Role of Cholesterol-Associated Steatohepatitis in the Development of NASH

Nonalcoholic fatty liver disease (NAFLD) encompasses a wide histological spectrum of disease ranging from simple steatosis and nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma.⁽¹⁾ It is the most common cause of chronic liver disease worldwide, with a prevalence estimated to be 24%-26%.^{(2, 3)} The prevalence of NASH in North America is estimated to be about 24.1%, with the highest prevalence reported in the Middle East (31.7%) and South America (30.4%).⁽³⁾ About 41% of patients with NASH experience progression of fibrosis with an incidence of stage 3 or 4 fibrosis of 68 per 1,000 person-years.^{(1, 3, 4)} NAFLD/NASH is currently the second leading indication for liver transplantation and is expected to become the number-one indication in the next few years, with excellent long-term posttransplant survival. ^{(1-3, 5, 6)}

Many risk factors for developing hepatic steatosis have been identified including the metabolic syndrome (MetS), obesity, insulin resistance with hyperinsulinemia, personal or family history of type 2 diabetes mellitus (T2DM), and dyslipidemia.^{(1, 3)} Of these risk factors, T2DM and insulin resistance are very common in NAFLD and may play a pivotal role in NAFLD/NASH development.^{(3, 7-10)} Despite these known risk factors, we do not yet know the causative factor(s) without which development and progression of NASH cannot possibly occur in certain patients. In this review, we examine the data supporting the hypothesis that hepatic cholesterol is a key pathogenetic factor driving the development of NASH at least in a subset of patients, and propose the term cholesterol-associated steatohepatitis (CASH) to describe this mechanistic pathway by which hepatic cholesterol may result in the development of steatohepatitis. These considerations are critical, because unless a causative agent is uncovered, it is unlikely that a highly effective treatment of NASH will ever be identified. Although there is mounting evidence that cholesterol may also lead to hepatic carcinogenesis, we will not focus on the association between cholesterol and hepatocellular carcinoma in this review.

Pathogenesis of NASH: Conceptual Models and the Role of Cholesterol

Historically, the two-hit hypothesis proposed a stepwise progression from normal liver to hepatic steatosis and then to NASH.^{(11, 12)} This theory postulates that insulin resistance is the “first hit,” which promotes accumulation of fatty acids in the liver, leading to steatosis.⁽¹³⁾ Hyperinsulinemia results in increased lipolysis from peripheral adipose tissue and altered hepatic gene transcription, which promotes free fatty acid uptake and de novo lipogenesis.^(13-15) Oxidative stress is the “second hit,” resulting from increased oxidation of fatty acids, and causing reactive oxygen species (ROS) formation, lipid peroxidation, DNA damage, mitochondrial dysfunction, and release of proinflammatory cytokines.^{(16, 17)} These cellular mechanisms result in hepatocyte damage, inflammation, and fibrosis, characteristic of steatohepatitis.^{(16, 17)}

More recently, a “multiple parallel hits” hypothesis has been proposed, in which multiple cellular mechanisms, working simultaneously to cause a “perfect storm,” result in hepatic inflammation and progression to NASH.⁽¹⁸⁾ Cellular mechanisms that could be altered and lead to inflammation include abnormal lipid metabolism, mitochondrial oxidative injury, endoplasmic reticulum (ER) stress, genetic polymorphisms, altered immune responses, and gut microbiome dysbiosis.^(18-20) It is postulated that the accumulation of lipotoxic lipids within the liver, which interact with pro-inflammatory signals, causes these cellular abnormalities, which leads to inflammation and fibrosis.⁽²¹⁾ Although triglycerides are the most common lipids in the liver by far, it is likely that they represent a “safe” storage molecule for fatty acids.⁽²²⁾ Instead, it is the accumulation of other lipotoxic lipids, such as cholesterol (and potentially free fatty acids, diacylglycerol, ceramides, and others), which are postulated to result in cellular dysfunction.^{(21, 23, 24)} Cholesterol has a relatively “safe” storage option (i.e., its esterification to cholesterol esters [CEs]); however, hepatic free (i.e., unesterified) cholesterol is highly toxic to multiple cellular processes and organelles even if only slightly increased.⁽²⁵⁾ Thus, we propose that in a subset of patients with NASH, hepatic cholesterol accumulation results in the development of cholesterol-associated steatohepatitis (CASH) and is the main driver of the necroinflammation and fibrosis causing NASH, while dietary, genetic, and lifestyle co-factors either lead to the accumulation of hepatic cholesterol or interact which hepatic cholesterol to promote NASH, as shown in Fig. 1.

