Nonalcoholic fatty liver disease and vascular disease: State-of-the-art

Table 1 Prospective and retrospective studies of the risk of cardiovascular mortality in patients with nonalcoholic fatty liver disease diagnosed by liver biopsy and/or by ultrasonography

Ref.	Study design	NAFLD patients	Diagnosis of NAFLD	Mean duration follow-up (yr)	Result
Matteoni et al[26], 1999	Retrospective, Hospital-based	132	Histology	18.0	No adjustment made. Higher all-cause, liver-related mortality but no difference in CVD mortality (NASH vs simple steatosis)
Dam-Larsen et al[21], 2004	Retrospective, Hospital-based	109	Histology	16.7	Analysis performed by gender. No difference in all-cause and liver-related or CVD mortality (simple steatosis vs general population)
Adams et al[20], 2005	Retrospective community-based	420	US and/or histology	7.6	Matched for gender, age and country Higher all-causae, liver-related and CVD mortality (CVD is the second cause of death by frequency) in NAFLD patients (especially cirrhosis)
Targher et al[12], 2005	Prospective case-control, Hospital-based	248/21031	US	5.0	NAFLD was independently associated with increased nonfatal CVD and CVD mortality
Ekstedt et al[5], 2006	Retrospective, Hospital-based	129	Histology	13.7	Matched for gender, age and country Higher all-cause, liver-related and CVD mortality (NASH but no simple steatosis vs general population)
Hamaguchi et al[28], 2007	Prospective, community-based	312/16372	US	5.0	NAFLD was independently associated with increased risk of nonfatal CVD events
Targher et al[27], 2007	Prospective, Hospital-based	1421/21031	US	6.5	NAFLD was independently associated with increased risk of nonfatal CVD events and CVD mortality
Haring et al[29], 2009	Prospective, community-based	2490/41603	US and altered GGT	7.3	NAFLD was independently associated with increased risk of all-cause and CVD mortality in men
Rafiq et al[22], 2009	Retrospective, Hospital-based	173	Histology	13.0	No adjustments made Higher liver-related mortality, but no difference in overall mortality (NASH vs simple steatosis)
Söderberg et al[23], 2010	Retrospective, Hospital-based	118	Histology	18.0	Matched for gender, age and year Higher all-cause, liver-related and CVD mortality (NASH but no simple steatosis vs general population)
Lazo et al[32], 2011	Prospective, population-based (third NHANES study population 1988-1994)	2089/113714	US	14.3	Independent increased risk of CVD but no increased risk in all-cause, liver-related and CVD mortality
Stepanova et al[33], 2012	Prospective, population-based (third NHANES study population 1988-1994)	2492/113714	US	14.3	Independent increased risk of CVD but no increased risk in all-cause, liver-related and CVD mortality
Treeprasertsuk et al[31], 2012	Prospective, community-based	309	US, CT, MRI, and or Histology	11.5	Higher 10-Year CVD risk (NAFLD vs general population)
Kim et al[34], 2013	Prospective, population-based (third NHANES study population 1988-1994)	4083/111544	US and NAFLD Fibrosis Score	14.5	US-Defined NAFLD was not associated with overall mortality. NAFLD with advanced fibrosis was independently associated with overall mortality (majority of deaths were due to CVD)
Stepanova et al[25], 2013	Retrospective, Population-based	289	Histology	6.25	No adjustments made Higher risk of liver-related mortality in NASH than non-NASH. NAFLD and type II diabetes highest risk for overall and liver-related mortality

¹Patients with type 2 diabetes;

²Participants of health checkup program;

³West Pomerania population;

⁴United Stated adult population. US: Ultrasonography; CT: Computed tomography; MRI: Magnetic resonance imaging; CVD: Cardiovascular disease; NAFLD: Nonalcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis.

Table 2 Studies of the impaired left ventricular function and disturbance of rhythm in patients with nonalcoholic fatty liver disease

