First Moscow Medical University

Chair of cardiology department of the clinic of the Internal

Medicine

Atherosclerosis is the liver disease

Prof. O. Drapkina
PACE
Moscow 17.10.14
 Mr. Lipoprotein

Professor Emeritus of Medicine

Former Director of Cardiovascular
Research Institute
University of California, San
Francisco

Richard J. Havel
 Lipoprotein Structure
Free
cholesterol

Phospholipids

Apolipoprotein

Triglycerides
Cholesterol esters
 Non-alcoholic fatty liver disease

NAFLD is probably the most common liver

disease in many countries affecting 10%
to 24% of the general population.
There is a direct correlation between body
mass index (BMI) and prevalence and
severity of NAFLD.

Annals of hepatology 2002; 1(1): January-March: 12-19

Nonalcoholic steatohepatitis:
morphology

CMAJ 2005;172(7):899-905
 Prevalence of NAFLD in Europe
Total population (people with normal weight)
15 – 20 % children
20 – 24 % adults – on average 22%
 Increases with age
 Found more frequently in men
 More frequently found among Europeans
than Latin Americans

Fan, 2009, EASL Congress

 NAFLD in Russia

27% of patients seeking help from

general practitioners
(DIREG, 2007)
30787 primary care patients were
enrolled into open multicenter
national-wide prospective study

1. Drapkina O, Ivashkin V, EASL, 2010

2. Drapkina O, Ivashkin V., London, 2009
 NAFLD in Russia

27% of primary care patients in Russia (DIREG, 2007)*

NAFLD was found in

100% of MS patients.
Simple liver steatosis in
58 % , NASH in 42 %
(n=25) of MS patients**

*Ivashkin V, Drapkina O, EASL, 2010,

Drapkina O, Congress on Prediabetes and the Metabolic
Syndrome, 2011
 Obesity - a major ethiologic factor
in NAFLD

The prevalence of fatty liver in the general population is

about 23%
The prevalence among alcoholics reaches 46%, among the
obese - 76%, and among alcoholics  who are
overweight - 95%
Consequently, fatty liver  is caused by  obesity in a greater
extent than by alcohol

1. Drapkina OM, Smirin VI, VT Ivashkin Nonalcoholic fatty liver disease - a modernapproach to the problem. Attending Doctor. 2010. Т. 5. # 5. pg.

57–61.
2. Drapkina OM, Smirin VI, VT Ivashkin Pathogenesis, treatment and epidemiology ofNAFLD - what's new? Epidemiology of NAFLD in Russia.
RMJ. 2011; 28: 1717-1722
Metabolic syndrome today
20 – 30 % of population in
economically advanced
countries, but…
Only 5 % in those with
normal BMI;
22 % of overweighted
patients
60 % of patients with obesity
 THE METABOLIC SYNDROME
Steatohepatitis.. TYPE II
DIABETES MELLITUS

INSULIN
DYSLIPIDEMIA RESISTANCE HYPERTENSION

ATHEROSCLEROSIS
 Visceral obesity

Increase in liver free fatty acids inflow

(VLDL )
Glucose utilization in peripheral tissues
 …  hyperinsulinemia
SMC proliferation with phenotypic
changes Fasting hypertriglyceridemia
 HDL, LDL
 Liver in metabolic syndrome
Liver is a major target of injury in patients with MS

Insulin resistance (≈ 30 % of adults)

Fat accumulation into hepatocytes (gluconeogenesis,

glycogenolysis)

Nonalcoholic fatty liver disease (up to 20 % of adults)

Nonalcoholic steatohepatitis

cirrhosis and end-stage liver disease

American Journal of the Medical Sciences. 330(6):326-335, Dec 2005.
 Cardiovascular diseases and NAFLD:
disease and mortality rates.
Results of prospective studies

Adams LA et al. Gastroenterology 2005;129:113–12

Ekstedt M et al. Hepatology 2006;44:865–873.873
Dunn W et al. Am J Gastroenterol 2008;103:2263–2271
Ong JP et al. J Hepatol 2008;49:608–612 . . . .

Cardiovascular diseases are the main cause

of mortality among patients with NAFLD!
 NAFLD and the risk of
cardiovascular disorders
Great prevalence of traditional risk factors

Obesity, diabetes type Marchesini et al. 2003, Tsai et al. 2008,

II, oxidized LDL, MS Schwimmer et al. 2008

Large prevalence of "surrogate" markers

Increasing thickness Perseghin et al. 2008

of pericardial fat
Endothelial dysfunction Senturk et al. 2008

Framingham risk scale Ioannou et al. 2006

Thickening of the intima-media Targher et al. 2004, Brea et al. 2005,

Volzke et al. 2005, Pacifico et al. 2008
CRP Yoneda et al. 2007
1. Драпкина О.М., Смирин В.И., Ивашкин В.Т. Патогенез, лечение и эпидемиология НАЖБП – что нового? Эпидемиология НАЖБП в
России. РМЖ. 2011; 28: 1717-1722
2. Ghouri N., Preiss D., Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and
clinical perspective of prospective data. Hepatology 2010; 52:1156–1161.
 Cholesterol synthesis

Acetyl CoA

synthesis in the liver (1g) Сholic acid

(500-700 mg)
Exogenously Pool of cholesterol
(300-500 mg) (~140 g)
Bile cholesterol
(600 mg)

Cell membranes (85 mg)

Steroids (40 mg)
 Cholesterol synthesis in NASH

Acetyl CoA

HMGCR
(srebp-2)