Hepatic Cholesterol Metabolism

The liver is the most important organ that controls body cholesterol homeostasis. In the nonpathologic state, the mouse liver has a relatively low cholesterol concentration (132 mg/kg), but it has a high flow of sterols through the liver every day, consistent with its role in lipoprotein and bile acid synthesis and homeostasis (143 mg/kg/day).⁽²⁶⁾ When the sum total of the pathways involved in synthesis and uptake of cholesterol (FIG. 2A) exceeds the pathways that lead to removal of cholesterol (FIG. 2B), cholesterol accumulates in hepatocytes.⁽²⁷⁾

A critical component of the CASH hypothesis is that the liver (not adipose tissue) is the body’s storage site for excess cholesterol. Excess cholesterol is stored in the liver within hepatocyte lipid droplets (LDs) as CEs.⁽²⁸⁾ Once previously believed to be inert storage vessels, LDs have now been recognized as metabolically active organelles within cells that serve a wide variety of functions. LDs are derived from the ER and consist of a core of neutral lipids (CEs and triglyceride) that are surrounded by a phospholipid monolayer, studded with a diverse array of proteins.^{(29, 30)} The phospholipid monolayer contains FC, which affects LD membrane properties, including surface and line tension, size, and interaction with other LDs^{(29, 30)} (FIG. 2C).

Regulation of Cholesterol Homeostasis

Cholesterol homeostasis is tightly regulated by a number of nuclear transcription factors, three of which have also been linked to NAFLD pathogenesis: sterol regulatory element binding protein-2 (SREBP-2), farnesoid X receptor (FXR), and liver X receptor (LXR) (FIG. 3).

SREBPs are a family of membrane-bound transcription factors that sense membrane cholesterol and fatty acid content and modulate the transcription of genes involved in cholesterol and fatty acid synthesis and uptake.^{(31, 32)} SREBP-1 is primarily involved in fatty acid, triglyceride, and phospholipid pathways, whereas SREBP-2 is involved in cholesterol metabolism.^{(33, 34)} SREBP-2 is a resident of the ER, where it is bound to SREBP cleavage activating protein (Scap).⁽³⁵⁾ When Scap senses cholesterol depletion, SREBP-2 is transported to the Golgi complex, where it is cleaved to the active form and enters the nucleus to activate the transcription of genes for cholesterol synthesis and uptake, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and low-density lipoprotein receptor (LDLR).^{(35, 36)}

FXR is a nuclear receptor that senses bile acids and is extensively involved in bile acid, lipid, and glucose homeostasis.^(37-39) In the liver, FXR up-regulates scavenger receptor class B type 1 (SR-B1), resulting in increased uptake of high-density lipoprotein (HDL) cholesterol from the circulation, increases ATP-binding cassette transporter (ABC) G5 and G8 (ABCG5/G8) specifically in mice, and bile salt export pump (BSEP) synthesis, resulting in biliary excretion of cholesterol and bile acids, but also inhibits CYP7A1 preventing cholesterol conversion to bile acids.^{(37, 40, 41)} FXR also promotes removal of triglycerides from hepatocytes by increasing β-oxidation and decreasing lipogenesis.⁽⁴²⁾ In hepatic stellate cells (HSCs), FXR creates a quiescent and pro-apoptotic phenotype, which promotes liver fibrosis resolution.⁽⁴³⁾

LXRs are nuclear cholesterol sensors that are activated by high intracellular oxysterols.^{(44, 45)} Following activation by oxysterols, LXRα forms a heterodimer with retinoid X receptor.⁽⁴⁴⁾ LXRα results in reverse cholesterol transport and hepatic cholesterol metabolism by increasing the expression of macrophage ABCA1/G1, resulting in increased HDL levels, and increasing hepatic, macrophage, and intestinal ABCG5/G8, causing net cholesterol excretion from the body, but also increases LDLR degradation on hepatocytes.^(46-50) In rodent models, LXR also induces expression of CYP7A1, resulting in cholesterol conversion to bile acids; however, this phenomenon is not seen in humans.⁽⁵¹⁾ Additionally, duodenal Niemann-Pick type C1 like 1 protein (NPC1L1) expression has been shown to be negatively correlated with LXR expression, inhibiting intestinal cholesterol absorption, resulting in fecal excretion of cholesterol.⁽⁵²⁾ LXRα agonists in mice demonstrated reduced hepatic inflammation and fibrosis by decreasing cholesterol-mediated activation of hepatic Kupffer cells (KCs) and HSCs.^{(53, 54)}

