1. Non-alcoholic steatohepatitis and cardiovascular risk
V.G. Athyros, MD, FESC, FRSPH, FASA, FACS
2nd Department of internal Medicine, Aristotle University Thessaloniki, Greece

2. Defining NAFLD…
Clinico-pathologic syndrome encompassing a wide range of fatty liver disease
in the absence of significant alcohol intake
(2 drinks or fewer daily) and other common causes of steatosis.

3. NAFLD - Background
1958: Zelman reported association of obesity with fatty
liver
1980: Ludwig coined “non-alcoholic steatohepatitis”
2010: 400 million subjects with NAFLD and
120 million with NASH

4. NAFLD - Spectrum of Disease
Steatosis
Steatohepatitis (NASH)
NASH with Fibrosis
Cirrhosis
NAFLD

6. Possible role of adipose tissue insulin resistance and lipotoxicity in the progression from NAFLD and NASH. (1) In the setting of obesity or T2DM, increased rates of lipolysis and plasma FFA, combined with hyperinsulinemia and hyperglycemia, stimulate excessive hepatic TG synthesis. (2) Steatosis in turn may (i) exacerbate hepatic insulin resistance, (ii) stimulate VLDL secretion, and (iii) increase mitochondrial beta-oxidation. If a new steadystate is achieved, only benign steatosis takes place. (3) If mitochondrial function cannot adapt to the increased FFA flux and respiratory oxidation collapses, lipid-derived toxic metabolites activate inflammatory pathways and hepatocyte lipotoxicity leading to.
Endoplasmic reticulum stress and the unfolded protein response also participate in the pathogenesis of NASH. (4) The cross-talk between hepatocytes, macrophages, and hepatic stellate cells (HSC) determines the degree of the fibrogenic response and potential progression to cirrhosis. (From Cusi K. Non-alcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2009;16:141–9; with permission.

7. Prevalence 10-35% in various populations United States
15-39% with NAFLD
1.2-11% with NASH
Most common liver disease in Western world
Cause of ↑ transaminases in 42-90%

8. Non-Alcoholic Liver Disease as a model for the study of the secondary complications of obesity
 Fibrosis
Increased risk of
hepatocellular carcinoma
From: Ariel E. Feldstein and Marsha H. Kay, ACG website
NAFLD affects up to 25 % of adults and nearly 5 % of children.
NASH  2-5 % of adult Americans; up to 20 % of obese subjects.
The majority of individuals with NAFLD have no symptoms and a normal examination

9. NAFLD – Epidemiology of Histological forms
Cirrhosis
Time Progression
Fibrosis
Lobular Inflammation
Macrovesicular Steatosis

10. Fibroscan a non-invasive modality is able to detect NASH with fibrosis
NAFLD - Imaging
Ultrasound
Computed Tomography
Magnetic Resonance Imaging
Fibroscan a non-invasive modality is able to detect NASH with fibrosis
Saadeh et al. The Utility of Radiological Imaging in NAFLD. Gastroenterology 2002; 123:

11. NAFLD activity score (NAS)
Findings:
Macrovesicular steatosis
Lobular inflammation
Hepatocyte balooning
Perisinusoidal fibrosis
__________________________________________________
Histologic scoring system
Score 5 or greater is consistent with NASH
Score 2 or less is consistent with simple fatty liver

13. NAFLD – (Liver) Prognosis
Increased overall mortality compared to matched control populations.
Commonest cause of death in patients with NAFLD, NAFL and NASH is cardiovascular disease.
Increased liver-related mortality rate – increasingly common indication for liver transplantation (15-20%).
Kawamura Y et al (2011). Large scale long term follow up study of Japanese patients with NAFLD for the onset of HCC. American Journal of Gastroenterology doi: /ajg

14. NAFLD – (CVD) Prognosis
Simple steatosis is benign
Steatohepatitis increases CVD risk
Steatohepatitis with fibroses exacerbates CVD risk.
Athyros VG et al (2015). Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease World J Gastroenterol Jun 14;21(22):

15. NAFLD – (CVD) Prognosis
66-85% increase in CVD death risk
N=11,154 ; 11.5 years
NASH with liver fibrosis
Athyros VG et al (2015). Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease World J Gastroenterol Jun 14;21(22):
Kim D, et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013; 57:

