NASH

Non-Alcoholic Fatty Liver

Disease
(NAFLD)
• An epidemic of new millenium.
• A new consequence of the obesity
epidemic.
• Represents a spectrum of conditions
characterized by macrovesicular
hepatic steatosis in the absence of
significant alcohol intake.
• Includes histological pattern:
– Simple steatosis( without inflammation)
– Steatohepatitis(NASH) with inflammation
fibrosis & cirrhosis
 Non-Alcoholic Fatty Liver Disease
(NAFLD)

Normal liver Fatty liver (Steatosis)

Cirrhosis Steatohepatitis
- inflammation
- fibrosis
 The Brief History of NAFLD

1979 ~8 papers published

1998 First NIH conference
1999 First Clinical Trials
2002 ~60 papers published
6 Release of first book on NAFLD/NASH
2005 ~354 papers published

Fatty Liver Disease: NASH and Related Disorders

Blackwell Publishing, 2005
 Prevalence of fatty liver
• “Estimated” prevalence is 2.8 - 25 %
of population
• 20 to 30 % adults in western
countries have NAFLD of which 2 to 3
% are NASH
(Imaging & autopsy
study)
• Steatosis seen in 80 % obese
patients

• NASH seen in 9 - 30 % obese

Hepatology
2003
 NAFLD

1. Most common of all liver disorders.

2. Frequent cause of chronic liver
disease.
3. Present in 3% of children and >50% of
obese children.

Fatty Liver Disease: NASH and Related Disorders

Blackwell Publishing, 2005
 Prevalence of NAFLD In General
Population In Asian Pacific Region

Name of the Percentage NAFLD in

Country Adults
Japan 9 – 30%
China 5 – 18%
Korea 18 %
India 5 – 28%
Indonesia 30%
Malaysia 17 %
Singapore 5%
 Prevalence of NAFLD In High Risk
Population In Asian Pacific Region

Name of the Diabetes Obesity Dyslipidemia

country
Japan 40-50% 50-80% 42-58%
China 35% 70-80% 57%
Korea 35% 10-50% 26-35%
India 30-90% 15-20% NA
Indonesia 52% 47% 56%
 Aetiological Classification
• Primary NAFLD: associated with
metabolic syndrome.

• Secondary NAFLD: includes fatty liver

diseases with a proximate causes.
 Types of NAFLD
Primary Secondary
1 Insulin resistance 1 severe weight loss
Obesity jejunoileal bypass
Diabetes gastric bypass
Hypertriglyceridemia severe starvation
Hypertension 2 total parenteral
nutrition
3 Iatrogenic
Amiodarone
Diltiazem
Tamoxifen
Steroids
HAART
3 Refeeding syndrome
4 Toxic exposure
Hydrocarbon ,
yellow phosphorus
5 Disorders of lipid
metabolism

Abetalipoproteinemia
 Morbid Obesity
• Four studies evaluating > 600
morbidly obese patients undergoing
gastric bypass
– All patients underwent intraoperative
liver biopsies
– Prevalence of NAFL ranged from 30-90%
and NASH was documented in 33-42%. 
– > 2/3 of morbidly obese patients
undergoing gastric bypass surgery
have NAFL/NASH
Abrams GA, et al. Hepatology 2004;40:475-483; Frantzides CT, et al. J
Gastrointest Surg 2004;8:849-855; Dallal RM, et al. Obes Surg 2004;14:47-53;
Beymer C, et al. Arch Surg 2003;138:1240-1244.
 Type 2 Diabetes Mellitus
• Recent study surveyed 100 patients
with type 2 DM and used U/S to
screen for NAFLD
– Detected fatty liver in 50% of patients
– Performed subsequent liver biopsy in
those with NAFLD:
• NAFL: 13%
• NASH: 86%
• Fibrosis: 22%
Gupte, et al. J Gastro Hepatol 2004;19:854-858.
 Dyslipidemia
• Canadian study used U/S to screen
95 adults with dyslipidemia
– Detected fatty liver in 50%
– Steatosis was particularly common in
individuals with moderate to severe
hypertriglyceridemia or mixed
dyslipidemia
– Hypertriglyceridemia and mixed
dyslipidemia increased the risk for
hepatic steatosis by ~5-fold
Assy N, et al. Dig Dis Sci 2000;45:1929-1934.
Pathophysiology

Salgado W, et al. Acta Cir. Bras. 2006; 21.

