NON-ALCOHOLIC

NON-ALCOHOLIC

STEATOHEPATITIS

FATTY LIVER DISEASE

(NAFLD)

(NASH)

&

ADDRESSING A GROWING SILENT

EPIDEMIC

PREVALENCE OF NAFLD/NASH

USA Prevalence in Middle Age Patients

NAFLD Overall

0

20

40

60 58.3%

30%

46% 45% 44.6%

33% 35.1%

24%

29.9%

12.2%

Prev

alen

ce (%

)

NAFLD Hispanic

NAFLD Caucasian

NAFLD African

American

NASH Overall

NASH among

diagnosed NAFLD

San Antonio, Texas (Williamset al., Gastroenterology2011; 140:124-31)

Dallas Heart Study PrevalenceNumbers (Browning et al.,Hepatology 2004;40:1387-95)

Worldwide prevalence of NAFLD: 20-30%

13-44% in Middle Eastern countries

Approx. 20% in Asian countries

Approx. 30% in European countries

NASH worldwide prevalence unknown(estimate from U.S. study: 6-8%)

NAFLD80-90%

NASH56-69%

ADVANCEDFIBROSIS

37-50%

NAFLD/NASH Prevalence among Patients with diabetes

NAFLD70-90%

NASH25-30%

Prevalence among bariatric surgery patients

NAFLD/NASH Prevalence among obese Patients

NAFLD is an umbrella term thatencompasses the spectrum of fattyliver disease, from isolated steatosis

to cirrhosis and liver cancer withunderlying CVD risk.

NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

ISOLATED STEATOSIS

NON-NASHNAFLD

NASH WITHMILD FIBROSIS

NASH WITHADVANCED FIBROSIS

CIRRHOSIS

HEPATOCELLULARCARCINOMA

CVD

Hierarchy of Histologic Features

NATURAL HISTORY OF NAFLD

Associated with disease progression and mortality

Progression of isolated steatosis to cirrhosis is very rare

Fatty liver with inflammation but not NASH may progress but at a slower rate than NASH

NASH with fibrosis is at greater risk for disease progression

Patients with NASH and metabolic syndrome are also an enriched population for disease progression

NAFLD/NASH is now the second leading cause for liver transplantation in the U.S.

Modified from Torres DM et al. Features, diagnosis, and treatment of NAFLD. Clin Gastro Hepatol 2012;10:837-858

Isolated Fatty Liver

Fatty Liver withMild inflammation

Ballooning NASH FibrosisPortalinflammation

c - Major Prognosis Factors

~70-75%

~20-25%

~11% over 15 years, butsignificant variability

Possible sampling variability with some risk of progression

HCC~7.2%over 6.5 years

Decompensation~19-45%over 7-10 years

1- None to very minimalprogression to fibrosis2- No risk of death compared with the general population

1- risk of death compared with general population 1- Cardiovascular 2- Malignancy 3- Liver-related2- NASH with fibrosis portends worse prognosis 1- Fibrosis progression a/w DM, severe IR, weight gain>5kg, rising ALT, AST

NAFLD

NASH

NASHCirrhosis

a - increased mortality or lt

B - Increased risk of liver-related event

Fibrosis, stage 1Predictors

Fibrosis, stage 2Fibrosis, stage 3

Age (years)Diabetes (yes)Smoking

Statins use (yes)

NeverFormerCurrent

Fibrosis, stage 4

1.18, 2.81 .00795% Cl of HR P value

1.20, 3.03 .0071.16, 3.12 .01

1.05, 1.08 <.0011.11, 2.30 .01

0.15, 0.71 .005

0.71, 1.73 .6401.67, 4.10 <.001

3.35, 12.04 <.001

Hazard Ratio

1.00 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0

Decreasedrisk

Increasedrisk

Fibrosis, stage 1Predictors

Fibrosis, stage 2Fibrosis, stage 3Fibrosis, stage 4

95% Cl of HR P value0.63, 8.91 .198

4.35, 43.65 <.00111.94, 188.61 <.001

2.26, 24.94 .001

Hazard Ratio

1.00 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0Decreased

riskIncreased

risk

Mod

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from

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iagn

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, an

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FLD

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32:

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8

Red Flags IncreasingProbability for NASH

When deciding who to biopsy

No lab test or imaging study will be able to predictwith 100% accuracy

All variables have been shown to predict NASH

AgeGenderHispanicHypertensionObesity

ALT and AST levelAST/ALT ratioInsulin levelPNPLA3

NAFLD & MORTALITY: TOP 3 CAUSES

CARDIOVASCULAR DISEASE (CVD)1

ALL CAUSE MALIGNANCY2

LIVER-RELATED DEATH3

Hyper-lipidemia

Hypo-thyroidism

Hyper-tension

CVD

Adeno-matouspolyps

MetabolicSyndrome

PCOS

Diabetes

Vitamin Ddeficiency

OSA

NAFLD

CONDITIONS ASSOCIATED WITH NAFLD

AASLD practice guidelines require liver biopsy to diagnose NASH

Liver enzymes can be normal in up to 60% of patients with NASH

No non-invasive test with sufficient sensivity or specificity to rule in or rule out NASH

DIAGNOSIS

Diet and exercise are not always satisfactory options, and there is a lack of treatment. To address this unmet need, enrollment in

one of the clinical trials underway can be considered.

TREATMENT

Diet, lifestyle modification and exercise remain the top priority. Ultimate goal is to achieve 10% weight loss as this has been shown to improve all histopathologic parameters of NASH.

No approved therapies for the treatment of NASH.

NASH: KEY CONSIDERATIONS

NASH is the liver manifestation of metabolic diseases. NASH patients are often obese, have type 2 diabetes, and cardiovascular disease. NASH is the underlying cause of cirrhosis and its complications: treating NASH is the appropriate approach to prevent progression to cirrhosis. Liver biopsy is required to diagnose NASH. How to reverse NASH: stop the disease activity i.e. necroinflammation (ballooning + inflammation) that is the driver leading to liver fibrosis and progressive liver fibrosis. NASH therapies should be efficacious against both the underlying liver disease and comorbid conditions associated with NAFLD such as insulin resistance, diabetes, and hyperlipidemia. Because NASH is a chronic and silent disease, therapies should be safe and well tolerated.

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