Hepatic Cholesterol Accumulation in NASH

In the setting of NAFLD, numerous derangements to hepatic cholesterol homeostasis have been identified, which lead to the accumulation of hepatic cholesterol.⁽⁶⁰⁾ In mice, both hyperinsulinemia and inflammation lead to loss of the inhibitory effect of elevated plasma cholesterol on Scap/SREBP-2, resulting in hepatic cholesterol accumulation.^(61-63) Increased levels of nuclear SREBP-2, HMGCoAR messenger RNA (mRNA), HMGCoAR protein, and HMGCoAR dephosphorylation, resulting in the active form of the enzyme, have been demonstrated in patients with NAFLD/NASH.^{(60, 64)} Despite elevated nuclear SREBP-2 levels, LDLR levels are actually down-regulated in patients with NAFLD/NASH, but an alternative hepatic scavenger receptor for oxidized low density lipoprotein (oxLDL) particles, CD36, is increased relative to the severity of steatosis.^{(15, 60, 63, 64)} Export of cholesterol out of the cell is also decreased, with decreased mRNA levels of ABCA1, ABCG1, and ABCG5.^{(60, 63)}

Typical esterification/de-esterification activity in healthy individuals is determined by the relative concentration of ACAT2, while the concentration of nCEH remains relatively constant.⁽⁵⁵⁾ However, in patients with NAFLD, there is a 6-fold higher concentration of nCEH compared with healthy controls.^{(60, 63, 65, 66)} Increased expression of nCEH in animal models was also associated with reduced expression of CYP7A1 and CYP27A.⁽⁵⁹⁾ These cellular abnormalities, coupled with the decreased expression of ABC cholesterol exporters noted previously, result in the accumulation of toxic FC within hepatocytes.

Dietary Cholesterol and NASH

Human studies consistently support the association between cholesterol intake and the development of NASH or cirrhosis (Table 1). A nested case-control analysis of the multiethnic cohort, a large prospective study with over 215,000 older-adult participants in Hawaii and California, showed a positive association between dietary cholesterol intake and development of NAFLD with cirrhosis.⁽⁶⁷⁾ Another study, representative of the U.S. population, reported that dietary cholesterol consumption (but not total fat consumption) was significantly associated with the development of cirrhosis from all etiologies of liver disease combined.⁽⁶⁸⁾

Experimental animal models (e.g., mice, rats, rabbits, gerbils, pigs) also consistently demonstrate that the addition of dietary cholesterol leads to progression of liver disease to fibrosing steatohepatitis and cirrhosis (Table 2). These studies generally show that while dietary fat intake alone causes the development of only simple steatosis without substantial necroinflammation or fibrosis, the addition of dietary cholesterol causes the progression from steatosis to NASH. Studies in some animal models, such as Ossabaw swine, showed that marked steatosis is not always necessary for the development of dietary cholesterol-induced ballooning degeneration, KC activation, and fibrosis.^{(69, 70)}

Genetic Polymorphisms Associated With NASH Are Related to Hepatic Cholesterol Metabolism

Many human genetic polymorphisms that have been strongly linked to NAFLD, NASH, and NASH-related cirrhosis appear to be related to hepatic cholesterol metabolism, although some clearly affect other lipids too. The most common and well-described is the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant, which causes impairment of very low density lipoprotein (VLDL) secretion, LD remodeling, and hydrolase activity for triglycerides and retinyl esters.^{(71, 72)} Homozygous carries of the PNPLA3 I148M variant have a greater risk of progressive steatohepatitis and fibrosis.⁽⁷³⁾ Carriers of the TM6SF2 (transmembrane 6 superfamily member 2) E167K variant have impaired hepatic VLDL secretion, and are at higher risk for liver disease; however, they are at lower risk of cardiovascular events.⁽⁷⁴⁾ ApoB mutations, characteristic of familial hypobetalipoproteinemia, impair hepatic secretion of VLDL particles, which results in worsening steatosis, steatohepatitis, and cirrhosis.⁽⁷⁵⁾ Polymorphisms in farnesyl diphosphate farnesyl transferase 1 (FDFT1), encoding squalene synthase, the first enzyme in the sterol biosynthesis pathway, have been associated with NAFLD activity scores and fibrosis.⁽⁷⁶⁾ Patients with mutations in the LIPA (lysosomal acid lipase) gene, encoding lysosomal acid lipase, accumulate CEs and triglycerides in the liver, with progression to hepatic steatosis, fibrosis, and cirrhosis.⁽⁷⁷⁾ Nongenetic reductions in lysosomal acid lipase activity have been identified in patients with NAFLD, with higher reductions in lysosomal acid lipase activity, resulting in worsening disease.⁽⁷⁸⁾ Finally, a newly investigated protein, HSD17B13 (17β hydroxysteroid dehydrogenase 13), a LD enzyme with retinal dehydrogenase activity that also plays a key role in cholesterol and fatty acid metabolism, was found to have 5.9-fold higher hepatic expression in patients with NASH compared with controls.⁽⁷⁹⁾ Although it is intriguing that these polymorphisms appear to affect hepatic cholesterol homeostasis directly or indirectly, it is important to emphasize that some also affect other lipids and that the specific mechanisms by which each polymorphism causes NASH are complex and not fully elucidated.

