Browse the corpus

A 60-year-old woman with a past medical history significant for hypertension, dyslipidemia, and diabetes mellitus presents for management of newly diagnosed metabolic dysfunction-associated steatohepatitis (MASH). She has a strong family history of coronary artery disease and a personal history of dyslipidemia characterized by a serum triglyceride level of 220 mg/dL, low-density lipoprotein (LDL) cholesterol of 180 mg/dL, high-density lipoprotein (HDL) cholesterol of 50 mg/dL and total cholesterol of 274 mg/dL. Based on these values, her primary physician has recommended she start a lipid-lowering medication. However, with her history of liver disease she is uncertain whether she can safely take lipid-lowering medications.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (, ), is the most common cause of chronic liver disease in the United States, affecting up to a third of adults (-). MASH is the inflammatory and fibrotic form of MASLD and can progress to cirrhosis and hepatocellular carcinoma. In addition to significant morbidity and mortality from end-stage liver disease, MASLD confers an increased risk of cardiovascular disease (CVD) (). CVD is the leading cause of mortality among individuals with MASLD (). The dyslipidemia attributable to MASLD may be one of several important and modifiable CVD risk factors.

MASLD is characterized in part by steatosis, or excess lipid deposition as lipid droplets within hepatocytes. These lipid droplets consist largely of triglycerides and are the result of an imbalance of hepatic lipid processing (). Steatosis can occur when one or more of the following conditions are present: 1) excess delivery of free fatty acids (FFA) to the liver from adipose tissue through the plasma, 2) increased de novo lipogenesis (DNL) within the liver, 3) decreased oxidation of fatty acids within hepatocytes and 4) impaired export of triglycerides from the liver in the form of very-low-density lipoproteins (VLDL).

In the setting of excess adiposity and insulin resistance, FFA release from adipocytes is increased (). Upon release, FFA are then delivered via the circulation to the liver and may exceed the liver’s capacity to oxidize or export lipids, contributing to the development of steatosis. The fatty acid translocase FAT/CD36 mediates uptake of FFA into the liver and is upregulated in human and experimental MASLD, which may contribute to steatosis (-).

Hyperinsulinemia, often observed in the setting of obesity and the metabolic syndrome, can also contribute to excess DNL as the result of increased transcriptional activities of sterol regulatory element binding protein (SREBP) 1c- and peroxisome proliferator-activated receptor (PPAR)-γ (, , ). Increased circulating glucose levels also mediate lipogenesis by activating cholesterol regulatory element binding protein (ChREBP) (). The increased synthesis of lipids within the liver can lead to accumulation within hepatocytes and can promote the development of steatosis.

Export of triglycerides from the liver requires the formation of VLDL particles. Steatosis can occur when VLDL formation is insufficient or is impaired. VLDL are formed when triglycerides are complexed to apolipoprotein B100 (apoB100) via the action of microsomal triglyceride transfer protein (MTP). Genetic or pharmacologic alteration of MTP or the truncation or absence of ApoB100 can lead to steatosis (-). In addition, ApoB100 levels can be decreased as a result of FFA accumulation. FFA accumulation within the liver can lead to chronic stress of the hepatocyte endoplasmic reticulum (ER). Increased ER stress results in increased ApoB100 degradation, decreasing the ability of the liver to export triglycerides and potentially worsen steatosis.

