|Year : 2021 | Volume
| Issue : 3 | Page : 112-116
The association between nonalcoholic fatty liver disease and cardiovascular disease: A window of opportunity
Narendra Singh Choudhary MD, DM 1, Neeraj Saraf MD, DNB 1, Mohammad Shafi Kuchay MD, DM 2, Ravi R Kasliwal MD, DM 3
1 Department of Hepatology, Medanta – The Medicity, Gurugram, Haryana, India
2 Division of Endocrinology and Diabetes, Medanta – The Medicity, Gurugram, Haryana, India
3 Division of Clinical and Preventive Cardiology, Medanta – The Medicity, Gurugram, Haryana, India
|Date of Submission||13-May-2021|
|Date of Decision||04-Jun-2021|
|Date of Acceptance||15-Jun-2021|
|Date of Web Publication||23-Sep-2021|
Dr. Narendra Singh Choudhary
Department of Hepatology, Medanta – The Medicity Hospital, Sector 38, Gurugram, Haryana
Source of Support: None, Conflict of Interest: None
Cardiovascular diseases (CVDs) are the leading cause of mortality in India. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in India. People with NAFLD generally share common metabolic risk factors with CVD; yet, NAFLD is independently associated with CVD. As NAFLD is easily diagnosed due to the availability of ultrasound, the awareness regarding association of NAFLD to CVD may prevent both cardiovascular and liver-related morbidity/mortality. We discuss association of NAFLD and CVD and preventive potential in the Indian population.
Keywords: Cardiovascular disease, mortality, nonalcoholic fatty liver disease, prevention
|How to cite this article:|
Choudhary NS, Saraf N, Kuchay MS, Kasliwal RR. The association between nonalcoholic fatty liver disease and cardiovascular disease: A window of opportunity. J Clin Prev Cardiol 2021;10:112-6
|How to cite this URL:|
Choudhary NS, Saraf N, Kuchay MS, Kasliwal RR. The association between nonalcoholic fatty liver disease and cardiovascular disease: A window of opportunity. J Clin Prev Cardiol [serial online] 2021 [cited 2021 Dec 3];10:112-6. Available from: https://www.jcpconline.org/text.asp?2021/10/3/112/326472
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is increasingly being recognized as an etiology of liver disease and cirrhosis., NAFLD is associated with several extrahepatic diseases that include cardiovascular diseases (CVD), type 2 diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease. Although NAFLD is associated with obesity and metabolic syndrome in majority (which are common risk factors for CVD), multiple studies have shown that NAFLD is also independently associated with CVD., CVD-related mortality is the most common cause of mortality in patients with NAFLD., It is not uncommon in primary care practice that a patient visits for unrelated reason and an abdominal ultrasound picks up fatty liver. It provides an opportunity for proper workup regarding cardiac risk in these patients. In this report, we discuss the association of NAFLD and CVD and implications for the Indian population.
| Diagnosis of Nonalcoholic Fatty Liver Disease|| |
NAFLD is defined as the presence of ≥5% steatosis on liver histology. The spectrum of NAFLD include nonalcoholic fatty liver (either steatosis alone or steatosis plus mild inflammation), nonalcoholic steatohepatitis (NASH, steatosis with ballooning and inflammation, generally associated with fibrosis), and NASH-related cirrhosis., Although hepatocellular carcinoma develops in patients with NASH related cirrhosis (generally), it can occur in patents without cirrhosis also. The diagnosis of NAFLD is usually made on imaging showing liver steatosis; exclusion of other causes of steatosis and raised liver enzymes is required. Ultrasound is the most common modality as it is easily available, does not expose to radiation (in contrast to computed tomography) and is relatively inexpensive. Ultrasound is a reliable imaging technique for the presence of ≥20%–30% steatosis; however, it is not good to pick up lesser amount of steatosis. Magnetic resonance (MR) spectroscopy is very good (almost comparable to histology) in detecting amount of steatosis, also provides idea of fibrosis if combined with MR elastography, however, both these techniques are not available at all centers., None of these imaging modalities detect inflammation and ballooning, hence imaging techniques are not good in differentiating between NAFL and NASH. As patients with fibrosis are at risk of higher mortality and liver biopsy is uncommonly used in practice due to risk of complications, several indirect measures of fibrosis are proposed. Fibroscan (transient elastography) is a commonly used noninvasive modality that measures liver stiffness, thus providing idea of fibrosis.,
NAFLD is commonly associated with obesity, insulin resistance, and metabolic syndrome, but can occur lean patients also., NAFLD is very common, but the role of population screening is not clear at present due to limited resources. Patients with obesity, metabolic syndrome, and diabetes are at a higher risk of NAFLD and a low threshold for screening should be adopted. Similarly, patients with raised liver enzymes should be screened as it is very common in India. Patients older than 45 years, having female gender, aspartate transaminase and alanine transaminase ratio >1, low platelets, diabetes or metabolic syndrome are associated with risk of fibrosis and should be screened for fibrosis. Although raised liver enzymes are not necessary for significant liver injury, patients with raised liver enzymes should be evaluated for the presence of NASH or fibrosis.
