Nonalcoholic fatty liver disease (NAFLD) is defined as hepatic steatosis without significant alcohol consumption or other known liver diseases. It includes nonalcoholic fatty liver (NAFL) characterized by hepatic fat accumulation without inflammation or fibrosis, and nonalcoholic steatohepatitis (NASH) characterized by fat accumulation with inflammation and hepatocyte injury. NAFLD is strongly associated with obesity and metabolic syndrome. Lifestyle interventions including weight loss and exercise are recommended first-line treatment, while pioglitazone and vitamin E may improve liver histology in non-diabetic adults with NASH. Liver biopsy is needed to distinguish NASH from NAFL and assess fibrosis to guide management.

1. NON ALCOHOLIC
FATTY LIVER
DISEASE
DR SARIU ALI
MEDICAL OFFICER, IGMH
SUPERVISOR : DR FATHIMATH NADHIYA ,
CONSULTANT IN INTERNAL MEDICINE, IGMH

2. DEFINITION
Nonalcoholic Fatty Liver Disease (NAFLD)
(a) there is evidence of hepatic steatosis, either by imaging or
by histology and
(b) (b) there are no causes for secondary hepatic fat
accumulation such as significant alcohol consumption, use
of steatogenic medication or hereditary disorders
Histologically further categorized into
 Nonalcoholic Fatty Liver (NAFL)
 Nonalcoholic Steatohepatitis (NASH)

4. NONALCOHOLIC FATTY LIVER
DISEASE (NAFLD)
 Most common of All liver Disorders
 Most frequent cause of chronic liver disease
most common cause of End stage Liver
Disorder Needing liver transplantation.
 Present in up to 75% of individuals with
obesity and type 2 Diabetes
 Present in 3% of children and > 50%obese
children.

5. Nonalcoholic Fatty Liver (NAFL)
Evidence of Hepatic steatosis either by imaging or Histology
(> 5% of hepatocytes histologically) without any other Cause
for secondary Fat Accumulation with no evidence of
hepatocellular injury in the form of ballooning of the
hepatocytes or no evidence of fibrosis.
The risk of progression to cirrhosis and liver failure is minimal.
Nonalcoholic steatohepatitis (NASH)
Presence of hepatic steatosis and inflammation with hepatocyte
injury (ballooning) with or without fibrosis.
This can progress to cirrhosis, liver failure and rarely liver cancer

6. METABOLIC SYNDROME ; ALARMING
FIGURES

7. NFLD : A BURDEN WORLDWIDE

9. ENVIRONMENTAL FACTORS FOR A
FATTY WORLD

10. ETHNIC FACTORS AND NAFLD

12. PREVALENCE OF NAFLD IN HIGH RISK
GROUPS
Population studied prevalence of NAFLD
excessive BMI and visceral obesity are
recognized risk factors
Severe obesity undergoing bariatric
surgery
90% NAFLD
5% of patients may have
unsuspected cirrhosis
An ultrasonographic study of patients
with T2DM
69% prevalence of NAFLD
Another study 127 of 204 diabetic patients
displayed fatty infiltration on ultrasound,
62% fatty infiltration and 87%
those who consented to
biopsy had histologic
confirmation of NAFLD
Individuals with dyslipidemia attending
lipid clinics
prevalence of NAFLD
estimated to be 50%.

14. PATHOGENESIS AND RISK FACTORS
Insulin resistance is related to obesity and is central to the
pathogenesis of NAFLD.
In addition, oxidative stress and cytokines are important contributing
factors, together resulting in steatosis and progressive liver damage
in genetically susceptible individuals.
Key histologic components of NASH are steatosis, hepatocellular
ballooning, and lobular inflammation

16. MULTI-HIT HYPOTHESIS

17. RISK FACTORS AND ASSOCIATED CONDITIONS

18. NASH SCORING SYSTEM IN MORBID
OBESITY

19. PROGNOSIS AND COMPLICATIONS
Disease progression from NAFLD to NASH to cirrhosis/liver
failure and HCC.
Concurrence of NAFLD with hepatitis C or human
immunodeficiency virus (HIV) worsens their prognoses and
decreases their responses to therapy.
Liver biopsy may indicate the severity of disease, but only
fibrosis, and not inflammation or necrosis, has been confirmed
to predict the disease prognosis.
End-stage NASH is an often under-recognized cause of
cryptogenic cirrhosis
NASH-related (cryptogenic) cirrhosis increases the risk of
hepatocellular carcinoma (HCC).