VLDL assembly and secretion rely on several additional steps. Following the formation of nascent VLDL particles, additional lipidation is needed to create mature VLDL particles. The process of lipidation is not well understood but may rely on fusion with lipid droplets (). Interruption of lipid mobilization from lipid droplets to VLDL may also contribute to the development of steatosis (). Genetic studies have demonstrated a strong link between a polymorphism in the gene patatin-like phospholipase domain-containing 3 (PNPLA3) and MASLD. This coding region polymorphism (I148M) reduces hepatic VLDL secretion, possibly by interfering with triglyceride mobilization, and results in hepatic steatosis (-). However, conflicting data suggest that some patients with MASLD exhibit a compensatory increase in VLDL export, although this response remains insufficient to offset the elevated hepatic triglyceride burden (). The transmembrane 6 superfamily 2 (TM6SF2) E167K variant results in decreased hepatic VLDL secretion and is associated with MASLD, fibrosis, and cirrhosis in the setting of decreased plasma LDL and triglyceride levels. This variant is associated with progressive liver disease but decreased risk of cardiovascular disease (, ). As for TM6SF2 variants, PNPLA3 I148M and ApoB polymorphisms that promote MASLD have been associated with reduced risk of cardiovascular disease, presumably owing to decreased hepatic secretion of ApoB-containing lipoproteins (, ). Familial hypobetalipoproteinemia (FHBL) is a condition characterized by diminished levels of functional ApoB100, resulting in impaired VLDL export and the development of hepatic steatosis. Magnetic resonance spectroscopy studies have shown that individuals with FHBL exhibit hepatic fat content approximately fivefold higher than that of controls (, ). Progression to steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC) has been noted in these individuals (-).

The degree of hepatic free cholesterol accumulation in MASLD correlates with the presence and severity of cytologic ballooning (). Decreased expression of ATP-binding cassette (ABC) A1 and ABCG8 cholesterol efflux proteins, may disrupt transfer of cholesterol from hepatocytes, driving up hepatocyte cholesterol (, ). Transcriptional upregulation of the LDL receptor and downregulation of cholesterol conversion to bile acids may further contribute to excess hepatic accumulation ().

Dyslipidemia is frequent in adults with radiographic and biopsy-proven MASLD and is characterized by hypertriglyceridemia, increased LDL particle concentrations, decreased LDL particle size, and decreased HDL-cholesterol levels (). High ratios of total cholesterol or triglyceride to HDL-cholesterol are associated with MASLD (). Recent analyses have revealed that circulating sulfatides redistribute from HDL to LDL and are associated with the hepatic inflammatory pathways implicated in the initiation of fibrosis in MASLD. These bioactive molecules prove clinically useful non-invasive biomarkers capable of predicting mild fibrosis in MASLD ().

In addition, non-HDL-cholesterol (non-HDL-C), a composite measure of apolipoprotein-B containing lipoproteins and an important marker of CVD risk, is elevated in individuals with MASLD and MASH (, ). MASH is also characterized by alterations in lipoprotein subfractions. Lipoprotein subfraction assays measure lipoprotein particle size, density, and composition. MASH is characterized by large VLDL particle size and decreased sizes of LDL and HDL particles (). However, there are conflicting data on the association between MASH and VLDL particle size (). Furthermore, increased levels of LDL-III and IV particles, which are more atherogenic LDL fractions, and reduced HDL2b levels, which are cardioprotective, are observed in MASH (, ). Fortunately, resolution of MASH is associated with increases in HDL, decreases in triglycerides, and increases in mean both LDL particle diameter and the frequency of the atherogenic LDL phenotype A (, ).

A distinct LDL-like particle is formed when the glycoprotein apolipoprotein(a) is covalently linked to apoB-100, resulting in lipoprotein(a) (Lp(a)). Elevated Lp(a) concentrations have been associated with an increased risk of cardiovascular disease, including myocardial infarction (). The association between Lp(a) and liver disease appears to depend upon the extent of liver disease. In advanced fibrosis and cirrhosis, circulating Lp(a) levels decline, likely reflecting impaired hepatic synthetic capacity (). Similar patterns have been reported in individuals with type 2 diabetes (). Considering this, cardiovascular risk may be underestimated if evaluation is limited to Lp(a) without accounting for the presence of advanced liver fibrosis ().

Apart from increasing FFA delivery to the liver and stimulating DNL, insulin resistance can increase circulating VLDL and plasma triglyceride concentrations through several mechanisms. First, insulin resistance leads to a loss of suppression of MTP transcription, increasing the efficiency of VLDL assembly (, ). In addition, insulin resistance reduces the expression of lipoprotein lipase (LPL) that is bound to endothelial cells within muscle and adipose tissue. LPL hydrolyzes triglycerides from circulating VLDL and thereby facilitates fatty acid delivery to muscle and adipose tissues. As a result, impaired VLDL clearance due to LPL downregulation results in increased plasma triglyceride concentrations (). Insulin resistance can also increase circulating levels of ApoCIII, an apolipoprotein that binds to VLDL and inhibits LPL activity, thereby further reducing VLDL clearance from the circulation (). Notably, ApoCIII also appears to modulate plasma triglyceride levels by LPL-independent mechanisms. In patients with LPL deficiency due to familial chylomicronemia syndrome, administration of an ApoCIII mRNA inhibitor for 13 weeks reduced plasma triglycerides by 56-86% ().