Ref.	Study design	Study population	Study size	Diagnosis of NAFLD	Cardiac parameters examined	Results
Left ventricular function
Goland et al[78], 2006	Retrospective, Case-control study, Hospital-based	NAFLD vs control	38 NAFLD 25 non-NAFLD	US or histology	Complete echocardiographic study, TDI, peak velocities of E and A diastolic filling, E/A ratio, Vp, E', and S' of mitral annulus	NAFLD patients had increased thickening of the intraventricular septum and posterior, lower E diastolic filling velocity, lower E/A ratio, longer, lower Vp and lower E' No differences were found according to LV systolic function
Lautamaki et al[79] 2006	Retrospective, Case-control study, Hospital-based	Patients with type 2 diabetes and CVD	28 low liver fat 27 high liver fat Matched for age, BMI, fasting glucose	H-MRS	Positron emission tomography. Myocardial perfusion was measured with[15O]H2O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[18F]fluoro-D-glucose during hyperinsulinemic euglycemia	Liver fat content is independently associated with impaired myocardial metabolism
Fallo et al[80] 2009	Retrospective, Case-control study, Hospital-based	Never-treated essential hypertensive patients	48 NAFLD 38 non-NAFLD Matched for sex, age and blood pressure levels	US	Complete echocardiographic study: TDI, peak velocities of E and A diastolic filling, E/A ratio, Vp, E', and S' of mitral annulus	NAFLD patients had increased prevalence of left ventricular hypertrophy , diastolic dysfunction that increased according to the degree of NAFLD
Perseghin et al[81] 2008	Retrospective, Case-control study, Hospital-based	Young non-diabetic men	21 fatty liver 21 non fatty liver Matched for age, BMI, blood pressure levels, lipid values	H-MRS	MRI and MRS	No difference in morphological parameters of the LV, systolic and diastolic functions NAFLD patients had reduced values of PCr/ATP ratio
Bonapace et al[17] 2012	Retrospective, Case-control study, Hospital-based	Patients with type 2 diabetes	32 NAFLD 18 non-NAFLD Matched for age, sex, BMI, waist circumference, hypertension, smoking, diabetes duration, microvascular complication status, medication use	US	Complete echocardiographic study, TDI, peak velocities of E and A diastolic filling, E/A ratio, Vp, E', and S' of mitral annulus	NAFLD patients had lower E', tissue velocity, higher E-to-e' ratio, higher time constant of isovolumic relaxation, higher LV-end diastolic pressure (EDP), higher LV EDP/end diastolic volume No difference in morphological parameters of the LV, systolic functions
Hallsworth et al[82] 2013	Retrospective, Case-control study, Hospital-based	NAFLD and healthy controls	19 NAFLD 19 non-NAFLD Matched for age, sex, BMI, weight, and body surface area vs control	H-MRS	MRI and MRS	NAFLD patients had thicker left ventricular walls at systole and diastole, decreased longitudinal shortening, higher concentric remodelling. No difference in PCr/ATP ratio
Disturbance of cardiac rhythm
Targher et al[19] 2013	Prospective, Hospital-based	Type 2 diabetes	281 NAFLD 119 non-NAFLD Adjustments for age, sex, hypertension and electrocardiographic features	US	12-lead electrocardiogram	NAFLD was associated with an increased risk of incident AF

A: Late; BMI: Body mass index; E: Early; E': Early diastolic velocity; H-MRS: Proton magnetic resonance spectroscopy; cardiac MRI: Magnetic resonance imaging; MRS: 31P-MR spectroscopy; NAFLD: Nonalcoholic fatty liver disease; PCr/ATP ratio: Phosphocreatine/adenosine triphosphate ratio; S': Systolic velocity; TDI: Tissue Doppler imaging; US: Ultrasonography; Vp: Flow propagation velocity; AF: Atrial fibrillation.

Table 3 Studies on the association between non-alcoholic fatty liver disease and carotid intima-media thickness in adults: evaluation of the independent predictors for intima-media thickness increase

Ref.	cases n	Cohort	NAFLD diagnosis by	Independent predictors for IMT
Brea et al[40] 2005	80	NALFD and matched population controls	US	NAFLD, age, serum ferritin
Volzke et al[41] 2005	1261 + 2961	German population	US	Hepatic steatosis
Lonardo et al[129] 2006	449	Population/NAFLD	US	Age
Targher et al[52] 2006	145	NAFLD and matched healthy controls	Biopsy	Severity of histological feature of NAFLD
Targher et al[55] 2006	200	Type2 diabetes +/- NAFLD	US	HOMA-IR
Aygun et al[49] 2008	80	NAFLD and matched healthy controls	US	NAFLD and BMI
Sookoian et al[7] 2008 (Meta-regression analysis)	3497	Subjects	US	ALT, GGT, NAFLD
Fracanzani et al[15] 2008	375	NAFLD and matched population controls	US and biopsy	Steatosis, age and blood pressure
Kim et al[42] 2009	1021	Cross sectional	US	NAFLD with MS
Petit et al[58] 2009	101	Type 2 diabetes	MRS	Age, no association with steatosis
Ramilli et al[43] 2009	154	Referred subjects for abdominal US	US	NAFLD
Wang et al[130] 2009	170	Healthy subjects	US	ALT levels
Salvi et al[50] 2010	220	NAFLD, healthy controls		NAFLD and MS
Mohammadi et al[44] 2011	335	Male NAFLD controls	US	NAFLD with or without MS
Neri et al[110] 2011	90	Chronic hemodialysis plus steatosis and healthy controls	US, biopsy	Histological steatosis
Valenti et al[131] 2011	506	NAFLD	US	Systolic blood pressure, glucose, LDL, abdominal circumference, age, ferritin
Huang et al[46] 2012	2590 + 6042	Chinese population +/- NAFLD	US	NAFLD
Kang et al[47] 2012	633	Non-diabetic +/- NAFLD	US	NAFLD with or without MS
Thakur et al[51] 2012	80	Non-diabetic NAFLD, healthy controls	US	NAFLD
Kim et al[132] 2013	769	Healthy subjects	US	Upper normal range of ALT in women with NAFLD
Oni et al[13] 2013 Systematic review	16 studies	Population, cross- sectional, case-control	US, biopsy	Positive association between IMT and NAFLD
Petta et al[126] 2013	162 + 267	NAFLD and validation cohort	Biopsy	PNPLA3 polymorphism in younger patients
Kim et al[133] 2014	4437	Type 2 diabetes	US	NAFDL with insulin resistance

US: Ultrasonography; MS: Metabolic syndrome; IMT: Intima-media thickness; NAFLD: Nonalcoholic fatty liver disease; MRS: Magnetic resonance spectroscopy.