20. NONALCOHOLIC FATTY LIVER
DISEASE (NAFLD)

22. Disease progression from NAFLD to NASH to cirrhosis/liver failure and
HCC.

24. Independent predictors for progression of
fibrosis:
Age > 45–50
BMI > 28–30 kg/m2
Degree of insulin resistance
Diabetes
Hypertension
The degree of fibrosis on liver biopsy (stage) is predictive of the prognosis

25. FIBROSIS STAGE : INDEPENDENT
FACTOR FOR LIVER MORTALITY

26. NASH SURVIVAL RATES IN COMPARISON WITH
SIMPLE STEATOSIS AND ALCOHOLIC
STEATOHEPATITIS (ASH)

27. Causes of mortality in cirrhotic NASH patients:
— Liver failure
— Sepsis
— Variceal hemorrhage
— HCC
— Cardiovascular disease

28. DIAGNOSIS
PATIENT HISTORY AND CLINICAL EVALUATION
Asymptomatic
vague symptoms of fatigue, malaise, and
abdominal discomfort.
Detailed patient history of alcohol—
Appropriate specialized questionnaires or scoring
systems for the evaluationof alcohol
consumption Eg.— CAGE questionnaire

29.  Abdominal obesity
 Enlarged liver
 RUQ tenderness on palpation
Central obesity correlates with severity of inflammation
on biopsy, and dorsocervical lipohypertrophy (buffalo
hump) correlates with hepatocyte injury.
In case of progression/advanced liver disease: spider
angiomas, ascites, hepatomegaly, splenomegaly, palmar
erythema, jaundice, hepatic encephalopathy.
Physical exam

30. The presence of any of the following, especially
with a history of abnormal AST/ALT, should
lead to a work-up for NAFLD/NASH:
— Presence of obesity, especially morbid obesity (BMI > 35)
— Diagnosis of type 2 diabetes mellitus
— Diagnosis of metabolic syndrome
— History of obstructive sleep apnea
— Presence of insulin resistance
— Chronic elevation of AST/ALT, otherwise unexplained

31. CALCULATION OF INSULIN RESISTANCE

32. ROUTINE LABORATORY FINDINGS AND
IMAGING TESTS
Elevated ALT and AST:
 In 10% of NASH patients, ALT and AST may be normal,
especially with simple steatosis.
 AST/ALT ratio < 1—this ratio is usually > 2 in alcoholic
hepatitis.
An abnormal ferritin level in the presence of normal
transferrin saturation should always suggest a need to
rule out NASH.
Tests to exclude: secondary causes of hepatic steatosis

33. Imaging - confirming fat accumulation in
the liver:
• The magnetic resonance imaging (MRI) test has a
quantitative value, but cannot distinguish between NASH
and ASH.
• Ultrasound is the usual screening test for fatty liver.

34. WHEN TO OBTAIN A LIVER BIOPSY
IN PATIENTS WITH NAFLD?
Liver biopsy should be considered in patients with NAFLD who are at
increased risk to have steatohepatitis and advanced fibrosis. (Strength
– 1, Evidence - B)
The presence of metabolic syndrome and the NAFLD Fibrosis Score
may be used for identifying patients who are at risk for steatohepatitis
and advanced fibrosis. (Strength – 1, Evidence - B)
Liver biopsy should be considered in patients with suspected NAFLD in
whom competing etiologies for hepatic steatosis and co-existing chronic
liver diseases cannot be excludedwithout a liver biopsy. (Strength – 1,
Evidence - B)

35. NASH CLINICAL RESEARCH NETWORK HISTOLOGICAL SCORING SYSTEM

36. DIAGNOSTIC TESTS FOR FATTY LIVER

37. A wide variety of attempts have been made to develop
scoring systems or imaging techniques that will allow
noninvasive diagnosis of NASH and avoid the need for a
liver biopsy.
Specialized imaging modalities, including FibroScan, using
a novel “controlled attenuation parameter,” and positron
emission tomography (PET) scanning suffer from the same
limitations of limited availability, high cost, and lack of
sufficient controlled data.
NON-INVASIVE ASSESSMENT OF
STEATOHEPATITIS AND ADVANCED
FIBROSIS IN NAFLD

38. NON-INVASIVE ASSESSMENT OF
STEATOHEPATITIS AND ADVANCED
FIBROSIS IN NAFLD
 The NAFLD Fibrosis Score
 Enhanced Liver Fibrosis (ELF) panel
 Transient Elastography
 Circulating levels of cytokeratin-18 (CK18)

39. NAFLD FIBROSIS SCORE
http://nafldscore.com
Age
BMI
Hyperglycemia
Platelet count
Albumin
AST
ALT
< -1.455: 90% sensitivity and 60% specificity to
exclude advanced fibrosis
> 0.675: 67% sensitivity and 97% specificity to identify
the presence of advanced fibrosis.