Mechanisms of CASH Development

Cholesterol accumulation results in dysfunction of many organelles within hepatocytes and activation of other liver cells critical to fibrosing steatohepatitis, such as KCs and HSCs. The fluidity of a cell’s membranes, both the outer plasma membrane as well as membranes of internal organelles, is dependent on a precise ratio of FC to phospholipids, as well as the saturation status of the phospholipids.⁽⁸⁰⁾ FC accumulation within a cell membrane causes liquid-ordered rafts to become too rigid, which affects transmembrane proteins that require a degree of fluidity in order to function properly.⁽⁸⁰⁾ Figure 4 summarizes the processes by which hepatic FC accumulation leads to hepatocyte dysfunction (FIG. 4A).

Ezetimibe and Statins in NASH

Cholesterol-lowering medications (such as statins and ezetimibe) are very common in patients with NAFLD/NASH due to the high prevalence of hypercholesterolemia, diabetes, and CVD. In addition to their proven cardiovascular benefits, statins and ezetimibe also appear to have beneficial effects on NAFLD/NASH.^(129-131) Table 3 summarizes studies that evaluated the effects of cholesterol-lowering medications on NAFLD/NASH, identified through a comprehensive review of the literature. Multiple small prospective studies in patients with either NAFLD or NASH assessed the effect of ezetimibe on steatosis, inflammation, and fibrosis. Although these studies have shown benefit in biochemical, metabolic, and histologic outcomes from ezetimibe therapy, the small size and relatively short follow-up of these studies limit their interpretation.^(132-136) A meta-analysis performed in 2017 encompassing six studies and 273 patients with NAFLD or NASH suggested that ezetimibe improved serum liver enzymes, hepatocyte steatosis and ballooning, but had no effect on inflammation or fibrosis.⁽¹³⁷⁾

TABLE 3. Summary of Human Studies Investigating the Effects of Cholesterol-Lowering Medications on NAFLD/NASH