16. NAFLD - Weight Loss/Exercise
Palmer et al. Gastroenterology 1990
--39 obese patients, no primary liver disease
--Retrospective analysis after weight loss
--Lower ALT seen in patients with >10% weight loss
Anderson et al. Journal Hepatology 1991
--41 obese patients with biopsy-proven NAFLD
--Low calorie diet (~400 kcal/d) x 8 months then re-biopsied
--Most improved, but 24% with worse fibrosis/inflammation
--Histological worsening associated with rapid weight loss

18. Athyros V.G, et al. Lancet 2010 ;376(9756):1916-22.
Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis
Athyros V.G, et al. Lancet 2010 ;376(9756):

19. Athyros V, et al. Lancet 2010 ;376(9756):1916-22.
Effect of statin treatment on liver function tests
Of 437 patients with moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease, 227 who were treated with a statin (mainly atorvastatin 24 mg per day) had substantial improvement in liver tests (p<0·0001) whereas 210 not treated with a statin had further increases of liver enzyme concentrations. 
3-ετής παρακολούθηση των ηπατικών ενζύμων σε ασθενείς με αυξημένες τιμές (A) Ασθενείς υπό αγωγή με στατίνη (n=227). (B) Ασθενείς χωρίς στατίνη (n=210). ALT=alanine aminotransferase. AST=aspartate aminotransferase. GGT=γ-glutamyl transferase. Για περισσότερες πληροφορίες, ανατρέξτε στα slide 4, 22,23.
Athyros V, et al. Lancet 2010 ;376(9756): 19

20. Impaired liver Function
Cardiovascular Relative Risk Reduction within and between the Treatment Groups
Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (1
0·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). 
Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease.
Impaired liver Function
Καρδιαγγειακά συμβάματα παρατηρήθηκαν σε 22 (10%) από τους 227 ασθενείς με διαταραγμένες ηπατικές εργαστηριακές εξετάσεις που λάμβαναν στατίνη (3·2 συμβάματα ανά 100 ανθρωπο-έτη) και σε 63 (30%) από τους 210 ασθενείς με διαταραγμένες ηπατικές εργαστηριακές εξετάσεις που δεν λάμβαναν στατίνη (10·0 συμβάματα ανά100 ανθρωπο-έτη; 68% μείωση σχετικού κινδύνου, p<0·0001). Για περισσότερες πληροφορίες, ανατρέξτε στα slide 4, 22,23.
Athyros V, et al. Lancet 2010 ;376(9756): 20

21. Cardiovascular Relative Risk Reduction within and between the Treatment Groups
All patients with abnormal elevations of AST/ALT up to 3 times the ULN, probably due to NAFLD/NASH, who were treated with a statin experienced a substantial improvement (normalization) in LTs over the 3-year follow-up period.
Statin treatment reduced the risk for CVD events by 68% in patients with abnormal LTs (p<0.0001). Interestingly, the statin-related RRR was greater in patients with abnormal LTs than in those with normal LTs (68 vs. 39%, respectively; p=0.0074).
Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (1
0·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). 
Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease.
Athyros V, et al. Lancet 2010 ;376(9756): 21

22. ATTEMPT
Assessing The Treatment Effect in Metabolic syndrome without Perceptible diabeTes (ATTEMPT). A prospective-randomized study in middle aged men and women. Safety and impact on CVD events of long-term multifactorial treatment in patients with MetS and Abnormal liver function tests. Athyros VG, Giouleme O, Ganotakis ES, Elisaf M, Tziomalos K, Vassiliadis T, Liberopoulos EN, Theocharidou E, Karagiannis A, Mikhailidis DP.; for the Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible diabeTes (ATTEMPT) Collaborative Group*
Arch Med Sci 2011 Oct;7(5): 22

23. ATTEMPT Liver post hoc Analysis
Effect of atorvastatin treatment on liver function tests in patients with MetS & NAFLD
Time course of AP, GTT, ALT, AST change in the statin treated patients with NAFLD
Athyros V, et al. Arch Med Sci 2011 Oct;7(5):

24. Effect of atorvastatin treatment on Event free survival of A2 and B2
ATTEMPT Liver post hoc Analysis
Effect of atorvastatin treatment on Event free survival of A2 and B2
Time course of AP, GTT, ALT, AST change in the statin treated patients with NAFLD
Athyros V, et al. Alimentary Pharmacology and Therapeutics 2011 (in Press).

