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Nonalcoholic fatty liver disease: implications for endocrinologists and cardiologists

Rodriguez-Araujo, Gerardo

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Cardiovascular Endocrinology & Metabolism: March 23, 2020 - Volume 9 - Issue 3 - p 96-100
doi: 10.1097/XCE.0000000000000197
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Nonalcoholic fatty liver disease (NAFLD), particularly its severe form [nonalcoholic steatohepatitis (NASH) with advanced fibrosis], is the second leading indication for liver transplant. More than a third of all patients with type 2 diabetes mellitus (T2DM) have this silent and severe disease [1,2]. NASH is often overlooked as many consider it a non-serious disease that has no available pharmacotherapy; however, its pathophysiology has many of the elements present in both T2DM and cardiovascular disease (CVD), such as oxidative stress, endothelial dysfunction, chronic inflammation, etc. In addition, there is current evidence that certain drugs intended to treat T2DM and CVD have also a positive or negative impact on the liver biology, such as steatosis, inflammation (NASH), and fibrosis [i.e., glucagon-like peptide-1 agonists (GLP-1 agonists), sodium-glucose cotransporter 2 (SGLT-2) inhibitors and beta-blockers] [3–6]. Endocrinologists and cardiologists often surprise when patients under their watch have advanced forms of this silent disease when screened using current noninvasive methods to assess liver fibrosis, such as transient elastography, FIB-4, AST to platelet ratio index (APRI), etc. Patients with advanced liver fibrosis are at the highest risk to present not just cardiovascular events but also liver-related complications. Therefore, it is important to identify patients at high risk for a close clinical monitoring or for enrollment into a clinical trial, so the patient can have access to NASH pharmacotherapy.

Nonalcoholic fatty liver disease in type 2 diabetes mellitus and cardiovascular disease

NAFLD is commonly present in populations that have T2DM and CVD and affects approximately 25% of the worldwide population [7]. The severe or inflammatory version of NAFLD is called NASH, which leads to subsequent liver fibrosis and its associated cardiovascular and liver-related mortality [8]. Globally, the prevalence of NASH in patients with T2DM has been estimated to be approximately 37.3%, resulting in millions of affected patients across the globe [2]. Liver biopsy studies have shown that the more fibrosis, the higher the mortality due to cardiovascular and liver-related complications (stage 3 and 4 by CRN scoring) [8]. The relative risk of all-cause mortality is almost a 2-fold increase and 5-fold increase in liver-related mortality/transplantation in advanced liver fibrosis (stages 3 and 4) compared to milder stages of NASH-related liver fibrosis (stages 1 and 2) [8,9]. T2DM is the main driver of fibrosis in the liver and other vital organs according to the National Health and Nutrition Examination Survey and other registries. This favors internal endocrine dysregulation and its associated end-organ complications, such as nonalcoholic cirrhosis, renal insufficiency, retinopathy, etc [10].

In this regard, there is evidence that glucose toxicity at cellular and epigenetic levels induce oxidative stress in multiple cells and organs [11]. Oxidative stress is also present in CVD and in NASH and its believed to be an important therapeutic target. Antioxidants (vitamin E), polyphenol-like, and other pharmacotherapies are currently under development to tackle this important node avoiding the domino effect of inflammation and subsequent organ fibrosis [10,12] (Table 1).

Table 1
Table 1:
Comparison on the pathophysiology and pharmacotherapy of nonalcoholic fatty liver disease, type 2 diabetes mellitus, and cardiovascular disease

Another important element for endocrinologists and cardiologists is glucagon. Patients with T2DM display fasting and postprandial hyperglucagonemia as the alpha-beta cell ratio may be favoring a higher density of alpha cells due to an increase in the apoptosis rate in beta cell and dedifferentiation of beta cells into alpha cells which are more resistant to cellular stress than beta cells. GLP-1 agonists decrease fasting and postprandial hyperglucagonemia, therefore, resulting in better glycemic control particularly when combined with an SGLT-2 inhibitor. This effect certainly may have an impact on the body weight and Acetyl Co-A availability for de novo lipogenesis in the liver and other organs (Fig. 1) [17–19].

Fig. 1
Fig. 1:
Pathophysiology and pharmacotheraphy of NAFLD.

