Nonalcoholic fatty liver disease - A multisystem disease?

Table 1 Principal retrospective studies of cardiovascular diseases mortality and morbidity risk in patients with nonalcoholic fatty liver disease (published in the past 10 years)

Ref.	Study design	Study size	Diagnosis of NAFLD	Follow-up duration (yr)	Adjusted clinical variables	Major findings
Ekstedt et al[13]	Retrospective; Hospital-based	129	Histological	13.7	Matched for gender, age and country	NASH subjects (not those with simple steatosis) had higher rates of all-cause, CVD and liver-related mortality than the general population
Stepanova et al[15]	Retrospective; Population-based	289	Histological	6.25	No adjustments made	Higher risk of liver-related mortality in NASH than non-NASH. NAFLD and type II diabetes had the highest risk for overall and liver-related mortality
Ekstedt et al[14]	Retrospective; Community-based	229	Histological	26.4		NAFLD patients had increased risk of death, with a high risk of death from CVD and liver-related disease
						Fibrosis stage predicted all-cause, CVD and liver-related death
Rafiq et al[10]	Retrospective; Hospital-based	173	Histological	13	No adjustments made	Higher liver-related mortality but no difference in overall mortality (NASH vs simple steatosis)
Soderberg et al[11]	Retrospective; Hospital-based	118	Histological	18	Matched for gender, age and year	Increased total mortality in NAFLD was predominantly CV-related compared with matched reference population
Dunn et al[16]	Retrospective cohort	2343	Computed tomography	5		No significant association was found between NAFLD and risk of all-cause mortality and cause-specific
						(CVD, cancer and liver) mortality and morbidity. NAFLD patients
						(steatosis > 30% on imaging) averaged 8 yr younger than those without NAFLD

NAFLD: Nonalcoholic fatty liver disease; CVD: Cardiovascular diseases; NASH: Nonalcoholic steatohepatitis.

Table 2 Principal prospective studies of cardiovascular diseases mortality and morbidity risk in patients with nonalcoholic fatty liver disease (published in the past 10 years)

Ref.	Study design	Study size	Diagnosis of NAFLD	Follow-up duration (yr)	Adjusted clinical variables	Major findings
Targher et al[17]	Prospective; Hospital-based	2013	Ultrasound	6.5	Gender, age, BMI, smoking status, diabetes duration, alcohol consumption, BP, HbA1c, TG, HDL, LDL cholesterol, GGT, use of medications (anti-hyperglycemic, antihypertensive, lipid-lowering, or anti-platelet drugs), and metabolic syndrome	NAFLD was independently associated with increased risk of nonfatal CVD events and CVD mortality
Hamaguch et al[18]	Prospective; Community-based	1637	Ultrasound	5.0	Gender, age, BMI, smoking, alcohol consumption, BP, TG, HDL, LDL cholesterol, MetS	NAFLD was independently associated with increased risk of nonfatal CVD events
Haring et al[19]	Prospective; Community-based	4160	Ultrasound	7.3	Gender, age, WC, diabetes, alcohol consumption, BP, physical activity, education level, civil status, equalized income, and Functional Co-morbidity Index	NAFLD was independently associated with increased risk of all-cause and CVD mortality in men
Wong et al[24]	Prospective; Hospital-based	612	Ultrasound	1.8	Gender, age, BMI, WC, smoking status, diabetes, alcohol consumption, BP, fasting glucose, ALT, TG, HDL, LDL cholesterol, creatinine	NAFLD was independently associated with an increased prevalence of CVD at baseline, but there was no significant association between NAFLD and risk of incident CVD events
Lazo et al[28]	Prospective; Population-based	11371	Ultrasound	14.3	Gender, age, ethnicity, BMI, education, smoking status, BP, alcohol consumption, physical activity, hypercholesterolemia diabetes	Independent increased risk of CVD but no significant association between NAFLD and all-cause and cause-specific (CVD, cancer and liver) mortality
Stepanova et al[22]
Zhou et al[20]	Prospective; Community-based	3324	Ultrasound	4.0	No adjustment made	Patients with NAFLD had about 3-fold higher rates of all-cause and CVD mortality than those without NAFLD
Treeprasertsuk et al[25]	Prospective; Community-based	309	Ultrasound/CT	11.5	Gender, age	Framingham risk score accurately predicted the higher 10-yr CAD risk in NAFLD patients and was the only variable significantly associated with the risk of developing new onset CVD events
Kim et al[23]	Prospective; Population-based	11154	Ultrasound and advanced fibrosis score systems	14.5	Gender, age, ethnicity, education, income, diabetes, BP, history of CVD, lipid-lowering medication, smoking status, WC, alcohol consumption, caffeine consumption, total and HDL cholesterol, transferrin saturation, and CRP	NAFLD was not associated with increased all-cause mortality. However, NAFLD with advanced hepatic fibrosis was independently associated with increased risk of all-cause mortality. Increase in mortality was almost entirely from CVD causes

NAFLD: Nonalcoholic fatty liver disease; BMI: Body mass index; BP: Blood pressure; TG: Triglycerides; GGT: Gamma-glutamyl transferase; MetS: Metabolic syndrome; WC: Waist circumference; ALT: Alanine aminotransferase; CRP: C-reactive protein; CVD: Cardiovascular diseases; NASH: Nonalcoholic steatohepatitis.