Insulin resistance also impacts LDL metabolism by upregulating hepatic lipase and increasing LDL receptor degradation. Hepatic lipase is an enzyme that removes triglycerides from intermediate-density lipoproteins (IDL), leading to the development of smaller, denser low-density lipoproteins, including LDL. In MASLD and insulin resistance, hepatic lipase levels are upregulated, resulting in increased levels of small, dense LDL particles (). Insulin resistance can further increase circulating LDL levels by reducing LDL receptor abundance. Insulin upregulates proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating protein that binds to and promotes degradation of the LDL receptor (). Increased PCSK9 expression decreases LDL receptor availability on hepatocytes, thereby elevating circulating LDL concentrations.

In addition to the changes in LDL metabolism, upregulation of hepatic lipase contributes to reduced HDL-cholesterol concentrations by hydrolyzing triglyceride-enriched HDL particles. This in turn leads to dissociation of apoA-1 from HDL particles and accelerated renal clearance (, ). Insulin resistance also decreases circulating HDL levels by interfering with HDL particle assembly. HDL is formed within plasma at the hepatocyte surface and requires the interaction of ApoA-1 and ATP-binding cassette transporter A1 (ABCA1) (). Nascent HDL particles are formed when ApoA-1, secreted by the liver or released from other lipoproteins, is lipidated with phospholipids and free cholesterol by ABCA1. Insulin resistance hampers HDL formation by promoting the phosphorylation and degradation of ABCA1 and by reducing ABCA1 activity (). In addition to hampering HDL production and promoting catabolism, insulin resistance may interfere with reverse cholesterol transport. Insulin resistance can result in the formation of triglyceride-rich HDL particles owing to the action of cholesterol ester transfer protein (CETP) (). These triglyceride-rich HDL are cleared more efficiently by the liver, further contributing to reduced circulating HDL levels.

Diet and exercise are the foundations of the management of both MASLD and the associated dyslipidemia. Small studies have indicated that both a low carbohydrate diet as well as the Mediterranean diet may improve both serum lipids and MASLD (-). Further, adherence to a Mediterranean diet reduces the development of CVD (). As CVD is a cause of considerable morbidity and mortality in MASLD patients, adherence to a Mediterranean diet may have benefits beyond liver disease per se . Routine aerobic exercise, defined as 30 minutes of moderate exercise most days of the week, can result in significant improvements in lipid levels and may improve hepatic lipid content (, ). Individuals with MASLD should be advised to engage in aerobic exercise on a regular basis.

Given the weight loss, improved glycemic control and reduced risk of major cardiovascular events associated with glucagon-like peptide-1 receptor agonists (GLP-1RA), such as semaglutide (), their potential efficacy has been evaluated in MASLD and MASH. GLP-1RA treatment has been shown to reduce liver fibrosis in patients with MASH with moderate or advanced fibrosis (), as well as to lower circulating triglycerides and total cholesterol levels. Based on these effects, semaglutide received accelerated FDA approval in 2025 for the treatment of adults with non-cirrhotic MASH, with continued approval contingent upon confirmatory clinical outcomes data. However, no improvement in LDL-C levels has been observed, suggesting that additional lipid-lowering strategies may be required to adequately mitigate cardiovascular risk (). The first pharmacological therapy approved for MASH, is the liver-directed selective thyroid hormone receptor-β agonist resmetirom, which targets key pathways involved in lipid metabolism and inflammation (). A meta-analysis revealed reductions in LDL-C, triglycerides, Lp(a), apoB and apoCIII (). MASH resolution was achieved in 25.9% to 29.9% of patients, depending on the dose, compared with only 9.7% of patients who received placebo ().

