Dr.K.

PANDURANGA RAO
Professor & HOD
Department of Gastroenterology
Osmania General Hospital.
Hyderabad.
Visit: www.drsarma.in

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• Ludwig Nonalcoholic steatohepatitis (NASH) for
alcohol like liver disease that developed in persons
who were not heavy drinkers (<20 grams/day for men
and <10 grams/day for women).

• Fatty liver disease more than 5% of the hepatocytes

containing fat / more than 5% of the liver weight due
to fat.
• Non Alcoholic Fatty Liver Disease – NAFLD
• Non Alcoholic Steato Hepatitis – NASH
• Non Alcoholic Cirrhosis (> 60% of cryptogenic)
These three are a consequence of Obesity & MS
• Alcoholic Fatty Liver Disease – ALFD

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• 1979 8 papers published
• 1998 First NIH conference
• 1999 First Clinical Trials
• 2002 > 60 papers published
• 2004 First book on NAFLD/NASH
• 2005 > 354 papers published
• Today > 1000 papers published

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1. Most common of all liver disorders & Abn. LFT.
2. Most frequent cause of chronic liver disease.
3. Affects about 10-24% of general population.
4. Up to 75% of individuals with Obesity, T2DM.
5. Children 3% and > 50% of obese children.

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 Diet Fats Burnt
Fatty Liver VLDL-TG
FFA

Susceptibility 1st Hit

Oxidative Stress
Saturated >
Unsaturated
Toxins 2nd Hit
Inflammatory
Molecules
Apoptosis
Damaged Liver
Donnelly et al. J. Clin. Invest. 113: 1343, 2005
Day and James. Gastroenterol. 114: 842, 1998
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Normal 1st HIT NASH 2nd HIT

FAT >5% Inflammation Scarring DCLD

NAFLD IR and MS Cirrhosis

IR and MS  CV Risk

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 Simple Steatosis or Fat Deposition of > 5%
Benign course 3% develop cirrhosis

NASH – Ballooning, Inflammation,  Fibrosis

Worse prognosis 30% develop cirrhosis

Severe NASH with fibrosis – 75% go in for cirrhosis

5 yr survival 67% 10 yr survival 45%

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Waist Circum  90 (M), 80 (F)

Triglycerides >150 mg

HDL <40 (M) < 50 (F)

2 of 5 Dysglycemia FPG >100 or DM

Hypertension >130 or 85

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Rx. for any of the above conditions
 Insulin Resistance Syndrome

Visceral Steatosis
Obesity NASH

NIDDM TG HDL Hypertension

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NAFLD is the Hepatic
component of MS
NAFLD IR

DM MS

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 These are ONE If we find - look for

IR
98%

NASH

DM MS
70% 85%

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• 75% patients of NAFLD/NASH are women
• All ages are affected – Risk of NASH  with age
• Caucasians > Hispanics > Africans > Asians
• Indian Fatty Liver – BMI < 25, Non obese,  WC
• OSAS increases NASH; Its Rx. Reduces NASH

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A. Mayo Clinic Score for NASH (Next slide)
B. HAIR index (HTN; ALT > 40; Insulin Resistance)
≥ 2 are 80% Sensitive, 89% Specific of NASH
C. BAAT index (BMI > 28; Age > 50; ALT > 2 times the
normal; increased Triglycerides)
≤ 1 has 100% Negative Predictive Value for NASH

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 Six Parameters included Calculation of the score

A constant is used [- 1.675 +

1. Age (in years) (0.037 x Age) +
2. BMI (kg/m2) (0.094 x BMI) +
3. IFG or DM (1.13 x 0 or 1 for IFG/DM) +
4. SGOT / SGPT {(0.99 x (SGOT/SGPT)} –
5. Platelet count (109/l) (0.013 x Platelet count) –
6. Serum Albumin (g%) (0.66 x Albumin)}]
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- 1.455 or lower score No fibrosis / NASH