 Two-hit Hypothesis

Diet Burned
Fatty Liver
FFA VLDL-TG
1st Hit
Susceptibility
Oxidative Stress
Toxins 2nd Hit
Inflammatory
Molecules

Damaged Liver

Donnelly et al. J. Clin. Invest. 113: 1343, 2005

Day and James. Gastroenterol. 114: 842, 1998
 Fatty Liver

2nd Hit 2nd Hit

Sat FA
Liver Damage Liver Damage

Apoptosis

Hepatocyte Mass
 Pathophysiology
• Other factors involved in NASH
pathogenesis
– Bacterial overgrowth
• Increased hepatic oxidative stress
• Production of ethanol and TNF-α
• Direct activation of inflammatory cytokines
and liver macrophages via release of
lipopolysaccarides
– Leptin
– Obesity gene
• Regulates food intake and body composition
• Leads to hepatic steotosis by promoting
insulin resistance or by modulating insulin
signalling in hepatocytes
 Pathophysiology: others

• Serum and liver iron

– Mitochondrial β oxidation leads to
generation of hydrogen peroxide
– In presence of increased iron hydrogen
peroxide converted to hydroxyl free
radicles
– This leads to oxidative stress and
hepatocellular injury
 Pathophysiology: others

• TNF- α
– Corelates with obesity
– Derives from adipose tissue
– Decrease phosphorylation of insulin
receptor
– Reduce expression of GLUT-4
– Contributes toward insulin resistence
– Also causes chemotaxis, activation of
stellate cells, Mallory hyaline formation,
collagen synthesis
 Clinical Presentation
• Variable clinical presentation
• Typically asymptomatic, but may
have hepatomegaly and abdominal
discomfort
• Liver enzymes may be normal in
>75% of cases, making them
insensitive in detecting NAFLD
– When increased, usually only modestly
and limited to aminotransferases
– ALT upper limits of normal: <30 in M,
<20 in F
 Natural history and clinical
outcomes of NASH
20% 30—40%
NASH CIRRHOSIS Liver
related Death

Sub acute HCC

Post-OLTX
Failure
recurrance
 Diagnosis
• Cf
• h/o
• Disturbed liver enzymes

• Radioimaging
• Biopsy
 Lab Studies
• No laboratory studies can help definitively
establish a diagnosis of fatty liver or NASH.
• Aminotransferases
– Elevated AST or ALT
– As much as 10-fold
– In the absence of cirrhosis, an AST-to-ALT ratio
of greater than 2 suggests alcohol use,
whereas a ratio of less than 1 may occur in
patients with NASH.
• Alkaline phosphatase
– Can be elevated
– Usually less than 2 to 3 times normal
 Diagnosis
• Diagnosis of NAFLD can often be
made by imaging studies, including
U/S, CT or MRI – detects presence of
fat
 Diagnosis (cont.)
• MR spectroscopy accurately measures
hepatic triglyceride content
– Has advantage over U/S, CT and MRI as it
is quantitative rather than qualitative
 Diagnosis (cont.)
• No imaging studies can differentiate
between the histological subtypes of
benign steatosis or aggressive NASH,
or stage the degree of fibrosis
– Need tissue for staging
and to make diagnosis
of NASH
• Liver biopsy
– A liver biopsy and histopathological
examination are required to establish
the diagnosis.
– The diagnosis should be considered in
all patients with unexplained elevations
in serum aminotransferases (eg, with
findings negative for viral markers or
autoantibodies or with no history of
alcohol use).
• Doing liver biopsy is controversial
– Arguments favoring
• Exclusion of other cause
• To distinguish steatosis from NASH
• Estimation of prognosis
• Determination of progression
– Arguments against biopsy
• Good prognosis
• Lack of effective therapy
• Risk & cost associated with biopsy
 Histology
• Histologic
diagnosis of
NAFL requires
presence of ≥ 5%
steatosis
– Indistinguishable
from alcoholic
fatty liver
 Histology
• NASH involves
presence

