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Cirrhosis Steatohepatitis
- inflammation
- fibrosis
The Brief History of NAFLD
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.
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
Diet Burned
Fatty Liver
FFA VLDL-TG
1st Hit
Susceptibility
Oxidative Stress
Toxins 2nd Hit
Inflammatory
Molecules
Damaged Liver
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
• 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
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