1. NASH and nonalcoholic liver disease
Dr. Umesh Khanna
Mumbai
NASH – NonAlcoholic SteatoHepatitis

2. Introduction Non-alcoholic fatty liver diseases [NAFLD]
represents a spectrum of diseases ranging from
“simple steatosis,” which is considered relatively benign, to
Non alcoholic steatohepatitis (NASH) and NAFLD-associated cirrhosis and end-stage liver disease
Has become a common cause of liver transplant
Also been identified as an important risk factor for development of primary liver cancer , mostly due to NAFLD-associated cirrhosis
J Lipid Res April; 50: S412–6.

3. NAFLD : Natural history over 8–13 years
HCC, hepatocellular carcinoma; OLTx, liver transplantation.
Journal of Hepatology 2008;48: S104–12

4. NonAlcoholic Fatty Liver Disease
Histopathologic Spectrum Steatosis Steatohepatitis
Cancer
Fibrosis
Cirrhosis
Progression to cirrhosis and cancer have been documented from few studies in the Asian Pacific Region but still exact magnitude of the problem is not known.

5. Introduction NAFLD However,
Health dilemma for the recent 3 decades provoking quite less concerns in the past
However,
Nowadays, its prevalence has grew to 30% in the United States general population and like other gastrointestinal disorders it also grew in developing countries
NAFLD is rapidly becoming a worldwide public health problem*
It is the most common liver disease in the United States and, indeed, worldwide
Hepat Mon. 2011;11(2):74-85 ;* J Lipid Res April; 50: S412–6.

6. Non-Alcoholic Steatohepatitis [NASH]
Represents only a part of wide spectrum of non alcoholic fatty liver
One of the leading causes of chronic liver disease [CLD]
3rd most common cause of CLD in North America after alcoholic liver disease & Hepatitis C
The most common cause of raised transaminases > 6 months

7. Introduction
NASH
was coined by Ludwig et al in while describing a
Series of patients of non-alcoholic, diabetic patients, mostly females, in whom
Liver histology was consistent with alcoholic liver disease but
did not have a history of alcohol consumption

8. Epidemiology: NALFD, NASH
Problems In Studying Epidemiology Of NAFLD And NASH
Lack of definitive laboratory test
Studies dependence on different definitions
Published series with biopsy confirmation are selected cases that have presented to medical attention
Values of alcohol consumption in published series ranged from < 20 gm/week to <140 gm/week

9. Epidemiology: NALFD, NASH
Prevalence of NAFLD
Appears to be increasing, in part due to the increasing numbers of adult and pediatric individuals who are obese or overweight or have metabolic syndrome or type 2 diabetes, all major risk factors for development of NAFLD
J Lipid Res April; 50: S412–6.

10. Epidemiology: NALFD, NASH
Problems in Assessing NAFLD In Asian Pacific Region
Inaccurate evaluation of alcohol abuse
Infrequent use of liver test in general practice
Lack of presentation of asymptomatic individual
Burden of viral hepatitis
Reluctance to do liver biopsy
Lack of awareness of the severity
Pursued slowly progressive nature
Considered as a disease of affluence
Chitturi S, Farrell G, George J JGH 2004

11. Epidemiology: NALFD, NASH
Steatosis
Most common cause of raised transaminases & affects % of gen.population while
only 2-3 % of gen.population have steatohepatitis
In pts undergoing liver biopsy, the prevalence ranges
NAFLD [NonAlcoholic Fatty Liver Disease] %
Steatohepatitis %

12. Epidemiology: NALFD, NASH
Prevalence of NAFLD In General Population In Asian Pacific Region
Name of the Percentage NAFLD in Country Adults
Japan 9 – 30%
China 5 – 18%
Korea 18 %
India 5 – 28%
Indonesia 30%
Malaysia 17 %
Singapore 5%

13. Epidemiology: NALFD, NASH
NASH In Asia Pacific – Future Shock!!
Western Eastern Population Population
Age at Presentation 4th – 8th decade 4th – 8th decade
Prevalence 20-30% -10%
Obesity 71% (30-100) 44% (12-89)
T2DM 28% (2-55) 34% (11-39)
Hyperlipidemia 38% (15-81) 41% (28-81)
Natural History Worse with Limited data severe firbosis
Chitturi Et al JGH 2004

14. NASH in India India Among pts from India,
Many diabetics but very few studies on NASH
Among pts from India,
50 – 70% had one of the 3 risk factors – diabetes, obesity, hyperlipidemia
Mean age of pts is 35 – 55 yrs
Predominant in men
NASH constitute 6% of all chr.hepatitis cases

15. NAFLD: Risk factors
Obesity
Diabetes
Hyperlipidemia
Female sex

16. NALFD: Etiology
To date, major gaps remain in our understanding of the etiology of NAFLD and why it progresses
Generally agreed that dysregulation of lipid metabolism is involved
Furthermore, it seems likely that dysregulation of the immune response plays an important role, particularly in progression
J Lipid Res April; 50: S412–6.

17. NAFLD: Factors that may impact
Any or all metabolic pathways may play a role in NAFLD and its progression dependent on an individual's cohort of genes and genetic and epigenetic interactions. The question mark indicates that little evidence is available supporting an influence, but that, hypothetically, one may exist
J Lipid Res April; 50: S412–6.