- 1.456 to + 0.676 Probable NASH

More than + 0.676 NASH Definite

Paul Angelo et al – Hepatology, Vol. 45, No. 4, 2007, p 846 - 854

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• Ht, Wt, BMI, WC • Hemogram complete
• Blood Pressure • USG Abdomen
• OGTT – IR, DM • HCV, HBsAg, ANA
• Fasting Lipid Profile • Liver Biopsy, CT Abd
• SB, SGPT, SGOT, AKP, • F and PP C-peptide
GGT, Serum Proteins • aPTT, PT, body fat

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RF/Metabolic Fatty Liver on Elevated
Syndrome Imaging Transaminases

Measure GOT/GPT, R/O other

Image liver Image liver
Assess Alcohol use Liver disease

Excessive Limited
Neg Pos Neg
Alcohol Alcohol

AFLD NAFLD

Reproduced from AGA Guidelines

Biopsy 22
• USG is enough; CT if USG is not informative

• Imaging can detect > 33% fat on liver biopsy

• Cannot differentiate Steatosis from steatohepatitis

• Liver biopsy is usually not needed to diagnose fatty liver

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• HBV – HBsAg, (HBV DNA)
• HCV – anti-HCV, (HCV RNA)
• Autoimmune hepatitis – ANA
• Alfa-1 anti-trypsin deficiency
• Wilson’s disease
• Hepatic malignancy
• Hepatic infection; Biliary disease

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Diffuse fat accumulation in the liver at US.
The echogenicity of the liver is greater than that of the
renal cortex (rc). Intrahepatic vessels are not well depicted.
The ultrasound beam is attenuated posteriorly,
and the diaphragm is poorly delineated.
Diffuse fat accumulation in the liver at unenhanced
CT. The attenuation of the liver (15 HU) is
markedly lower than that of the spleen (40 HU).
Intrahepatic
vessels (v) also appear hyperattenuated in comparison
with the liver.
Diffuse fat accumulation in the liver at MR imaging.
Axial T1-weighted GRE images show a marked
decrease in the signal intensity of the liver on the opposed
phase image (a), compared with that on the in-phase
image (b).
• Liver biopsy gold standard for evaluation of
degree of hepatic necroinflammation and
fibrosis.
– Should be considered in situations when there is a
diagnostic uncertainty
– For assessment of histological disease severity in
patients with suspected advanced fibrosis
– In patients undergoing laparoscopy,
cholecystectomy, or bariatric surgery
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2020 g Mallory Bodies - Hyaline

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Steatosis Inflammation Ballooning
• 0 : < 5% • 0 : No foci • 0 : None
• 1 : 5 – 33% • 1 : < 2 / 200x • 1 : Few cells
• 2 : 33 – 66% • 2 : 2-4 / 200x • 2 : Many cells
• 3 : > 66% • 3 : > 4 / 200x prominent
ballooning.

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NAS  5 • NASH

NAS 3-4 • Probably NASH

NAS  2 • No NASH

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• Consists of treating liver disease as well as
the associated metabolic comorbidities
such as obesity, hyperlipidemia, insulin
resistance and T2DM
• Dietary restrictions and exercise cornerstone
of NAFLD management.

• Patients should be set on a target of BMI of 22

BMI over this - critical BMI for development of
fatty liver

• Lifestyle modification may reduce

aminotransferases and improve hepatic steatosis
• Dietary recommendations individualized
• Aim achieve energy deficit of 500–1000 kcal/day
depending on the patient’s BMI

• Saturated fat < 30% of the total energy intake;

reduced intake of refined sugars with an increase in
soluble fiber intake.
Diet
 No association between total caloric or protein vs
severity of NAFLD
Soiga et al, Dig Dis Sci 2004

 Low carbohydrate and low fat diet

– Weight loss
– Lower BMI
– Lower insulin resistance
– ? Some benefit in NAFLD
Huang et al., Am J Gastroenterol 2005
Daubioul et al. Eur J Clin Nutr 2005
• Physical activity recommended 60
minutes/day for at least 3 days a week with
progressive increase to five times a week
Physical Activity