25. IDEAL: Study design Atorvastatin 80 mg/day 8,888 Patients
Patient population
Enrolled at 190 sites
History of MI (no restriction on time since MI)
Men and women aged ≤80 years
Eligible for statin therapy
9,689 screened
Serum ALT levels <2 × the upper limit of normal (ULN)
Open-label period with blinded endpoint evaluations
Atorvastatin 80 mg/day
8,888 Patients
Randomised
Simvastatin 20 mg/day
(titrated to 40 mg/day at week 24)*
4.8 Year Follow-up
* Simvastatin dose was increased to 40 mg/day at week 24 in patients whose plasma TC remained >5.0 mmol/L or whose LDL-C remained >3.0 mmol/L
Pedersen TR et al. Am J Cardiol 2004 ; 94: 25

26. IDEAL Study: Post-hoc analysis in CVD patients with altered liver biochemistry
Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in
coronary heart disease patients with mild-to-moderate baseline elevations in
alanine aminotransferase levels
Primary endpoint: reduction in recurrent CVD events
Int J Cardiol Oct 9;168(4): 26

27. Change in ALT levels according to statin treatment
Simva: σιμβαστατίνη, Atorva: ατορβαστατίνη, ULN,: ανώτερο φυσιολογικό όριο
Mean change of ALT during the study
Tikkanen MJ, et al. Int J Cardiol Oct 9;168(4):

28. Effect of therapy on CVD events in patients with increased or normal ALT levels
Of 8863 IDEAL patients with non-missing baseline ALT values, 7782 (87.8%) had an ALT b ULN and 1081
(12.2%) had an ALT ≥ ULN. In patients with elevated baseline ALT, major CV event rates were 11.5% for simvastatin and 6.5% for atorvastatin, indicating a significant risk reduction with intensive statin therapy (hazard
ratio, 0.556; 95% confidence interval, 0.367–0.842; p = ). Significant heterogeneity of treatment effect
was observed for major CV events, cerebrovascular events, and major coronary events, with a trend towards
treatment difference for the other outcomes, indicating a greater benefit with atorvastatin in the elevated
ALT group.
The CV benefit of intensive lipid lowering with atorvastatin compared with a more moderate regimen
with simvastatin was generally greater in patients with mildly-to-moderately elevated baseline ALT than
patients with normal baseline ALT. Moderate elevations in liver enzyme levels should not present a barrier to
prescribing statins, even at higher doses, in high-risk patients.
Tikkanen MJ, et al. Int J Cardiol Oct 9;168(4): 28

29. Effect of rosuvastatin (10 mg) on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia A preliminary report.
Konstantinos Kargiotis, Niki Katsiki, Vasilios G. Athyros,
Olga Giouleme, Kalliopi Patsiaoura, Evangelia Katsiki,
Dimitri P. Mikhailidis, Asterios Karagiannis.
Current Vascular Pharmacology 2014 May;12(3):

31. After 1 year monotherapy
Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome
Before
After 1 year monotherapy
World J Gastroenterol. 2015 Jul 7;21(25):

32. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome
World J Gastroenterol. 2015 Jul 7;21(25):

33. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome
World J Gastroenterol. 2015 Jul 7;21(25):

34. NAFLD – (CVD) Prognosis
64-85% increase in CVD death risk
NASH with liver fibrosis
Athyros VG et al (2015). Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease World J Gastroenterol Jun 14;21(22):
Kim D, et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013; 57:

35. NAFLD/NASH - Conclusions
NAFLD affects up to 35% of the Western Populations
Steatosis is relatively benign, but NASH has significant liver and CVD morbidity/mortality risk
Insulin resistance and cellular damage are the key pathogenetic mechanisms
Sustained gradual weight loss and exercise are hallmark therapies
Insulin sensitizers, cytoprotectants, and antioxidants may play role in the future for those who fail conservative therapy
Statins may be a very promising treatment solution