NONALCOHOLIC
FATTY LIVER
DISEASE
HISTORY
1980 ludwing & colleague from
mayoclinic coined the term ,
Non alcoholic steatohepatitis (NASH)
Form of liver disease observed in middle
– aged patients with
abnormal liver biochemical test result &
histologic e/o alcoholic hepatitis , but no
history of alcohol abuse
NASH is a part spectrum of nonalcoholic
fatty liver disease (NAFLD)
NAFLD , encompasses
Fatty liver
NASH
NAFLD – associated cirrhosis
NAFLD
80 %
Isolated fatty liver (IFL)
20%
Fatty liver (steatosis) + parenchymal
inflammation with or without necrosis
NASH
With varying degree of fibrosis cirrhosis
NAFLD
Fat accumalation in more than 5% of
hapatocytes (macrovesicular steatosis)
Alcohol intake
< 40g/d in males
< 20g/d in females
EPIDEMIOLOGY
Prevalence of NAFLD – undefined
Discovered in 4th- 6th decades of life
Increasing frequency in obese
children ,adolescents & in older
Female > male
ETIOLOGY
NAFLD
etiology
Metabolic
Drugs & abnormalitie
toxin s
congenital /
aquired
TABLE 85.1
NAFLD is now considered to be the hepatic
manifestation of the metabolic syndrome
Defined by the presence of 3 or more of
the following:
Abdominal obesity
Hypertriglyceridemia
Low HDL level
Systemic Hypertension
Elevated fasting plasma glucose levels
The risk & severity of NAFLD increases with
number of component of metabolic syndrome
Diabetes mellitus may be an
independent predictor of advanced
NAFLD , including cirrhosis & HCC
PATHOGENESIS
Pathogenesis of NAFLD is poorly understood
multi-hit process
Hepatic steatosis is the hallmark histologic feature
of NAFLD ( first hit)
After steatosis a number of factor including (lipid
peroxidation, oxidative stress , cytokine alteration.
Mitochondrial dysfunction, kupffercell activation)
initiate inflammatory process in patients with
genetic or environmental susceptibility
Leading to fibrosis & cirhhosis
Current evidence points to Insulin
resistance & hyperinsulinemia as the
primary pathogenic factor in steatosis in
most patients with NAFLD .
FIGURE 85.1 PATH
RISK FACTORS
Starvation
Obesity
Metabolic syndrome
Insulin resistance
Low adiponectin level
Leptin resistance
RISK FACTORS
Lifestyle is important
Increase consumption of high fructose corn
syrup
Sugar-containing sodas
Sedentary lifestyle.
Genetic influences
Single nucleotide polymorphisms (SNPs)
CLINICAL AND LABORATORY
FINDING IN NAFLD
SYMPTOMS SIGNS LABORATORY FINDING
COMMON Hepatomegaly •2- to 4-fold elevation of serum
None (48-100%) ALT and AST levels
•AST/ALT ratio <1 in most
patients
•Serum alkaline phosphatase
level is slightly elevated in one
third of patients
•Normal serum bilirubin and
serum albumin levels and
prothrombin time
•Elevated serum ferritin level
UNCOMMON Splenomegaly •Low-titer (<1:320) ANA
Vague RUQ pain Spider •Elevated transferin saturation
Fatigue telangiectases •HFE gene mutation (C282Y)
Malaise Palmar erythema
Ascites
Serum ferritin level may be elevated in
20-50% of patients with NAFLD
May be a marker of more advanced
disease
IMAGING
Hepatic usg- bright liver of increased
echogenicity hepatic steatosis.
Imaging studies may support the
diagnosis
Cant predict severity / cant confirm
diagnosis
GOLD STANDARD investigation
LIVER BIOPSY
HISTO PIC 85.3
DIFFERENCES BETWEEN
IFL AND NASH
To differentiate between IFL and NASH,
liver biopsy is performed
Features in liver biopsy
Degree of steatosis
Degree of lobular inflammation
Balloning of hepatocytes
ASSOCIATION OF NASH
SHARES STRONG ASSOCIATION WITH
Type 2 diabetes mellitus
Obstructive sleep apnea (OSA)
Cardiovascular disease
PCOS
Colonic adenoma
Hypothyroidism
Vit D deficiency
TABLE 85.4
DIAGNOSIS
NON INVASIVE MARKER
OF FIBROSIS
Fibrotest
Highly sensitive for detecting bridging
fibrosis or cirrhosis
NAFLD fibrosis score
( age , BMI, hyperglycemia ,AST/ALT
ratio,platelet count , serum albumin
level)
Fibroscan
NATURAL HISTORY
Benign disease in most patients
Can lead to cirrhosis , liver failure & HCC
Liver related morbidity & mortality
heigher in patient with e/o advanced
NAFLD on the initial liver biopsy
Long term survival of pateint with NASH
is significantly better compared to
alcohol related liver disease
TREATMENT
TREATMENT
Dietary Advice
Weight loss 5%-10%
Moderate caloric restriction with goal
500-750 kcal fewer per day
Eliminate or reduce sfas, high fructose
corn syrup
Omega-3 fatty acid replacement
Regular coffee consumption, 2-3 cups
per day
Exercise Advice
Aerobic and/or resistance training 3-4
times per wk with the goal of 400 kcal
expended
Improves insulin resistance
Best results when leads to weight loss
Bariatric Surgery
Sleeve gastrectomy, RYGB, LABG
PHARMACOLOGICAL
Vitamin E 800 IU daily
Improves NASH but modestly
No fibrosis benefit
Useful in nondiabetic populations
? Prostate cancer risk
Cardiovascular risk
Incretin mimetics (exenatide and
liraglutide)
Improve insulin resistance
Promote weight loss
Modest histologic improvement in small
trials
GI side effects
Ongoing trial with semaglutide
Pioglitazone 30-45 mg daily
Improves NASH, possible fibrosis
improvement
Side effect profile is often prohibitive
Weightgain
Osteoporosis
Edema
Congestive heart failure
Not FDA approved for NASH
Statins
Does not improve NASH histology
Safe in NAFLD
Reduces risk of cardiovascular disease
Ezetimibe
Modest improvement in pilot trial
Safe in NAFLD and can be used for
hyperlipidemia but not as NAFLD/NASH
therapy
CAUSE OF MORBIDITY
NAFLD - Cardiovascular disease
NASH - Liver-related morbidity and
mortality
THANK YOU
