Professional Documents
Culture Documents
Cirrhosis Steatohepatitis
- inflammation
- fibrosis
The Brief History of NAFLD
Diet Burned
Fatty Liver
FFA VLDL-TG
1st Hit
Susceptibility
Oxidative Stress
Toxins 2nd Hit
Inflammatory
Molecules
Damaged Liver
Apoptosis
Hepatocyte Mass
Pathophysiology
• 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
• 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
injury:
– Ballooning
Histology
• Histologic
evidence of
steatohepatitis
may disappear
with progression to
cirrhosis
– Thus, significant
proportion of
cryptogenic
cirrhosis is likely
related to
unrecognized
NASH
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
– Endstage NAFLD accounts for ~5-10% of liver
Matteonitransplants
C, et al. Gastroenterology 1999;116:1413-1419.
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