54].

A recent large multi-ethnic study demonstrated that NAFLD, diagnosed through the Liver/Spleen ratio, although unassociated with total CH or LDL-CH, was indeed associated with higher fasting serum TG, lower serum HDL-CH, LDL particle concentration, and negatively associated with LDL particle size. Such lipoprotein abnormalities

Chronic hepatitis B

The interaction of hepatitis B virus (HBV) vital cycle with the host lipid metabolism is not characterized as fully as is the case for HCV infection.

Acute hepatitis B is associated with transient hypertriglyceridemia [86], [87]. The biological basis underlying this reversible dyslipidemia, however, remains poorly characterized and given its transient course, it is probably of scarce concern for CVR.

Chronic HBV infection is associated with reduced TG, total CH and HDL-CH and with significantly

Chronic hepatitis C

Chronic HCV infection is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide [103], [104].

An altered metabolic profile is a peculiar extra-hepatic feature in HCV infection, acknowledged to be a “systemic disease” [105]. It includes IR, steatosis, hypocholesterolemia and visceral fat hypertrophy. This unique cluster of dysmetabolic conditions named HCV-associated dysmetabolic syndrome differs from the “typical” MS on the grounds of reduced plasma lipids levels [11], [106],

Cirrhosis

Cirrhosis represents the stereotyped end-stage histologic lesion resulting from unopposed chronic action of a variety of liver injuring agents. ALD, HCV infection and NASH are the most common causes of cirrhosis in Europe and North America, whereas HBV infection is the prevailing cause in most parts of Asia and sub-Saharan Africa [128].

Liver cirrhosis is characterized by an abnormal plasma lipid and lipoprotein profile due to impaired liver biosynthetic capacity. In non-cholestatic

Primary biliary cirrhosis

As part of chronic cholestatic liver diseases, primary biliary cirrhosis (PBC) is often associated with mixed hyperlipidemia (hypercholesterolemia with markedly elevated TG, LDL and HDL serum concentrations) [164]. Reduced plasma LCAT activity, biliary lipids secretion and functional LDL receptors in hepatocytes, as well as increased hepatic CH synthesis are all deemed to concur to the development of the altered lipid profile [165], [166]. Two different patterns of serum lipoproteins are

Hepatocellular carcinoma

HCC frequently arises from cirrhosis and, much more rarely, from chronic, viral or metabolic, hepatitis [81]. While these predisposing conditions per se are often associated with deranged plasma lipid and lipoprotein profile [135], HCC patients will typically display slightly to significantly decreased TG, CH, free FA, HDL, LDL, Lp(a), Apo-AI and Apo-B plasma levels, which mirror a poorer prognosis [190], [191].

Lipid and lipoprotein metabolism is regulated by cytokines; HCC is associated with

Conclusions

Liver diseases due to various etiologies are associated with varying serum lipid and lipoprotein phenotypes. Noteworthy, the two major hepatotropic viruses, HBV and HCV, display different lipid profiles.

At variance with what observed in the general population, patients with liver disease fail to display the strict and proportional association between increasing (total and LDL-) CH and TG levels and cardiovascular morbidity, suggesting that other factors, such as steatosis and IR, further to

Acknowledgment

The Institutions of the Authors of this review are recipient of funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under agreement no. HEALTH-F2-2009-241762 for the project FLIP.

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