18. NASH: Potential etiologies
Hepat Mon. 2011;11(2):74-85

19. NASH: Potential etiologies
Hepat Mon. 2011;11(2):74-85

20. NASH: Potential etiologies
Hepat Mon. 2011;11(2):74-85

21. NASH: Pathogenesis Increased delivery of fatty acids to liver Obesity
Starvation
Increased synthesis of fatty acids in liver
excess carbohydrate ( TPN )
Decreased mitochondrial beta oxidation of fatty acids
Carnitine deficiency
Mitochondrial dysfunction
Decreased incorporation of triglycerides into functional VLDL
Impaired apolipoprotein synthesis

22. NASH: Pathogenesis Impaired cholesterol esterification
Choline deficiency
Protein malnutrition
Impaired export of VLDL from hepatocyte
Insulin resistance
increased lipolysis
hyperinsulinemia

23. NASH: Pathology Diagnosis of NASH depends on Liver biopsy features :
Histopathological features &
Exclusion of alcohol as the cause of disease
Liver biopsy features :
Steatosis polymorphonuclear and / mononuclear hepatocyte ballooning and necrosi, mallory hyaline,glycogenated nuclei,metamitochondria and fibrosis indistinguishable from alcoholic liver disease

24. NASH: Pathology Steatosis in NASH – macrovesicular
Inflammation of steatohepatitis is predominantly lobular,
[whereas intense portal inflammation with interface activity is seen in chronic viral, autoimmune & drug indued hepatitis]
But in children , NASH may have portal infiltrate
Neutrophilic cells in lobular inflammatory infiltrate
Balloon degeneration – recognized form & characteristic finding in NASH
Mallory hyaline may be +/-
Characteristic of alcoholic hepatitis

25. NASH: Pathology Pattern of fibrosis
Initial collagen deposition in perivenular & peri sinusoidal spaces of Zone 3 .
Chicken wire fibrosis
Fibrosis – in 66% pts
While 25% have severe fibrosis
And 14% have well established cirrhosis

26. JAPI 2005;53:

27. JAPI 2005;53:

28. Histological Differential Diagnosis
Hepatitis C
Primary Biliary Cirrhosis
Autoimmune hepatitis
Alpha 1 anti trypsin deficiency
Hemochromatosis

29. NALFD: Clinical features
NAFLD
Largely asymptomatic condition that may reach an advanced stage before it is suspected or diagnosed
Symptoms such as right upper quadrant discomfort, fatigue and lethargy have been reported in up to 50% of patients but are uncommon modes of presentation
Most patients with NAFLD are diagnosed after they are found to have hepatomegaly, or more commonly, unexplained abnormalities of liver blood tests performed as part of routine health checks or during drug monitoring (e.g., statin therapy)
Journal of Hepatology 2008;48: S104–12

30. NALFD: Clinical features
On examination
Most patients are centrally obese and dorsocervical lipohypertrophy (a ‘‘buffalo hump”) appears to be a particular feature of the fat distribution in patients with advanced NAFLD
Features of PCOS (hyperandrogenism) should be sought in young women with suspected NAFLD
Journal of Hepatology 2008;48: S104–12

31. NASH: Clinical features
Most of the patients are asymptomatic
1/3rd present with
Nonspecific constitutional symptoms like weakness, fatigue & malaise
Rapid onset of Fulminant hepatic failure
NASH d//t drugs like nucleoside analogues, tetracyclines
Hepatomegaly , splenomegaly
Presence of ascites, spider angiomata – indicate development of cirrhosis
Alcoholic hepatitis - symptomatic

32. Laboratory findings Mild – moderate elevations of S.Transaminases,
typically <4 times the upper normal limit
ALT level > AST in absence of cirrhosis
Liver biopsy

33. Diagnosis Clinical history Exclusion of significant alcohol intake
Pursue dietary history, medication, occupational exposure to organic solvents
Family history of liver disease
Other causes of CLD – infections, metabolic heriditary & autoimmune causes to be ruled out
Liver biopsy – confirm diagnosis & for prognostic information

34. Difference between NASH and alcoholic hepatitis
JAPI 2005;53:

35. Natural course Steatosis Steatohepatitis Cirrhosis
Steatosis – good prognosis
Steatohepatitis , cirrhosis – bad prognosis

36. NALFD: Treatment
Currently, the only accepted treatment for NAFLD regardless of stage is lifestyle modifications
These include weight loss by a combination of decreased caloric intake and increased physical activity
Of potential importance is choice of diet, for example, low fat/high carbohydrate versus high fat/low carbohydrate
Another option, generally available only for the morbidly obese, is bariatric surgery
An important caveat for both treatment approaches
Rapid weight loss by any means is to be avoided because it can cause NAFLD progression
J Lipid Res April; 50: S412–6.

37. NASH: Treatment Treatment options are limited Weight Reduction:
wt loss – normalization of s.aminotransferases.
Means of wt loss is important not the amount of wt loss
Recommended wt loss – 230 g/day or 1.6 kg/week
Diet : g high quality animal protein
<100g carbohydrates
<10 g fat per day providing
kcal

38. NASH: Treatment Ursodeoxycholic acid :
Has membrane stabilizing / cytoprotective / immunological effect
10-15 mg/kg/day for 6-12 months
Significant improvement in transaminases levels and degree of steatohepatitis

39. NASH: Treatment Liver Transplantation :
NASH – A relative contraindication
Many of pts with NASH with CLD who underwent Liver Transplant – redeveloped NASH in the new donor liver ( 2/3 cases ) &
1/3rd cases – liver transplantation is unsuccessful

40. Newer treatment modalities
Inhibition of macrophage activation:
Anti oxidant ( Vit E ) glutathione prodrugs
Antibiotics, preprobiotics
Anti cytokines ( anti TNF alpha antibodies, pentoxiphylline )

41. Newer treatment modalities
Protect hepatocyte ATP stores
PARP inhibitors
Minimize CYP2F activity
Dietary modification ( avoid fats )
Insulin sensitizers : pioglitazone
Antiobesity drugs : sibutramine, orlistat
Antilipid drugs : Simvastatin, Procusol

42. Thank You!