Nonalcoholic steatohepatitis with advanced fibrosis in patients with type 2 diabetes mellitus and cardiovascular disease

The current guidelines from the American Association of the Study of the Liver Disease and European Association of the Study of the Liver encourage the use and development of noninvasive tests (NITs) that can inform clinicians the risk for advanced liver fibrosis in patients. Among those NITs, FIB-4, NAFLD fibrosis score (NFS), and APRI are widely used to identify subjects at risk [20]. FIB-4 and NFS have high negative predictive values (NPV) to rule out advanced fibrosis (88 and 95%, respectively) but also high positive predictive values (PPV) to rule in advanced fibrosis (93 and 95%, respectively) [20,21]. These NITs should be used first when risk stratifying patients. However, caution may be needed when using NFS in patients with T2DM as several analyses have reported low performance in such population [22]. Instead, APRI can be used as it performs well in both diabetic and nondiabetic populations (NPV 65% and PPV 91%) [23]. Additionally, APRI can be used in the clinic as reference for interpretation of FIB-4 in diabetic populations, increasing the confidence of the clinician to proceed with the next steps of the patient’s care (Table 2).

Table 2
Table 2:
Noninvasive tests and cutoffs to rule in advanced liver fibrosis (F3–F4 vs F0–F2) in the general population

In certain clinics or hospitals, transient elastography (Fibroscan) and Magnetic Resonance Elastography (MRE) may be available. These diagnostic modalities constitute a second step for risk stratification of patients that have high scores by FIB-4, APRI, or NFS. However, Fibroscan is not part of the standard of care in many clinics, even for hepatologists, and reimbursement issues make it difficult to deploy it at the bedside. The cost of transient elastography is moderate compared with MRE. MRE is one of the most expensive testings of the liver at this point in time but has excellent NPV and PPV (94 and 95%) for the identification of advanced fibrosis (≥stage 3 or ‘F3 and above’) [25].

The liver forum and other international consortia recognize the value of the deployment of NITs to identify severe NASH patients, and there are ongoing efforts by NIMBLE (Foundation of NIH) and LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) in the USA and EU, respectively, to establish more advanced NITs. Nonetheless, currently available NITs are valuable low-cost risk stratification tools for clinicians, utilizing commonly used biomarkers in most clinics including endocrinology and cardiology practices at no additional cost for patients and healthcare systems.

Clinical implications for endocrinologist, cardiologists, and hepatologists

Patients with high NIT scores should be monitored closely and referred to a hepatologist for further confirmation of liver fibrosis staging. Once the staging is confirmed, hepatologists, endocrinologists, and cardiologists should work together to discuss long-term management plans. Many hospitals and clinics in the USA, Europe, and Canada have established clinical protocols for NASH patients with advanced fibrosis or cirrhosis. T2DM is not just a risk factor but a strong predictor of fibrosis progression. Therefore, endocrinologists and cardiologists, who are the gatekeepers of such patient population, need to implement similar programs. Such programs could include a continuous care done by the endocrinologist and cardiologist in their monthly or bimonthly standard of care patient office visits but including a 6 or 12 months additional visit to the hepatologist for any change on the treatment plan. Approval of NASH pharmacotherapy is underway, potentially starting this year 2020 with obeticholic acid (Ocaliva), followed by peroxisome proliferator-activated receptors (Elafibranor), CCR2-5 antifibrotic agents (Cenicriviroc), thyroid hormone receptor agonists (Resmetirom), etc in the following immediate years.

Therefore, physicians currently overseeing patients with T2DM need to be aware of the following:

  • 1. Patients at high risk for complications or death related to NASH-related advanced fibrosis (Table 2).
  • 2. Current antidiabetic and cardiovascular medications that have positive and negative effects in NASH patients with advanced liver fibrosis (Table 3).
  • 3. Upcoming NASH pharmacotherapy, including their potential clinical challenges and adverse effects (see above and Fig. 1).
Table 3
Table 3:
Antidiabetic drug profiles for nonalcoholic steatohepatitis, glycemic, and cardiovascular benefits