40. DIAGNOSTIC STRATEGY FOR NASH

41. MANAGEMENT
Therapeutic rationale
Targets for therapy : insulin resistance and
oxidative stress
Goals of treatment: reduce the histologic
features and improve insulin resistance and liver
enzyme levels.

42. LIFESTYLE
INTERVENTION
Weight loss generally reduces hepatic steatosis,
achieved either by hypocaloric diet alone or in
conjunction with increased physical activity.
Loss of at least 3–5% of body weight appears
necessary to improve steatosis, but a greater
weight loss (up to 10%) may be needed to improve
necroinflammation.
Exercise alone in adults with NAFLD may reduce
hepatic steatosis but its ability to improve other
aspects of liver histology remains unknown.

43. AVOID FRUCTOSE
Fructose (+++++ in corn syrup)
Soda, canned industrial dishes
Experimental Data
Mice fed with fructose devaloped more severe inflamatory
injuries compare to High fat diet Mice
-kholi, Hepatology 2010-
Human Data
In patients with NASH fructose consumption is associated
with liver fibrosis
-Abdel malek Hepatology 2010-

44. INSULIN SENSITIZING AGENTS
METFORMIN
A recent meta analysis concluded that 6–12 months of metformin
plus lifestyle intervention did not improve aminotransferases or
liver histology, compared with lifestyle intervention alone,
independently of metformin dose or the presence of diabetes.
June 2012 AGA 1597
Metformin has no significant effect on liver histology and is not
recommended as a specific treatment for liver disease in adults
with NASH. (Strength – 1, Evidence - A)

45. INSULIN SENSITIZING AGENTS
THIAZOLIDINEDIONES
•Rosiglitazone**: improved enzymes and
steatosis, but not inflammation
•Pioglitazone:***+weight gain, but
significantly improved aminotransferases,
steatosis, ballooning, and inflammation
*Uygun, et al Aliment Pharm Ther 2004
*Nair, et al Aliment Pharm Ther 2004
**Ratziu, et al Gastroenterology 2008
***Sanyal, et al NE J Med 2010

46. PIVENS STUDY
Pioglitazone , Vitamin E, placebo
96 weeks
Adults
• with NASH
• without DM, cirrhosis, Hep C, heart failure
• limited alcohol intake over previous 5 years
Randomized trial
• Pio group: 80
• Vit E group: 84
• Placebo: 83
Sanyal et al, New England J of Medicine 2010

47. PRIMARY OUTCOME
Vitamin E vs placebo
43% improvement
vs 19%: significant
(Steatosis, lobular
inflammation,
hepatocellular
ballooning and fibrosis)
Pio vs placebo
34% improvement
vs 19%: not significant
Sanyal et al, New England J of Medicine 2010

48. SECONDARY
OUTCOME
Vitamin E vs
placebo
• Also reduction in
SGOT/SGPT
Pio vs placebo
• Reduction in SGOT/SGPT
• Reduction in steatosis,
lobular inflammation
• Improvement in IR
• Increase in weight that did
not resolve after
discontinuance of Pio
Sanyal et al, New EngJ of Med 2010

49. PIVEN
CONCLUSIONS
Vitamin E was superior to placebo in adults with NASH and
without DM
Pioglitazone may have a role in treating patients with biopsy-
proven NASH, however long term safety and efficacy has not
been established
Sanyal et al, New EnglJ of Med 2010

50. AASLD
RECOMMENDATIONS:
Pio can be used to treat certain patients with biopsy-proven
NASH who do not have DM but long term safety and efficacy
has not been established
Vitamin E 800 IU/day improves liver histology in NASH pts
• Not recommended to treat NASH in those with other chronic
liver diseases, diabetics, those with NASH cirrhosis or
cryptogenic cirrhosis, NAFLD without biopsy

51. Oxidative stress is considered to be a key mechanism of hepatocellular
injury and disease progression in subjects with NASH.
Vitamin E is an anti-oxidant and has been investigated to treat NASH
 the use of vitamin E is associated with a decrease in aminotransferases
in subjects with NASH,
 causes improvement in steatosis, inflammation, and ballooning and
resolution of steatohepatitis in adults with NASH
 vitamin E has no effect on hepatic fibrosis.