 Aerobic exercise with dietary restriction can

improve insulin resistance and liver disease in
NAFLD in human
Cinar et al., JGH 2006
Nobili et al., Hepatology
2006
Kugelmas et al., Hepatol
2003
Ueno et al., J Hepatol 1997
Suzuki et al, J Hepatol 1005
Hicknam et al, Gut 2004
Screenivasa et al, JGH 2006
• Metformin : Currently weak but
substantial support for evidence based
recommendations for management of
NAFLD
• Thiazolidinediones: TZDs appear to have
a promising role in the treatment of NASH

• ?? Long term safety of TZDs (

cardiovascular adverse effects including
congestive heart failure, bladder cancer
and bone loss.
• Oxidative stress key mechanism of hepatocellular
injury and disease progression in NASH

• Therapy with vitamin E is associated with a

– Decrease in aminotransferases
– Improvement in steatosis,
– Decrease in inflammation and ballooning
– Resolution of steatohepatitis in adults with NASH,
• NO effect on hepatic fibrosis
• Single large multicenter randomized clinical
trial (RCT) UDCA offers no histological
benefit over placebo in patients with
NASH.

Lindor KD, Kowldey KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of
nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770-8
 Pharmacological Treatment

Controversial or Preliminary No Benefit

Metformin Ursodeoxycholic acid
Thiazolidinediones Vitamin C
Betaine
Angiotensin II inhibitor
Pentoxifyline
Probucol
Statins

Pharmacological treatment for NAFLD remains investigational

Adams and Angulo, Postgrad Med J 2006
• Pentoxifylline (PTX),
• Omega-3 fatty acids,
• Alpha-glucosidase inhibitor,
• Incretin analogues,
• Statins,
• Bile acid sequestrants,
• Angiotensin-converting enzyme
inhibitors (ACEI),
• Obeticholic acid.
A bile acid derivative, obeticholic acid (OCA), improves nonalcoholic
steatohepatitis (NASH), according to a study published online November 7
2014 in the Lancet
The FLINT Trial
Prof Brent A. Neuschwander-Tetri, MD, from Yale University in New Haven,
Connecticut, and colleagues tested OCA in adults with NASH in the multicenter,
double-blinded, placebo-controlled, randomized Farnesoid X Receptor Ligand
Obeticholic Acid in NASH Treatment (FLINT) trial

283 NASH patients in 8 centers: OCA 25 mg vs placebo

Duration: 72 weeks followed 24 weeks evaluation
Interim analysis: at 24 weeks: Showed improvement in Primary endpoint
Histology score and No cirrhosis
Secondary endpoint: Improvement in ALT, decrease in Insulin resistance
These reverted back on stopping the treatment
SE: Pruritus, Elevation of LDL and fall in HDL
Use of Statins in NAFLD

 Statins are safe in NAFLD

 Recommended if clinically indicated for treatment of

metabolic syndrome

 Frequent monitoring of liver enzymes is not required

Chalasani et al., Hepatology 2005

 • Statins : safe in patients with NAFLD even
in the presence of raised liver enzymes
• Can be prescribed safely without frequent
liver function test monitoring

Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease:
Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver
Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592-609.
• Bariatric surgery for weight loss has
been shown to be effective in improving
NASH
• But not to be prescribed routinely
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• It is the main cause of  liver enzymes; Isn’t that benign
• Spectrum of disease – NAFLD – NASH – Cirrhosis - HCC
• Insulin resistance, MS are the key pathogenic features
• DM, TG, Non fatty abdominal obesity, increasing age
• It is a marker of CV Risk. Rx. improve insulin sensitivity
• Modify underlying metabolic risk factors – diet, exercise
• Use Mayo scoring to predict NASH (fibrosis). No biopsy

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THANK YOU ALL

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