Free cholesterol

LAL LDLR

LDL-C
Min et al, Cell Metabol, 2012
18
 NAFLD
The thickness of the epicardial fat  and
DCHF
Endothelial dysfunction
Systemic inflammation
Traditional  atherosclerosis markers

1. Drapkina O 2011
2. Targer G., Day P.D., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363:1341–50.
 Epicardial fat – fat shell of the heart

Epicardial fat and … EF and the myocardium share the same

steatosis of the heart microcirculation, so the epicardial fat should be
considered the true visceral fat depot of the
heart.
MEASUREMENT OF EPICARDIAL FAT
USING
ECHOCARDIOGRAPHY

EF is measured from 2D
parasternal longaxis
at the point on the free
wall of the right
perpendicular to the
aortic valve
 POTENTIAL USES OF ECHOCARDIOGRAPHIC
EPICARDIAL
FAT THICKNESS FOR DIAGNOSIS

14 NASH (biopsy) vs 14 controls

EF was associated with intrahepatic fat accumulation (7.9±2.1
vs 4.1±1.8 mm)
EF was associated with visceral fat, BMI, Waist
Capristo E, 2010
circumferences, HOMA-IR and ALT (p<0.01)

• >7,5-9,5 mm - MS
• 7.9±1.6 (MS) vs. 5.1±1.9 mm (no MS)
• >9,5 mm - IR
• > 7 mm - atherosclerosis and CAD (only in woman)
• >4,5 мм - low coronary flow reserve in women.
• >3 мм - independent risk factor of CAD
 Epicardial fat:
marker of metabolic syndrome, early
vascular damage and diastolic
dysfunction
Patients with MS had significantly higher epicardial fat thickness than
controls (4.95±2.6 and 2.69±1.8 mm, p=0.01).
Age, BMI, waist circumference, fasting glucose, HOMA-IR, intima-media
thickness were significantly higher in subjects with MS and increased
epicardial fat than without, while the echocardiographic diastolic
function index early/atrial peak flow (E/A) was significantly lower.
At multivariate analysis HOMA-IR remained the independent variable
associated with epicardial fat (p=0.04, OR1.8, 95% CI1.037-3.58).

Heart Failure 2012 Congress, Belgrad, 20 May 2012

Drapkina O,Korneeva O
 NAFLD
The thickness of the epicardial fat  and
DCHF
Endothelial dysfunction
Systemic inflammation
Traditional  atherosclerosis markers

1. Drapkina O 2011
2. Targer G., Day P.D., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363:1341–50.
 NAFLD and endothelial
dysfunction
vasodilatation %

Villanova N, et al. Hepatology,2005

 Arterial stiffness and : the Cardio-GOOSE
study
• The study population consisted of 220 participants (123 women), aged between 30 and 70
years, who participated in the GOOSE study. Arterial stiffness was determined by measuring
the carotid-femoral pulse wave velocity (PWV) by means of the PulsePen device. Preclinical
atherosclerosis was detected by carotid intima-media thickness (IMT) measurement.

NAFLD+MS
NAFLD

PWW
Norma

Salvi P., Ruffini R., Agnoletti D. et al. Increased arterial stiffness in nonalcoholic
fatty liver disease: the Cardio-GOOSE study. J Hypertens. 2010; 28(8): 1699-707.
 Arterial stiffness

SI 9,8 м/с RI 25,6%

AIx 31,6% AIx75 21,1%
Spa, мм.рт.ст. 120
 NAFLD
The thickness of the epicardial fat  and
DCHF
Endothelial dysfunction
Systemic inflammation
Traditional  atherosclerosis markers

1. Drapkina O 2011
2. Targer G., Day P.D., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363:1341–50.
 NAFLD - a chronic inflammatory
process
In non-smoking patients with hepatic
steatosis observed elevated levels of CRP,
fibrinogen, v-WF, PAI-1, when compared with
patients without evidence of steatosis
Excluding the impact of other factors such as
age, BMI, BP, insulin resistance, triglyceride
levels

Targher G et al. Diabet Med 2005;22:999–1004

 NAFLD - a chronic inflammatory
process
There is a correlation between levels of CRP
and IL-6 and the degree of inflammation
and fibrosis in NAFLD 

Wieckowska A et al. Am J Gastroenterol 2008;103:1372–1379

 Statins and NAFLD
Safety: ↑ AST / ALT in 1-3% of patients

There are no convincing data on the relationship

between ↑ AST / ALT and histologicallyverified liver
damage against statins

Atorvastatin (80 mg) reduced the AST / ALT,
and possibly reduced steatosis[Gomez-Dominguez, 2006;
Kiyici, 2003]
Pravastatin (80 mg) reduced ALT [Lewis et al. 2007]
Possible mechanisms
- Reduction of TNF-alpha, IL-6, CRP,
- Reduced delivery of FFA to the liver, the effect on insulin
through adiponectin  
Statins are safe to use (GREACE study)

N= 1600

0 18 36
Time (months)

Athyros et al, Lancet. 2010 Dec 4;376(9756):1916-22.

 Statins for NAFLD: molecular mechanisms

• Effect on the metabolism of the

gene sonic hedgehog (sHh)
- progression of fibrosis
and reparative mechanisms

• Inhibition of sHh reduces weight
gain from dietary habits

• sHh: effects on stellate cells
and possible involvement in the
pathogenesis of C sonic hedgehog

Argo C.K., Loria P., Statins in liver disease: a molehill,

an iceberg, or neither? // Hepatology. 2008 Aug;48(2):662–9.
The Liver-Heart Connection