When diet and exercise are insufficient in individuals with MASLD, HMG-CoA reductase inhibitors or “statins” are recommended. Statins play an important role in both the primary and secondary prevention of CVD and should be considered in patients with MASLD. In a post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, statin therapy significantly reduced cardiovascular events in individuals with MASLD compared to placebo (). Beyond cardiovascular benefit, statins have also been shown to exert protective effects on liver histology in patients with MASLD/MASH, including dose-dependent reduction in steatosis, steatohepatitis and fibrosis stages F2-F4. However, protection against steatohepatitis in individuals carrying the I148M PNPLA3 risk variant did not reach statistical significance (). Despite these benefits, concerns regarding statin-associated hepatotoxicity persist among many physicians. Importantly, the incidence of statin-induced hepatotoxicity in the general population is extremely low and is not increased in individuals with MASLD or MASH (-). This ongoing apprehension among physicians may partly explain the under-prescribing of statins in patients with MASLD (, ).

Omega-3 fatty acids may be used in patients with MASLD for the treatment of isolated hypertriglyceridemia or when statins alone are insufficient to control triglyceride levels. Omega-3 fatty acids act to reduce hepatic VLDL secretion and lower serum triglyceride levels. Doses of up to 4 grams daily can decrease triglycerides by 25-35% (). Omega-3 fatty acids may reduce hepatic steatosis and aminotransferases (-).

Cholesterol absorption inhibitors, among which ezetimibe has been the most extensively studied, have shown promise in MASLD. A randomized controlled trial (RCT) involving 32 patients with MASLD demonstrated that ezetimibe use led to significant improvements in fibrosis stage and ballooning score (). However, ezetimibe did not significantly reduce liver fat content, as assessed by magnetic resonance imaging-proton density fat fraction and liver biopsy (). Consequently, the influence of ezetimibe across the various stages of MASLD pathogenesis remains to be fully characterized.

Treatment goals for cholesterol levels are guided by the Clinical Practice Guidelines from the American Heart Association and American College of Cardiology () and the Guidelines for the management of dyslipidaemias from the European Society of Cardiology and European Atherosclerosis Society (). These guidelines recommend high-intensity statin therapy for all adults with any form of CVD or an LDL-C ≥ 190 mg/dL, with a target of at least 50% reduction in LDL-C. Patients aged 45-70 years with diabetes and an LDL-C < 189 mg/dL, as well as individuals with a calculated 10-year global CVD-risk > 7.5%, should receive moderate-intensity statins therapy, aiming for a 30-50% reduction in LDL-C. Notably, a specific LDL-C target is no longer formally recommended.

An obese 48-year-old man with a past medical history significant for coronary heart disease, hypertension, and diabetes mellitus presents for management of newly diagnosed hepatic steatosis. He has a family history of coronary artery disease. He reports consuming 3 glasses of wine per night during the week (approximately 42 g alcohol daily) and an additional two glasses per evening on weekends. His fasting plasma triglyceride concentration is 350 mg/dL, his LDL cholesterol is 130 mg/dL, and HDL cholesterol is 55 mg/dL. The alanine aminotransferase level (ALT) is modestly elevated at 55 IU/L. He would like to know whether he has MASLD and whether you recommend continuing his current alcohol intake to protect against CVD, especially since he was told that his good cholesterol was elevated.

Metabolic dysfunction and alcohol-associated liver disease (MetALD) reflects a recently adopted classification for patients with MASLD who consume 140-350 g per week for women or 210-420 g per week for men, and have at least one metabolic risk factor, such as obesity, hypertension or type 2 diabetes (, ). In contrast, alcohol-associated liver disease (ALD) is diagnosed in individuals whose alcohol consumption exceeds these thresholds. These updated diagnostic criteria help identify distinct patient populations, thereby facilitating the design of more targeted and effective therapeutic interventions. Alcohol-associated liver disease (ALD) accounts for nearly half of cirrhosis-related mortality in the United States (). A hallmark feature of ALD is hepatic steatosis, which develops in more than 90% of heavy drinkers. However, less than one third of these individuals progress to advanced liver disease, including alcoholic hepatitis, cirrhosis, and HCC (). Risk factors for disease progression include female sex, obesity, drinking patterns, dietary factors, non–sex-linked genetic factors, and cigarette smoking (, ).

