Transcript Non-Alcoholic Fatty Liver Disease (Sept 2008)

NAFLD
Dr Allister J Grant
Consultant Hepatologist
How common is NAFLD?
• The most common cause of abnormal liver
function tests in the United States.
• Estimated 30.1 million with NAFLD and 8.6
million with NASH
• Affects 10-24% of the population
• 58-74% of the obese population
• Affects 2.6% of children
• 23-53% of obese children
Age Adjusted Prevalence (%) of
Overweight and Obese Americans Aged 20-74y
Dallas Heart Study Results
Healthy
Liver fat
< 5.5%
Fatty
Liver fat
> 5.5%
Steatosis = 31%
Mean BMI =29
Liver enzymes NORMAL in most (79%) with steatosis
Fatty Liver
• Better detected by abdominal imaging than
blood tests
• Common in individuals who are
– Overweight/obese
– Type 2 diabetic
– Dyslipidaemic
– Regular alcohol consumers
Hepatic Steatosis
Gender Disparities in Whites
FLD
45%
M
42%
F
M 24%
F
Hispanics
Whites
24%
M
F
Blacks
Non Alcoholic Fatty Liver Disease (NAFLD)
Spectrum of Hepatic Pathology
Steatohepatitis
Steatosis
Cirrhosis
Hepatocellular
carcinoma
NAFLD
Fatty Liver:
Macrovescicular steatosis with nucleus
positioning at cell periphery
NASH:
Mallory bodies, ballooning degeneration,
lobular neutrophil inflammation
and perisinusoidal fibrosis
AGA Technical Review on Nonalcoholic Fatty Liver Disease
Gastroenterology 2002;123:1705-1725
NASH
Steatosis
Cirrhosis
NASH- Peri-sinusiodal fibrosis
Grading and Staging of NAFLD
Brunt et al Am J Gastro 1999
Grading NAFLD
1.Macrovescicular steatosis
Grade 0: None
Grade 1: Up to 33%
Grade 2: 33%-66%
Grade 3: >66%
2. Necroinflammatory activity
Mild, Mod, Severe
NAFLD Diagnosis
Role for Liver Biopsy?
Role for Liver Biopsy?
• Confirmatory test
Resolves diagnostic confusion
(e.g. AIH, HH)
Refines staging
Sensitive for “subclinical” fibrosis
Imperfect (sampling error)
• Invasive procedure
Significant mortality.
Diseases associated with Steatohepatitis
1.Alcoholism
2.Insulin resistance
a.Metabolic Syndrome
i.Obesity
ii.Diabetes
iii.Hypertriglyceridemia
iv.Hypertension
b.Lipoatrophy
c.Mauriac Syndrome
d.PCOS
3.Disorders of lipid metabolism
a.Abetalipoproteinemia
b.Hypobetalipoproteinemia
c.Andersen’s disease
d.Weber-Christian syndrome
4.Total parenteral nutrition
5. HCV
6.Severe weight loss
a.Jejuno-ileal bypass
b.Gastric bypass
c.Severe starvation
7.Iatrogenic
a.Amiodarone
b.Diltiazem
c.Tamoxifen
d.Steroids
e.HAART
f. tetracycline
g.glucosamine
8.Refeeding syndrome
9.Exposure to toxic agents
a.Environment
b.Workplace – Sb,Th,Ba
NAFLD
• NAFLD is a spectrum of disease which includes Fatty liver
disease and NASH, but only NASH is known to progress to
cirrhosis.