of steatosis with
evidence

of inflammation
and

hepatocyte
 Histology
• Histologic
evidence of
steatohepatitis
may disappear
with progression
to cirrhosis
– Thus, significant
proportion of
cryptogenic
cirrhosis is likely
related to
unrecognized
 COMPLICATION
• Cirrosis
– Risk- 8 to 15%

• Hepatocellular carcinoma
– Risk: 1-2%
 NASH Criteria (AGA
guidelines)
• Characteristic liver biopsy that shows fatty
change with inflammation
– Indistinguishable from alcoholic hepatitis
• Convincing evidence of negligible alcohol
consumption (less than 20g alcohol per
day)
– Detailed history obtained independently by 3
physicians, interrogation of family members
• Absence of serologic evidence of Hep B or
Hep C infection
– Should not exclude those with evidence of past
Hep B infection, but should exclude patients
with positive HBs Ag or HCV Ab
• Clues for severe NASH
– Old age(>50 yrs)
– Presence of diabetes
– Pesence of obesity
– AST/ALT > 1
– ALT >2 times of normal
– TG >1.7m mol/L
 Prognosis
• Patients with bland steatosis (NAFL) have
a benign liver-related prognosis
– 1.5% develop cirrhosis
– 1% die from liver-related causes over 10-20
years
• Almost 30% of patients with NASH and
fibrosis become cirrhotic within 5-10 years
– Those with biopsy-proven NASH have a liver-
related death rate of ~10%
• NASH cirrhosis may develop into HCC
– ~13% of cases of all HCC are related to NASH
cirrhosis
Matteoni C, et al. Gastroenterology 1999;116:1413-1419.
– Endstage NAFLD accounts for ~5-10% of liver
 Treatment
• Aim to improve insulin sensitivity and
modify underlying metabolic risk
factors
– Diet and exercise
– Insulin Sensitizing Agents (metformin,
TZD)
– Lipid lowering medications (statins,
fibrates)
• L-Carnitine supplementation
McCullough AJ. N Engl J Med 2006; 355: 2361-3.
 Treatment
• Lifestyle modification
– Diet and exercise
• Weight reduction
• Insulin sensitizers
– Metformin
– Troglitazone
– Rosiglitazone
– Pioglitazone
• Lipid Lowering agents
• Antioxidants
– Vitamin E
– Vitamin C
• Hepatoprotective agents
– Betaine
– Ursodeoxycholic acid
– Pentoxyfylline

• Angiotensin-converting enzyme inhibitors

• Probucol
 Treatment (cont.)
• Beneficial according to preliminary
studies:
– Insulin sensitizers: TZD > metformin
• Benefit unproven by preliminary
studies
– Lipid lowering agents
– Antioxidants
– Probiotics (animal models only)
• Not beneficial
– Ursodiol
 Betaine
• Metabolite of Choline
• increases S-adenosylmethionine
levels (SAM)
• protect against steatosis and
decrease oxidative stress.
 Pentoxifylline
• Production of tumour necrosis factor-
alpha is one of the primary events in
many types of liver injury
• Patients with NASH have been shown
to have higher levels of TNF-alpha.
• Biochemical improvement was
demonstrated in certain study
 Probucol
• Probucol is a lipid-lowering drug with
potent antioxidant properties that
tends to accumulate in fatty tissues
• Significant improvement in ALT levels
with normalization of
aminotranferases