Patterns and prevalence of dyslipidemia in patients with different etiologies of chronic liver disease

Dyslipidemia, among other factors, is a major risk factor for cardiovascular disease (CVD) development and progression [1] and therefore, guidelines recommend lipid-lowering therapy in patients at increased risk for CVD. As the liver plays a central role in lipid metabolism [2], lipid profiles are altered by chronic liver disease (CLD) severity. Although a vast body of literature exists on the effect of CLD on lipid profiles in several etiologies, state of the art assessment of CLD severity by, e.g. grading fibrosis severity is lacking in many studies and advanced CLD (ACLD)/cirrhosis is usually classified as a distinct etiology [2]. This classification is insufficient, as dyslipidemia patterns change during ACLD, and baseline values are strongly dependent on the underlying etiology. In addition, concomitant CVD risk factors such as arterial hypertension and diabetes mellitus must be taken into account when assessing the overall CVD risk.

Nowadays, non-invasive methods such as transient elastography are available to reliably assess the severity of fibrosis and guide/monitor CLD severity [3]. Therefore, evaluation of fibrosis severity in large patient cohorts is feasible and allows correlation with readily available lipid profiles. Actual real-life data are therefore warranted as treatment in chronic liver disease has evolved and most patients are exposed to an altered lipid profile for an extensive period of time as progression to ACLD can be halted in many cases. In addition, although cut-off levels for initiation of lipid-lowering treatment/statin treatment are well-established and stratified by clinical atherosclerotic cardiovascular disease risk, no specific guidelines for CLD and concomitant CVD are available.

Despite altered metabolism of statins, the most common drug class used as lipid-lowering therapy, and an increased risk of rhabdomyolysis [4, 5], hepatotoxic effects and severe adverse events are lower than suggested in the past [4]. Nevertheless, statins remain underutilized in patients with non-ACLD [6]. This gap in clinical implementation of guidelines might further impair outcome in CLD as several studies have shown beneficial effects on portal hypertension of statin therapy in CLD irrespective of low-density lipoprotein (LDL)-cholesterol levels [7]. Until further evidence from prospective randomized controlled trials is available, real-life data in dyslipidemia patterns and severity with respect to CLD etiology and severity is needed. Therefore, this study aimed to investigate differences among the most common CLD etiologies, namely alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), hepatitis C (HCV), hepatitis B (HBV), cholestatic liver diseases, primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) as well as autoimmune hepatitis (AIH).

Hyperlipidemia promotes atherosclerosis via endothelial cell activation and dysfunction. Due to ingestion of LDL by foam cells, plaques develop and subsequently lead to atherosclerotic lesions [12]. This leads to further secretion of inflammatory cytokines and accelerates plaque development [13]. While the mechanisms involved in plaque formation are relatively well-studied and the beneficial effects of pharmacologic intervention aiming at decreasing LDL levels in patients at risk for CVD/CVD patients are well-established, less evidence is available for the impact of dyslipidemia in patients with CLD and especially for the respective different etiologies of liver disease.

Certain etiologies, e.g. hepatitis C, may directly impact on CVD risk. The hepatitis C virus particles require LDL (and VLDL) receptors to enter hepatocytes [14] and cure of hepatitis C virus infection is associated with altered total cholesterol and LDL levels [15]. On the other hand, HBV does not seem to alter CVD risk [16]; however, the data on prevalence and severity of dyslipidemia are insufficiently comparable to other liver disease etiologies and differences in liver disease severity does not allow a fair comparison across different studies and patient cohorts. The data therefore add important insights as all patients were analyzed according to liver disease etiology and liver disease severity by reliable LSM. Nevertheless, patient numbers are low in some subgroups of patients with rare etiologies of liver disease, such as cholestatic or autoimmune liver disease. Although the numbers reflect the prevalence of these diseases, greater numbers would be favorable.

Although the risk for CVD in alcoholic liver disease seems to considerably depend on the actual amount of ingested alcohol, dyslipidemia has not been reported to represent an additional risk factor for CVD in ALD [17]. In cholestatic liver disease, where LDL cholesterol concentrations are usually elevated, CVD risk is not proportionally increased. These findings are explained by elevated lipoprotein X levels, which cannot be distinguished from LDL by standard laboratory tests but does not exert the same risk for atherosclerosis and thus, CVD events [18, 19]. These differences are of immense importance, as they implicate a more differentiated approach in treatment strategies. Even within the etiology of viral hepatitis, HCV and HBV have different risk profiles. The HCV-RNA circulates in large spherical particles, which bind in a competitive way with LDL and VLDL [20] and inhibition of microsomal triglyceride transfer protein by HCV infection leads to reduced VLDL secretion by hepatocytes, ultimately leading to decreased serum concentrations of VLDL and LDL [21]. In HBV, on the other hand, serum lipid levels are not affected [22], leading to higher absolute serum cholesterol levels than in HCV. Based on the findings in this large patient cohort, further research on the association between dyslipidemia, steatosis and CLD of different etiologies is warranted. While recent studies focused on NAFLD and NASH, dyslipidemia and its impact on the course of liver disease and cardiovascular risk should not be neglected in other etiologies of CLD. While the underlying mechanisms and associations between dyslipidemia, hepatic steatosis and CVD risk are being explored, a recent study by Corey and Chalasani showed that aggressive lipid lowering therapy reduces the high risk of CVD in NAFLD [23]; however, no specific recommendations are given for concomitant dyslipidemia and/or steatosis in other etiologies [23]. Importantly, the change of pathological lifestyle remains a management priority in patients with metabolic diseases [24].

In this study, patients with ACLD showed a relatively high prevalence of arterial hypertension and diabetes of >50% and 15%, respectively. Notably, however, patients with ACLD were on average older than non-ACLD patients, which may represent a potential confounder. These differences in baseline characteristics highlight the complexity of CVD risk in CLD. Future studies evaluating statin therapy in the CLD setting should therefore focus on CVD risk factors and take into account that CVD accounts for significant morbidity in CLD. Clinical guidelines should take these interactions into account and adapted cut-off values for recommendations to initiate lipid-lowering therapy might be necessary.

While we demonstrated differences in baseline characteristics between different etiologies including distinct patterns of dyslipidemia, we could demonstrate that the dyslipidemia patterns remain to be present when CLD progresses to ACLD. Nevertheless, it was observed that absolute cholesterol levels are lower in all etiologies after ACLD develops, reflecting impaired liver synthetic function. In this study, hepatic steatosis as assessed by CAP, increased in patients with ACLD, which is paralleled by an increase in metabolic comorbidities. Notably, few patients with any CLD other than NAFLD had a CAP ≥284 dB/m, implicating significant steatosis [25]. In theory, portal hypertension with increased bile acid levels and subsequent increased Takeda G‑protein-coupled receptor 5 (TGR5) activation might result in reduced steatosis in cirrhosis [26]. These findings highlight the fragile metabolic condition of NAFLD patients. Interestingly, also patients with HBV and cholestatic liver disease, who are thought to have no increased CVD risk compared to the general population [16, 27], still had a high prevalence of concomitant metabolic diseases that in turn may affect CVD risk profile. In summary, available studies that pool together different stages of CLD might underestimate the effect of stage-specific changes as well as etiology-specific risk modifications.

Dyslipidemia is common in patients with CLD and significantly varies between different etiologies of liver disease. Progression of liver disease significantly alters lipid profiles, although etiology-specific patterns remain. It is warranted to systematically assess cardiovascular events after ACLD-induced “improvement” of dyslipidemia. Future studies should evaluate the impact of dyslipidemia and respective treatment on long-term outcome specifically in patients with CLD.