2nd hit
Fatty Liver
Obese BMI>28
Centipetal (apple)
Bright liver on USS
Insulin Resistance
Normal ALT
NASH
Obese BMI>28
Bright liver on USS
Abnormal ALT
Features of metabolic
syndrome
Dyslipidaemia
DM
HBP
Cirrhosis
Bright/ small liver on USS
+ splenomegaly
Abnormal ALT
Thrombocytopenia
Obesity
Poorly controlled DM
Poorly controlled lipids
Hypertension
High Fat/CHO Diet
Lack of Exercise
Pathogenesis of NASH
Hepatic
Steatosis
FFA oxidation
Lipogenesis
Lipid Export
White
Adipose
Tissue
Adipokines- adiponectin
Cytokines- TNF
IL-6
Insulin
Resistance
2nd Hit
NASH
Peroxidation of
hepatocyte membrane
Cytokine release
Stellate cell activation
Endotoxin
Cytokines
ROS
Toxins
Oxidative
Stress
High Fat/CHO Diet
Lack of Exercise
Pathogenesis of NASH
Hepatic
Steatosis
FFA oxidation
Lipogenesis
Lipid Export
CellularFFA
IB and NFB
activation
Insulin
Resistance
IL6 &TNFα
High Fat/CHO Diet
Lack of Exercise
Pathogenesis of NASH
Hepatic
Steatosis
FFA oxidation
Lipogenesis
Lipid Export
CellularFFA
GLUT 4 activity
Insulin
Resistance
Reduced glucose
entry into cells
Diet &Exercise
Orlistat
Sibutramine
Rimonabant
High Fat/CHO Diet
Lack of Exercise
Treatment Strategies
In NASH
Hepatic
Steatosis
Diet &Exercise
Bariatric Surgery
Statins
Gemfibrozil
Metformin
Pioglitazone
Rosiglitazone
FFA oxidation
Lipogenesis
Lipid Export
Adipokines- adiponectin
Cytokines- TNF
IL-6
Probiotics
Antioxidants
Insulin
Resistance
2nd Hit
NASH
White
Adipose
Tissue
Peroxidation of
hepatocyte membrane
Cytokine release
Stellate cell activation
Endotoxin
Cytokines
ROS
Toxins
Oxidative
Stress
Natural history
• Simple steatosis: relatively benign “liver” prognosis
with a risk of developing clinical evidence of cirrhosis
over 15–20 years in the order of 1%–2%.
• NASH and fibrosis: risk of progress to cirrhosis
between 0% at 5 years to 12% over 8 years.
• Cirrhotic: high risk of developing hepatic
decompensation and of dying from a liver-related
cause including HCC.
NASH
Affects 3.5-5% of the population
The rates of progression to cirrhosis have been estimated at
between 5% and 20% over 10 years.
There aren't any non-invasive means of predicting which
patients are at risk of progression, and there are no agreed
guidelines on how to monitor progression.
Current Management of |NAFLD and NASH. APT. Younossi Z: 2008
Initial Investigation
• Look for risk factors
– BMI, DM, HBP, Lipids,FHx, Drugs, Alcohol
• Liver screen
– Including Glc/GTT/HbA1c/Lipids/AST
– Pl, Alb, INR
• USS
– Spleen size, fatty liver, collaterals
Managemant of NASH
• The patient should lose weight and exercise
• Pharmacological treatment of Insulin-resistance
• Treatment of Hyperlipidaemia
• Hepatocyte-Protective treatment
NASH Management
1) All patients should be encouraged to exercise, as there is good evidence that even in
the absence of weight loss exercise improves NASH.
Obese Patients
Weight reducing diet (aim for 10%, 1-2lb per week)
In patients with BMI>28 with risk factors, or >30 without risk factors, consider
treatment with Orlistat.
2) Diabetic Patients
Good diabetic control (HbA1c <6.5%)
Metformin
Thiazolidinediones (rosiglitazone and pioglitazone)
Dietician for re-education.
Diabetologist if glucose control is difficult.
NASH Management
3) Patients with Hyperlipidaemia and abnormal LFT’s
Dyslipidaemia should be aggressively addressed
Dietician Review
Hypercholesterolaemia -Statins
Hypertriglycerideaemia -Fibrate.
Lipid Clinic
Avoid Drugs
amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic
estrogens, tamoxifen
Antioxidants?
Thank you