| Prevalence of Nonalcoholic Fatty Liver Disease in India|| |
NAFLD is very common in India. The prevalence of NAFLD in the urban Indians ranges from 16% to 53%.,,, The prevalence is higher in patients with type 2 diabetes.,
A worrying trend is also seen in the adolescent age group. In 218 overweight, 10–16 year aged individuals, Jain et al. noted 62.5% prevalence of NAFLD, Das et al. showed a 22.4% prevalence of NAFLD in school children., All these studies have used imaging to diagnose NAFLD, imaging may miss mild steatosis and the actual prevalence of NAFLD may be higher. An Indian study of apparently healthy living liver donors with a preoperative liver biopsy found a 50.4% prevalence of NAFLD. Although it can be argued that biopsy was done in selective donors with suspicion of NAFLD, a further study of donors with lean body mass index (BMI <23 kg/m2) and none or only one metabolic risk factors still showed NAFLD in 28.5%.
| The Independent Association of Nonalcoholic Fatty Liver Disease with Cardiovascular Diseases|| |
NAFLD and CVD share common metabolic risk factors such as diabetes, dyslipidemia, hypertension, and obesity. Although NAFLD may happen in the absence of these risk factors, it is generally associated with insulin resistance and metabolic syndrome [Figure 1]. As stated earlier, several studies have shown that NAFLD is associated with a higher risk of CVD independent of common risk factors. The possible links causing atherosclerosis acceleration in patients with NAFLD include presence of genetic and epigenetic predisposition factors, insulin resistance and atherogenic dyslipidemia, chronic systemic and vascular inflammation, renin-angiotensin aldosterone system activation and vascular remodeling, endothelial dysfunction, imbalance of pro-and anticoagulant factors leading to coagulopathy and plague formation.,,,,,,,,
|Figure 1: Multidisciplinary management is required in nonalcoholic fatty liver disease|
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| Cardiovascular Diseases in Nonalcoholic Fatty Liver Disease|| |
Several studies with long-term follow-up have shown that CVD is the common or the main cause of mortality in patients with NAFLD.,,, In a study from National Health and Nutrition Examination Survey III data (from 1988 to 1994), Stepanova and Younossi compared persons with NAFLD to those without (absence of NAFLD or other chronic liver diseases). During a follow-up period of median 171 month, 12.21% of participants died, 3.76% died due to CVD. The presence of NAFLD was independently associated with CVD, after adjusting for major confounders such as demographic, clinical, and metabolic risk factors.
It is important to understand that association of NAFLD to CVD is independent of other metabolic risk factors. In a meta-analysis of 11 studies, Zhou et al. showed that risk of CVD is increased synergistically. Patients with diabetes and NAFLD had two times increased risk of CVD compared with no-NAFLD (odds ratio = 2.20, 95% confidence interval: 1.67–2.90). NAFLD is also associated with other comorbidities that contribute to CVD as shown in [Figure 2].,,, Patients with NAFLD-related fibrosis or cirrhosis are at a higher risk of CVD.,, The guidelines from the Indian National Association for the Study of the Liver suggests evaluation of CVD in patients with old age or with having metabolic risk factors. A detailed cardiovascular evaluation is recommended in NASH-related cirrhosis or hepatocellular carcinoma before liver transplantation. While several studies have shown that patients with NAFLD-related fibrosis or cirrhosis are at a higher risk of CVD, it is no clear (in absence if data) if patients with significant CVD should be screened for NAFLD-related fibrosis.
|Figure 2: Association of nonalcoholic fatty liver disease with other comorbidities (* indicates in patients with diabetes)|
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| Indians are at Higher Risk of Cardiovascular Diseases|| |
Indians are predisposed to metabolic risk factors at a lower BMI and lower waist circumference. CVD has emerged as a leading cause of mortality in India, it is true for rural areas and in relatively poor states also.