Alcohol also synergizes with other etiologies of chronic liver diseases, including MASLD and viral hepatitis, to accelerate disease progression (). Hypertriglyceridemia is the predominant dyslipidemia associated with alcohol consumption (), and a J-shaped association exists between alcohol intake and CVD risk (), which may reflect a parallel effect of plasma triglycerides (). Although the contribution of alcohol to metabolic syndrome remains unclear, alcohol intake appears to interact with obesity to further increase plasma triglyceride concentrations ().

As with MASLD, the development of steatosis in response to alcohol is multifactorial. Alcohol impairs the β-oxidation of fatty acids by mitochondria, promotes de novo lipogenesis in the liver, and increases fatty acid uptake. VLDL secretion is also increased in response to alcohol.

Fatty acids from extrahepatic sources appear to contribute substantially to hepatic steatosis. In addition to increasing mobilization of fatty acids from adipose tissue (), alcohol intake augments hepatic lipid supply from the small intestine in the form of chylomicron remnants ().

Increased DNL synthesis contributes to alcohol-related steatosis through both direct and indirect mechanisms (). The alcohol metabolite acetaldehyde increases transcription of SREBP1c, which upregulates transcription of lipogenic genes. In parallel, alcohol-induced endoplasmic reticulum stress and inflammation enhance proteolytic processing and activation of SREBP1c protein within hepatocytes. Alcohol also inhibits key suppressors of lipogenesis, most notably the protein deacetylase Sirtuin 1 (SIRT1), which plays a central role (). Alcohol-mediated suppression of SIRT1 leads to hyperacetylation of multiple targets, including factors that promote lipogenesis. In addition, inhibition of adenosine monophosphate-activated protein kinase (AMPK) further contributes to increased lipogenesis. AMPK normally suppresses lipogenesis by phosphorylating SREBP1c, thereby reducing its transcriptional activity, and by phosphorylating and inhibiting acetyl-CoA carboxylate (ACC), the rate-limiting enzyme in fatty acid synthesis.

Alcohol decreases mitochondrial fatty acid oxidation principally by decreasing activity of the transcription factor peroxisome proliferator activated receptor alpha (PPARα). This occurs in response to increased NADH/NAD+ ratios and decreased AMPK activity, among other factors (). PPARα promotes the transcription of genes that mediate fatty acid oxidation. Alcohol intake may also inhibit autophagy (), which plays an important role removing lipids from the liver ().

Alcohol increases VLDL secretion (, ), apparently by increasing the transcription of MTP (). The increase in export of hepatic triglycerides is insufficient to offset the accumulation due to increases in fatty acid uptake and synthesis in the setting of decreased oxidation.

Increased VLDL secretion contributes to hypertriglyceridemia that is observed in the setting of alcohol consumption. This is exacerbated by decreased expression of LPL (), which promotes clearance of VLDL triglycerides into muscle and fat tissue. There is also an interaction between alcohol consumption and genetic polymorphisms in apoCIII, which circulates in the plasma and functions to inhibit lipoprotein lipase activity ().

Alcohol increases HDL lipids and apolipoproteins in a manner that depends on the amount of consumption. Moderate consumption tends to increase plasma concentrations of smaller HDL particles, whereas heavier consumption favors the accumulation of larger HDL particles (). Alcohol influences HDL metabolism at multiple steps, ultimately leading to increased reverse cholesterol transport, the process by which cellular cholesterol is transported to the liver for elimination into bile (, ). Heavier alcohol consumption impairs CETP activity, as a result, the typical inverse relationship between CETP activity and HDL levels observed in MASLD is not necessarily maintained in the setting of alcohol use, and HDL concentrations may be increased as well (, ). Moderate alcohol consumption also appears to enhance the anti-inflammatory and anti-oxidant properties of HDL particles ().