Study	Study type	Medication	Study Population	Duration of Treatment	Results
Chan et al. 2010(132)	Randomized, single-blind placebo controlled trial	Ezetimibe vs. placebo	25 obese patients (ezetimibe, n = 15; hypocaloric diet alone, n = 10)	16 weeks	Improved hepatic steatosis, inflammation, and LDL-apoB-100 metabolism
Park et al. 2011(135)	Prospective long-term study	Ezetimibe	45 patients with newly diagnosed biopsy-proven NAFLD	24 months	Improved biochemical parameters (AST, ALT, hsCRP, TC, LDL, ox-LDL, and TG), visceral fat, and histologic features (steatosis, necroinlammation, ballooning, and NAS)
Takeshita et al. 2014(133)	Open-label randomized controlled clinical trial	Ezetimibe vs. placebo	32 patients with NAFLD (ezetimibe, n = 17; placebo, n = 15)	6 months	Improved hepatic fibrosis, increased long-chain fatty acids, and Hgb A1c
Loomba et al. 2015(136)	Randomized, double-blind, placebo-controlled trial	Ezetimibe vs. placebo	50 patients with biopsy-proven NASH (ezetimibe: n = 25; placebo: n = 25)	24 weeks	No significant difference in liver fat as measured by MRI-PDFF; no significant difference in biochemical parameters or histologic response
Nakade et al. 2017(137)	Meta-analysis	Ezetimibe	Six studies (two randomized-controlled; four single-arm trials) including 273 patients with NAFLD or NASH	24 weeks, four studies	Improved serum liver enzymes (AST, ALT, and GGT), hepatic steatosis, and ballooning
				48 weeks, one study
				96 weeks, one study
Athyros et al. 2006(130)	Prospective, open-label randomized study	Atorvastatin vs. fenofibrate vs. combination	186 nondiabetic patients with MetS and biochemical and ultrasonographic evidence of NAFLD	54 weeks	Significantly higher percentage of patients who no longer had evidence of NAFLD in the atorvastatin and combination groups, including reduction in hs-CRP, TG, LDL-C, TC, and glucose
Nelson et al. 2009(179)	Double-blind, randomized, placebo-controlled trial	Simvastatin vs. placebo	16 patients with biopsy-proven NASH, 14 completed the study, 10 underwent repeat biopsy at 1 year	12 months	No statistically significant improvement in serum aminotransferases, hepatic steatosis, necroinflammatory activity, or stage of fibrosis
Athyros et al. 2010(129)	Post hoc analysis of prospective, randomized intention-to-treat study (GREACE)	Atorvastatin vs. placebo	1,600 GREACE patients with coronary heart disease, 437 patients with moderately abnormal liver enzymes possibly associated with NAFLD (227 treated with statin)	3 years	Statin-treated patients had significant improvement in liver enzymes and reduction in cardiovascular events
Athyros et al. 2011(141)	Post hoc analysis of prospective randomized controlled trial comparing two LDL-C targets, <100 mg/dL (A2) or <130 mg/dL (B2)	Atorvastatin	1,123 ATTEMPT patients with MetS without diabetes or CVD, 326 with modestly elevated liver enzymes and ultrasonographic evidence of NAFLD	42 months	86% in the A2 group and 74% in the B2 group had resolution of NAFLD (P < 0.001), mean LDL-C and TG targets were higher in the B2 group compared with the A2 group
Foster et al. 2011(144)	Prospective, randomized, placebo-controlled trial as part of the St. Francis Heart Study	Atorvastatin vs. placebo	1,005 patients, 80 with NAFLD at baseline	3.6 years	Treatment with atorvastatin plus vitamins C and E, significantly reduced the odds of NAFLD at the end of follow-up (70% vs. 34%, OR 0.29, P < 0.001)
Tikkan et al. 2013(140)	Post hoc analysis of a prospective randomized controlled trial (IDEAL)	Atorvastatin 80 mg/day vs. simvastatin 20-40 mg/day	8,863 IDEAL patients, 1,081 with ALT ≥ ULN	4.8 years	Major CVD event rates were 11.5% for simvastatin and 6.5% for atorvastatin; in patients with baseline elevated ALT, greater improvement in ALT was noted in atorvastatin group (13.4 ± 27.5 vs. 8.8 ± 28.8; P = 0.0073)
Dongiovanni et al. 2015(142)	Multicenter cohort study	Statins (simvastatin 49%; rosuvastatin 27%; atorvastatin 17%; pravastatin 4%; fluvastatin 2%) vs. no statins	1,201 European patients who underwent liver biopsy for suspected NASH, 107 on statin therapy for at least 6 months	6 months	Statin use was associated with lower risk of steatosis (OR 0.09, P = 0.004), steatohepatitis (OR 0.25, P < 0.001), and fibrosis stage F2-F4 (OR 0.42, P = 0.017)
Kargiotis et al. 2015(145)	Prospective study	Rosuvastatin	20 patients with biopsy proven NASH, MetS, and dyslipidemia	12 months	Postintervention liver biopsy showed complete resolution of NASH in 19 of 20 patients, normalization of AST/ALT and GGT by the third treatment month, and normalization of ALP by the sixth treatment month
Nascimbeni et al. 2016(143)	Cross-sectional study	Statins (45%) (simvastatin 15%; pravastatin 6%; fluvastatin 2%; atorvastatin 53%; rosuvastatin 15%) vs. no statins (55%)	346 patients with diabetes with biopsy-proven NAFLD	N/A	Statins use was associated with a lower risk of NASH (OR 0.57, P = 0.055) and F2-F4 fibrosis (OR 0.47, P = 0.011)
Kim et al. 2017(131)	Systemic review and meta-analysis	Statins vs. no statins	13 studies (10 cohort studies, 3 clinical trials) in 121,058 patients with chronic liver disease, 46% exposed to statins	N/A	In patients with cirrhosis, statin use was associated with a 46% lower risk of decompensation (RR 0.54) and 46% lower morality (RR 0.54). In patients with chronic liver disease without cirrhosis, statin use was associated with a 58% lower risk of development of cirrhosis or fibrosis progression (RR 0.42). Statin use was also associated with a 27% lower risk of variceal bleeding or progression to portal hypertension (HR 0.73)

• Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; apoB-100, apolipoprotein B-100; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; GREACE, Greek Atorvastatin and Coronary Heart Disease Evaluation; Hgb A1c, hemoglobin A1c; HR, hazard ratio; hsCRP, high sensitivity C-reactive protein; MRI-PDFF, magnetic resonance imaging proton density fat fraction; NAS, NAFLD activity score; OR, odds ratio; ox-LDL, oxidized LDL; RR, risk ratio; TC, total cholesterol; TG, triglyceride.

Despite concerns about statin-induced hepatotoxicity, studies reported very rare incidence of statin-related adverse events in patients with liver disease.^{(138, 139)} Post hoc analysis of three large randomized, controlled, trials designed to evaluate the effect of statins on CVD, consisting of 11,587 patients, including 1,844 with elevated aminotransferases, demonstrated that statins resulted in improvement in serum aminotransferase levels and ultrasonographic steatosis.^{(129, 140, 141)} In 2015, a multicenter cohort study consisting of 1,201 European patients who underwent liver biopsy for suspected NASH showed that the 107 patients who were taking statins had a protective effect from steatosis, inflammation, and NASH in a dose-dependent manner.⁽¹⁴²⁾ A multicenter, Italian cross-sectional study of 346 patients with diabetes with biopsy-proven NAFLD, confirmed that statins were independently associated with reduced odds of NASH and significant fibrosis.⁽¹⁴³⁾ Multiple small prospective trials using atorvastatin and rosuvastatin demonstrated improvement in biochemical, radiological, and histological features of NAFLD and NASH.^{(130, 144, 145)} A systemic review of 121,058 patients with chronic liver disease showed that statins reduced the risk of portal hypertension, progression to cirrhosis or decompensated cirrhosis, and mortality.⁽¹³¹⁾

Meta-analyses of randomized controlled trials, including very large numbers of participants, demonstrated that statins resulted in a slightly increased risk of development of diabetes,^{(146, 147)} but the risk was low both in absolute terms and when compared with the reduction in coronary events. Specifically, treatment of 255 patients with statins for 4 years resulted in one extra case of diabetes (or approximately one case of diabetes per 1,000 patient-years). In observational studies, statin-treated patients had increased hepatic de novo lipogenesis through activation of SREBP-1c and up-regulation of genes involved in fatty acid and triglyceride metabolism, suggesting that activation of these genes contributes to insulin resistance and diabetes.⁽¹⁴⁸⁾ Because insulin resistance and diabetes are important risk factors for NASH, these findings raise some concern about the role of statins as potential NASH pharmacotherapies.

In summary, this evidence suggests beneficial effect of statins on steatosis, inflammation, fibrosis, portal hypertension and cirrhosis, and confirms the safety of statins for the treatment of dyslipidemia in patients with NAFLD and NASH as recommended by the American Association for the Study of Liver Diseases.⁽¹⁾ However, large, randomized, placebo-controlled trials of statins in NASH adequately powered for histological outcomes are lacking. Such studies are desperately needed but very difficult to design, as it may be considered unethical to randomize patients with NASH to placebo, given that most would fulfill criteria for being on a statin for cardiovascular reasons.

Conclusions

NASH is rapidly rising in prevalence worldwide and currently has no approved pharmacological treatments. In the near future, the number of liver transplantations for NASH will surpass all other indications for liver transplantation. The evidence presented in this review strongly supports the role of cholesterol in causing “cholesterol-associated steatohepatitis” (CASH) and should serve to focus efforts on targeting cholesterol lowering as a therapeutic option. This strategy has multiple advantages. First, statins are widely available, inexpensive medications with a proven track record of safety. Second, statins are proven to reduce cardiovascular mortality, which is the number-one cause of death in patients with NASH, and may have even greater cardiovascular benefits in patients with NASH.⁽¹²⁹⁾ Therefore, treatment of patients with NASH with statins would potentially simultaneously ameliorate both cardiovascular mortality as well as liver-related complications (e.g., cirrhosis and portal hypertension) and mortality. Randomized controlled trials of statins in patients with NASH or cirrhosis that are under way are eagerly awaited, while clearly more such studies are urgently needed.