Indians are at risk of early CVD when compared to the Western population., The Interheart study found that South Asians were 10 years younger at the first presentation of acute myocardial infarction. Gupta et al. showed a rapid escalation of CVD risk factors in 30–39 years' age group. As NAFLD independently adds to risk of developing CVD, it should be part of risk scores for CVD risk assessment, however data are limited at present. We suggest to keep a lower threshold for CVD assessment in patients with NAFLD, particularly in patients with DM and NAFLD.,
| Poor Awareness Regarding Nonalcoholic Fatty Liver Disease|| |
As NAFLD and CVD progress to significant degree over many years, primary prevention should be possible. Treatment of NAFLD include lifestyle modification which is recommended for all (exercise, dietary modification, and weight loss) and pharmacotherapy (recommended for NASH and fibrosis).
Lifestyle modification and weight loss improves CVD risk profile also., In addition, certain medication used for NAFLD such as antilipidemic and certain antidiabetics agents improve CVD risk also. A diagnosis of NAFLD which is commonly picked up by ultrasound or by raised liver enzymes (checked for some other purpose in most of patients) provides an opportunity to prevent both CVD and liver-related morbidity and mortality. Most of these patients are diagnosed at primary care setting. However, awareness that NAFLD is associated with extra-hepatic morbidities and with CVD in particular is poor among people as well as among primary physicians. There are no data regarding awareness about association of NAFLD with CVD from India. Several studies from Western world show a significant lack of awareness regarding NAFLD among primary care physicians.,, Thus, increasing awareness among primary care physicians that NAFLD is an important diagnosis and it is associated with several diseases that require multidisciplinary management [Figure 1] is very important and carries a huge preventive potential for CVD-related and liver-related mortality. Raising awareness becomes more important in resource poor setting of India. We suggest a systematic study among primary care physicians and multiple campaigns by hepatologists and cardiologists.
| Approach to Treatment of Nonalcoholic Fatty Liver Disease|| |
The approach to treatment of NAFLD is shown in [Figure 3]. It is important to treat comorbidities such as obesity, diabetes, and dyslipidemia. Many studies have shown improvement of NAFLD with lifestyle changes alone. A study from our center among prospective liver donors showed a rapid improvement in steatosis after weight loss.
|Figure 3: Approach to treatment of nonalcoholic fatty liver disease, *limited data available|
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It is important to understand that pharmacotherapy is not a substitute to lifestyle changes and weight loss. The need of lifestyle changes (exercise, dietary modification, and weight loss) should be emphasized to all patients. Pharmacotherapy is not indicated for patients with steatosis alone. Two things need particular mention regarding pharmacotherapy. Ursodeoxycholic acid is a commonly used medicine by primary care physicians; however, it is not effective in treatment of NAFLD. There is a fear of hepatoxicity in using statins. Statin induced significant hepatoxicity is rare, even in patients with NAFLD or in patients with cirrhosis, and statins can be used whenever indicated. As NAFLD is associated with higher risk of CVD, use of statins can also decrease CVD-related morbidity or mortality, also there is suggestion of decreased hepatic complications with statin use. In general, statins cause raised liver enzymes, and it is more common with higher doses. Caution is advised in patients with decompensated cirrhosis.,
In patients with indications for bariatric surgery, it has been shown to produce improvement in liver histology in the majority of patients. However, bariatric surgery cannot be performed for patents with NAFLD alone in the absence of other indications in the absence of data and potential risk of complications.
| Conclusions|| |
As NAFLD is associated with several extrahepatic morbidities, a better knowledge of caregivers should result in improved outcomes. The association of NAFLD and CVD provides a huge prevention opportunity, which is more relevant in the Indian setting. Emphasis should be laid on patient and physician awareness.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Duseja A, Singh SP, Saraswat VA, Acharya SK, Chawla YK, Chowdhury S, et al.
Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian National Association for the Study of the Liver, Endocrine Society of India, Indian College of Cardiology and Indian Society of Gastroenterology. J Clin Exp Hepatol 2015;5:51-68.
Doycheva I, Issa D, Watt KD, Lopez R, Rifai G, Alkhouri N. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in young adults in the United States. J Clin Gastroenterol 2018;52:339-46.
Fargion S, Porzio M, Fracanzani AL. Nonalcoholic fatty liver disease and vascular disease: State-of-the-art. World J Gastroenterol 2014;20:13306-24.
Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, et al.
Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005;54:3541-6.
Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al.
Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-73.
Söderberg C, Stål P, Askling J, Glaumann H, Lindberg G, Marmur J, et al.
Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51:595-602.
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-402.
Krishan S, Jain D, Bathina Y, Kale A, Saraf N, Saigal S, et al.
Non-invasive quantification of hepatic steatosis in living, related liver donors using dual-echo Dixon imaging and single-voxel proton spectroscopy. Clin Radiol 2016;71:58-63.
Costa-Silva L, Ferolla SM, Lima AS, Vidigal PV, Ferrari TC. MR elastography is effective for the non-invasive evaluation of fibrosis and necroinflammatory activity in patients with nonalcoholic fatty liver disease. Eur J Radiol 2018;98:82-9.
Choudhary NS, Saraf N, Saigal S, Duseja A, Gautam D, Rastogi A, et al.
Non-alcoholic fatty liver in the lean: Clinico-biochemical correlates of histopathology in 157 liver biopsies from healthy liver donors. J Clin Exp Hepatol 2021. [doi: 10.1016/j.jceh. 2021.01.004].
Singh SP, Nayak S, Swain M, Rout N, Mallik RN, Agrawal O, et al.
Prevalence of nonalcoholic fatty liver disease in coastal eastern India: A preliminary ultrasonographic survey. Trop Gastroenterol 2004;25:76-9.
Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, et al.
Prevalence of non-alcoholic fatty liver disease: Population based study. Ann Hepatol 2007;6:161-3.
Mohan V, Farooq S, Deepa M, Ravikumar R, Pitchumoni CS. Prevalence of non-alcoholic fatty liver disease in urban south Indians in relation to different grades of glucose intolerance and metabolic syndrome. Diabetes Res Clin Pract 2009;84:84-91.
Najmy S, Duseja A, Pal A, Sachdev S, Sharma RR, Marwah N, et al
. Redefining the normal values of serum aminotransferases in healthy Indian males. J Clin Exp Hepatol 2019;9:191-9.
Kalra S, Vithalani M, Gulati G, Kulkarni CM, Kadam Y, Pallivathukkal J, et al.
Study of prevalence of nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes patients in India (SPRINT). J Assoc Physicians India 2013;61:448-53.
Vanjiappan S, Hamide A, Ananthakrishnan R, Periyasamy SG, Mehalingam V. Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease. Diabetes Metab Syndr 2018;12:479-82.
Jain V, Jana M, Upadhyay B, Ahmad N, Jain O, Upadhyay AD, et al.
Prevalence, clinical and biochemical correlates of non-alcoholic fatty liver disease in overweight adolescents. Indian J Med Res 2018;148:291-301.
] [Full text]
Das MK, Bhatia V, Sibal A, Gupta A, Gopalan S, Sardana R, et al.
Prevalence of nonalcoholic fatty liver disease in normal-weight and overweight preadolescent children in Haryana, India. Indian Pediatr 2017;54:1012-6.
Choudhary NS, Saraf N, Saigal S, Gautam D, Lipi L, Soin AS. Estimation of normal values of serum transaminases based on liver histology in healthy Asian Indians. J Gastroenterol Hepatol 2015;30:763-6.
Alkhouri N, Tamimi TA, Yerian L, Lopez R, Zein NN, Feldstein AE. The inflamed liver and atherosclerosis: A link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk. Dig Dis Sci 2010;55:2644-50.
DeFilippis AP, Blaha MJ, Martin SS, Reed RM, Jones SR, Nasir K, et al.
Nonalcoholic fatty liver disease and serum lipoproteins: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2013;227:429-36.
Nigam P, Bhatt SP, Misra A, Vaidya M, Dasgupta J, Chadha DS. Non-alcoholic fatty liver disease is closely associated with sub-clinical inflammation: A case-control study on Asian Indians in North India. PLoS One 2013;8:e49286.
Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46-54.
Sinn DH, Cho SJ, Gu S, Seong D, Kang D, Kim H, et al.
Persistent nonalcoholic fatty liver disease increases risk for carotid atherosclerosis. Gastroenterology 2016;151:481-8.e1.
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010;363:1341-50.
Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 2004;24:29-33.
Tripodi A, Fracanzani AL, Primignani M, Chantarangkul V, Clerici M, Mannucci PM, et al.
Procoagulant imbalance in patients with non-alcoholic fatty liver disease. J Hepatol 2014;61:148-54.
Kahali B, Liu YL, Daly AK, Day CP, Anstee QM, Speliotes EK. TM6SF2: Catch-22 in the fight against nonalcoholic fatty liver disease and cardiovascular disease? Gastroenterology 2015;148:679-84.
Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T, et al.
Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: A community-based cohort study. Am J Gastroenterol 2010;105:1567-73.
Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 2012;10:646-50.
Zhou YY, Zhou XD, Wu SJ, Hu XQ, Tang B, Poucke SV, et al.
Synergistic increase in cardiovascular risk in diabetes mellitus with nonalcoholic fatty liver disease: A meta-analysis. Eur J Gastroenterol Hepatol 2018;30:631-6.
Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Schattenberg JM, et al.
Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: An updated meta-analysis. Gut 2020. doi: 10.1136/gutjnl-2020-323082.
Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes Rev 2013;14:417-31.
Morrison AE, Zaccardi F, Khunti K, Davies MJ. Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: A meta-analysis with bias analysis. Liver Int 2019;39:557-67.
Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013;57:1357-65.
Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, et al.
Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547-54.
Choudhary NS, Duseja A. Screening of cardiovascular disease in nonalcoholic fatty liver disease: Whom and how? J Clin Exp Hepatol 2019;9:506-14.
Misra A, Chowbey P, Makkar BM, Vikram NK, Wasir JS, Chadha D, et al.
Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India 2009;57:163-70.
Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases in India: Current epidemiology and future directions. Circulation 2016;133:1605-20.
Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 2004;364:937-52.
Joshi P, Islam S, Pais P, Reddy S, Dorairaj P, Kazmi K, et al.
Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA 2007;297:286-94.
Gupta R, Misra A, Vikram NK, Kondal D, Gupta SS, Agrawal A, et al.
Younger age of escalation of cardiovascular risk factors in Asian Indian subjects. BMC Cardiovasc Disord 2009;9:28.
Lu H, Zeng L, Liang B, Shu X, Xie D. High prevalence of coronary heart disease in type 2 diabetic patients with non-alcoholic fatty liver disease. Arch Med Res 2009;40:571-5.
Targher G, Bertolini L, Padovani R, Poli F, Scala L, Tessari R, et al.
Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease. Diabet Med 2006;23:403-9.
Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al.
Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 2011;34:1481-6.
Pinckard K, Baskin KK, Stanford KI. Effects of exercise to improve cardiovascular health. Front Cardiovasc Med 2019;6:69.
Polanco-Briceno S, Glass D, Stuntz M, Caze A. Awareness of nonalcoholic steatohepatitis and associated practice patterns of primary care physicians and specialists. BMC Res Notes 2016;9:157.
Bergqvist CJ, Skoien R, Horsfall L, Clouston AD, Jonsson JR, Powell EE. Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists. Intern Med J 2013;43:247-53.
Ghevariya V, Sandar N, Patel K, Ghevariya N, Shah R, Aron J, et al.
Knowing what's out there: Awareness of non-alcoholic fatty liver disease. Front Med (Lausanne) 2014;1:4.
Choudhary NS, Saraf N, Saigal S, Gautam D, Lipi L, Rastogi A, et al.
Rapid reversal of liver steatosis with life style modification in highly motivated liver donors. J Clin Exp Hepatol 2015;5:123-6.
Chalasani N. Statins and hepatotoxicity: Focus on patients with fatty liver. Hepatology 2005;41:690-5.
Vargas JI, Arrese M, Shah VH, Arab JP. Use of statins in patients with chronic liver disease and cirrhosis: Current views and prospects. Curr Gastroenterol Rep 2017;19:43.
[Figure 1], [Figure 2], [Figure 3]