Antidiabetic drugs with cardiovascular benefits in nonalcoholic steatohepatitis

Several GLP-1 single, dual, or triple agonist with glugose dependent insulinotropic polypeptide and glucagon have shown benefits for not only HbA1c control but also for reduction of liver fat content with potential additional cardiovascular benefits in patients with T2DM and NASH. The recently Food and Drug Administration approved oral semaglutide has shown dose-dependent HbA1c and body weight benefits in patients with T2DM. Semaglutide and other GLP-1 agonist are currently under development for the indication of NASH due to its body weight reduction profiles. Tirzepatide is another example of dual agonist with impact on liver enzymes, CK-18, and adiponectin (2019 ADA and EASD scientific sessions) [31,32]. SGLT-2 inhibitors have shown dramatic improvement in HbA1c, body weight, and hemodynamics in patients with preexisting CVD due to their glucoretic effects [28]. Combination therapy with GLP-1a and SLGLT-2i maximize glycemic control, body weight loss, and potential suppression of hyperglucagonemia in patients with T2DM [19].

Endocrinologists have started to work together with hepatologists in this effort, which translates into an increasing volume and quality of relevant research presented at the ADA and EASD forums as well as the American Association of the Study of the Liver Disease and European Association of the Study of the Liver symposia. Cardiology practice is a logical and organic addition to this ongoing effort as patients with T2DM and NASH with advanced fibrosis are at even higher risk for cardiovascular complications, including myocardial infarction, stroke, and lower extremity amputation [33,34].

Cardiovascular drugs with potential impact on liver

Beta-blockers, such as propranolol, have being studied for the NASH indication but some reports have shown that this drug class may induce drug-induced liver injury [6]. In contrast, interleukin-1-beta mAb therapy (canakinumab) has shown reduction of residual cardiovascular risk independently of statin use in the CANTOS trial [35]. Similarly, NXY-059 has been studied as free radical trapping agent in stroke with promising results in the SAINT-1 trial [16]. This could potentially have a systemic impact on oxidative stress not only in the CNS but also in other vital organs such as liver and pancreas in those cardiovascular patients. Statins and antiplatelets have also anti-inflammatory properties via NLR family pyrin domain containing 3 attenuation or reduction of C-reactive protein that could potentially improve systemic chronic inflammation, such as in diabetes, obesity, and NASH [36–39]. Further studies are granted on those exploratory efforts to expand on safety and efficacy for diabetes and NASH endpoints in patients with CVD; however, clinicians should be aware of these potential positive and negative effects of cardiovascular drugs in patients with T2DM and NASH (Table 1).

Discussion and conclusion

There are still many missing gaps in our current understanding of NASH and its complications but as the field evolves, literature will be updated and both endocrinologists and cardiologists need to update their knowledge and clinical protocols as well to provide a truly state of the art-patient care for patients with T2DM with CVD that are at risk for severe forms of NASH. For example, to date, there is no literature about the NITs cutoff values in T2DM only. As T2DM is very symptomatic and involves many systems and organs, it would be recommended to validate such values and scoring performances to increase precision on the clinical decisions in such patient population.

Current medications have shown potential benefits for patients with T2DM and NASH. More phase 2b and 3 studies are currently underway to expand on efficacy not only just for T2DM or obesity endpoints but also for NASH endpoints as well. In addition, new therapies for NASH are just around the corner and endocrinologist and cardiologist need to familiarize themselves with those new drugs as they directly relate to their patients.

Establishing solid purposed multidisciplinary protocols in clinics and hospitals across the globe could represent an improvement in the overall patient’s quality of care and most importantly, patient’s quality of life, reducing the tremendous cost to the society of NASH complications in patients with T2DM, dyslipidemia, or obesity.


Conflicts of interest

There are no conflicts of interest.


1. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the united states. Gastroenterology. 2015; 148:547–555
2. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019; 71:793–801
3. Alkhouri N, Poordad F, Lawitz E. Management of nonalcoholic fatty liver disease: lessons learned from type 2 diabetes. Hepatol Commun. 2018; 2:778–785
4. Petit JM, Vergès B. GLP-1 receptor agonists in NAFLD. Diabetes Metab. 2017; 43Suppl 12S28–2S33
5. Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SØ, et al.; PIONEER 2 Investigators. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019; 42:2272–2281
6. McKee C, Soeda J, Asilmaz E, Sigalla B, Morgan M, Sinelli N, et al. Propranolol, a β-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis. Biochem Biophys Res Commun. 2013; 437:597–602
7. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the study of liver diseases. Hepatology. 2018; 67:328–357
8. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017; 65:1557–1565
9. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015; 149:389–97.e10
10. Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm J. 2016; 24:547–553
11. Rodriguez-Araujo G, Nakagami H. Pathophysiology of cardiovascular disease in diabetes mellitus. Cardiovasc Endocrinol Metab. 2018; 7:4–9
12. Pollack RM, Donath MY, LeRoith D, Leibowitz G. Anti-inflammatory agents in the treatment of diabetes and its vascular complications. Diabetes Care. 2016; 39Suppl 2S244–S252
13. Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver. 2012; 6:149–171
14. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005; 115:1111–1119
15. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al.; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association. Circulation. 2003; 107:499–511
16. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al.; SAINT II Trial Investigators. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007; 357:562–571
17. Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G, Harwood HJ Jr, et al. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology. 2017; 66:324–334
18. Sanders FW, Griffin JL. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc. 2016; 91:452–468
19. Hædersdal S, Lund A, Knop FK, Vilsbøll T. The role of glucagon in the pathophysiology and treatment of type 2 diabetes. Mayo Clin Proc. 2018; 93:217–239
20. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019; 156:1264–1281.e4
21. Anstee QM, Lawitz EJ, Alkhouri N, Wong VW, Romero-Gomez M, Okanoue T, et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology. 2019; 70:1521–1530
22. Xun YH, Fan JG, Zang GQ, Liu H, Jiang YM, Xiang J, et al. Suboptimal performance of simple noninvasive tests for advanced fibrosis in Chinese patients with nonalcoholic fatty liver disease. J Dig Dis. 2012; 13:588–595
23. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003; 38:518–526
24. Hoodeshenas S, Yin M, Venkatesh SK. Magnetic resonance elastography of liver: current update. Top Magn Reson Imaging. 2018; 27:319–333
25. Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008; 135:32–40
26. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375:1834–1844
27. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al.; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; 381:841–851
28. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128
29. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–657
30. Erdmann E, Dormandy J, Wilcox R, Massi-Benedetti M, Charbonnel B. Proactive 07: pioglitazone in the treatment of type 2 diabetes: results of the proactive study. Vasc Health Risk Manag. 2007; 3:355–370
    31. Hartman ML. Effects of Tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist, on biomarkers of nonalcoholic steatohepatitis (NASH) in patients with T2D. Diabetes. 2019; 68Suppl 1
    32. Haupt A. Effects of tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist, on biomarkers of non-alcoholic steatohepatitis (NASH) in patients with type 2 diabetes. EASD. 2019
    33. Patil R, Sood GK. Non-alcoholic fatty liver disease and cardiovascular risk. World J Gastrointest Pathophysiol. 2017; 8:51–58
    34. Francque SM, van der Graaff D, Kwanten WJ. Non-alcoholic fatty liver disease and cardiovascular risk: pathophysiological mechanisms and implications. J Hepatol. 2016; 65:425–443
    35. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al.; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377:1119–1131
    36. Diamantis E, Kyriakos G, Quiles-Sanchez LV, Farmaki P, Troupis T. The anti-inflammatory effects of statins on coronary artery disease: an updated review of the literature. Curr Cardiol Rev. 2017; 13:209–216
    37. Wang S, Xie X, Lei T, Zhang K, Lai B, Zhang Z, et al. Statins attenuate activation of the NLRP3 inflammasome by oxidized LDL or tnfα in vascular endothelial cells through a PXR-dependent mechanism. Mol Pharmacol. 2017; 92:256–264
    38. Tu X, Chen X, Xie Y, Shi S, Wang J, Chen Y, Li J. Anti-inflammatory renoprotective effect of clopidogrel and irbesartan in chronic renal injury. J Am Soc Nephrol. 2008; 19:77–83
    39. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Jimenez-Quevedo P, et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes. 2006; 55:780–784

    cardiology; cardiovascular disease; clinical implications; diabetes; endocrinology; hepatology; liver disease; non alcoholic fatty; non alcoholic steatohepatitis; pharmacotherapy; research and development

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