52. Vitamin E (-tocopherol) administered at daily dose of 800 IU/day
improves liver histology in non-diabetic adults with biopsy-proven NASH
and therefore it should be considered as a first-line pharmacotherapy for
this patient population.
(Strength – 1, Quality – B)
Until further data supporting its effectiveness become available, vitamin
E is not recommended to treat NASH in diabetic patients, NAFLD without
liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. (Strength – 1,
Quality – C)

53. VITAMIN E: OTHER
CONCERNS
Meta-analysis* including 136,000 participants found
taking Vitamin E supplements > 400 IU/day had a higher
risk of all cause mortality
Vitamin E** > 400 IU/day increases risk of prostate
cancer in relatively healthy men
*Miller et al Annals of Internal
Medicine 2005
** Klein, et al, JAMA 2011

54. URSODEOXYCHOLIC ACID (UDCA),
OMEGA-3 FATTY ACIDS
UDCA : no histologic benefit
UDCA is not recommended for the treatment of NAFLD or NASH.
(Strength – 1, Quality – B)
It is premature to recommend omega-3 fatty acids for the specific
treatment of NAFLD or NASH but they may be considered as the
first line agents to treat hypertriglyceridemia in patients with
NAFLD. (Strength – 1, Quality – B)
A large multicenter study of one omega-3 fatty acid
(eicosapentanoic acid) to treat NASH is ongoing in the United
States

55. STATIN USE IN PATIENTS WITH
NAFLD AND NASH
CVD common cause of death for NAFLD and NASH
Stratify risks and treat accordingly
Several studies show NAFLD and NASH pts are not at increased
risk of liver injury over general population*
Until RCTs with histological endpoints prove their efficacy, statins
should not be used to specifically treat NASH.
(Strength – 1, Quality – B)
*Chalasani, et al. Am J Gastro 2012

56. GREACE STUDY*
Concluded statins significantly
improve liver biochemistries and CV
outcomes in pts with elevated
enzymes likely due to NASH
Athyros et al Lancet 2010

57. AASLD RECOMMENDATION ON
STATINS
“Given lack of evidence that patients with NAFLD and NASH are at
increased risk for serious drug-induced liver injury from statins,
they can be used to treat dyslipidemia in patients with NAFLD and
NASH.”

58. BARIATRIC SURGERY
No RCTs
Cochrane review 2010: lack of RCTs prevents
definitive assessment of risks/benefits
Prospective study*
• 381 adults with severe obesity, fibrosis score<3
• Clinical, metabolic, liver biopsy comparisons at 1 year
and 5 years
• Significant improvement in steatosis, ballooning,
resolution of probable/definite NASH at 1 and 5 years
• Small but significant increase of fibrosis score at 5
years (96% had improvement)
*Mathurin et al Gastroenterology 2009

59. AASLD RECOMMENDATION
ON BARIATRIC SURGERY
Premature to consider foregut surgery as an option to
specifically treat NASH
Foregut surgery is not contra-indicated in otherwise eligible
pts with NASH or NAFLD WITHOUT cirrhosis
For those with cirrhosis: type, safety and efficacy of foregut
surgery is not established

60. MONITORING STRATEGY
DISEASE PROGRESSION AND COMPLICATIONS CAN BE DETECTED DURING THE
FOLLOW-UP AS INDICATED

61. MISCELLANEOUS RECOMMENDATIONS
PERTINENT TO CLINICAL PRACTICE
Patients with NASH cirrhosis should be screened for
gastroesophageal varices according to the AASLD/ACG practice
guidelines. (Strength – 1, Quality – B)
Patients with NASH cirrhosis should be considered for HCC
screening according to the AASLD/ACG practice guidelines.
(Strength – 1, Quality – B)
Current evidence does not support routinely repeating a liver
biopsy in patients with NAFL or NASH. (Strength – 2, Quality –
C)

62. SUMMARY
Metabolic Syndrome and NAFLD has reached epidemic
proportions
NFLD can lead to Cirrhosis and HCC
Patients with NFLD have lower overall survival
The diagnosis should be sought in all patients who present with
risk factors for NASH. Not all patients with risk factors will have
NAFLD or NASH, and not all patients with NASH will have
standard risk factors.
NFLD is a cofactor of liver progression
Lifestyle diet and Exercise still represents crucial therapeutic
measures
More trials are needed to validate efficient drugs

63. REFERENCES
World Gastroenterology Organisation Global Guidelines
Nonalcoholic Fatty Liver Disease and Nonalcoholic
Steatohepatitis June 2012
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 June 2012
AASLD PRACTICE GUIDELINE
The Diagnosis and Management of Non-Alcoholic Fatty Liver
Disease: Practice Guideline by the American Association for the
Study of Liver Diseases, American College of Gastroenterology, and
the American Gastroenterological Association 2012

64. THANK YOU