NAFLD

Non-Alcoholic Fatty Liver Disease (NAFLD)

An epidemic of new millenium. A new consequence of the obesity epidemic. Represents a spectrum of conditions characterized by macrovesicular hepatic steatosis in the absence of significant alcohol intake. Includes histological pattern:

Simple steatosis( without inflammation) Steatohepatitis(NASH) with inflammation fibrosis & cirrhosis

Non-Alcoholic Fatty Liver Disease (NAFLD)

Normal liver

Fatty liver (Steatosis)

Cirrhosis

Steatohepatitis - inflammation - fibrosis

Prevalence of fatty liver

Estimated prevalence is 2.8 - 25 % of population 20 to 30 % adults in western countries have NAFLD of which 2 to 3 % are NASH (Imaging & autopsy study)

Steatosis seen in 80 % obese patients

NASH seen in 9 - 30 % obese

Hepatology 2003

Prevalence of NAFLD In General Population In Asian Pacific Region

Name of the Country Japan China Korea India Indonesia Malaysia Singapore Percentage NAFLD in Adults 9 30% 5 18% 18 % 5 28% 30% 17 % 5%

Aetiological Classification
Primary NAFLD: associated with metabolic syndrome. Secondary NAFLD: includes fatty liver diseases with a proximate causes.

Primary

Types of NAFLD Secondary

1 severe weight loss jejunoileal bypass gastric bypass severe starvation 2 total parenteral nutrition 3 Iatrogenic Amiodarone Diltiazem Tamoxifen Steroids HAART 3 Refeeding syndrome 4 Toxic exposure Hydrocarbon , yellow phosphorus

1 Insulin resistance Obesity Diabetes Hypertriglyceridemia Hypertension

Pathophysiology

Salgado W, et al. Acta Cir. Bras. 2006; 21.

Two-hit Hypothesis
Diet FFA
Oxidative Stress Toxins Inflammatory Molecules Fatty Liver

1st Hit
Susceptibility

Burned VLDL-TG

2nd Hit

Damaged Liver

Donnelly et al. J. Clin. Invest. 113: 1343, 2005 Day and James. Gastroenterol. 114: 842, 1998

Pathophysiology

Other factors involved in NASH pathogenesis

Bacterial overgrowth
Increased hepatic oxidative stress Production of TNF- Direct activation of inflammatory cytokines and liver macrophages via release of lipopolysaccarides

Obesity gene
Regulates food intake and body composition Leads to hepatic steotosis by promoting insulin resistance or by modulating insulin signalling in hepatocytes

Pathophysiology: others

Serum and liver iron

Mitochondrial oxidation leads to generation of hydrogen peroxide In presence of increased iron hydrogen peroxide converted to hydroxyl free radicles This leads to oxidative stress and hepatocellular injury _ HFE mutations have been detected in 15-20% of these patients.

Pathophysiology: others

TNF-
Corelates with obesity Derives from adipose tissue Decrease phosphorylation of insulin receptor Reduce expression of GLUT-4 Contributes toward insulin resistence

Clinical Presentation
Variable clinical presentation Typically asymptomatic, but may have hepatomegaly and abdominal discomfort

NASH Criteria (AGA guidelines)

Characteristic liver biopsy that shows fatty change with inflammation
Indistinguishable from alcoholic hepatitis

Convincing evidence of negligible alcohol consumption (less than 20g alcohol per day)
Detailed history obtained independently by 3 physicians, interrogation of family members

Absence of serologic evidence of Hep B or Hep C infection

Should not exclude those with evidence of past Hep B infection, but should exclude patients with positive HBs Ag or HCV Ab

Lab Studies
No laboratory studies can help definitively establish a diagnosis of fatty liver or NASH. Aminotransferases
Elevated AST or ALT As much as 10-fold In the absence of cirrhosis, an AST-to-ALT ratio of greater than 2 suggests alcohol use, whereas a ratio of less than 1 may occur in patients with NASH.

Alkaline phosphatase
Can be elevated Usually less than 2 to 3 times normal

Diagnosis
Diagnosis of NAFLD can often be made by imaging studies, including U/S, CT or MRI detects presence of fat

Diagnosis (cont.)
MR spectroscopy accurately measures hepatic triglyceride content
Has advantage over U/S, CT and MRI as it is quantitative rather than qualitative

Diagnosis (cont.)
No imaging studies can differentiate between the histological subtypes of benign steatosis or aggressive NASH, or stage the degree of fibrosis
Need tissue for staging and to make diagnosis of NASH

 Doing liver biopsy is controversial

Arguments favoring
Exclusion of other cause To distinguish steatosis from NASH Estimation of prognosis Determination of progression

Arguments against biopsy

Good prognosis Lack of effective therapy Risk & cost associated with biopsy

Histology
Histologic diagnosis of NAFL requires presence of 5% steatosis
Indistinguishable from alcoholic fatty liver

 Benign steatosis Mild: <33% steatosis Moderate: 33%-66% Severe: >66% steatosis

Histology
NASH involves presence of steatosis with evidence of inflammation and hepatocyte injury:

Histology
Histologic evidence of steatohepatitis may disappear with progression to cirrhosis
Thus, significant proportion of cryptogenic cirrhosis is likely related to unrecognized

 The pattern of fibrosis is typically pericellular and sinusoidal (dubbed chicken-wire fibrosis). As cirrhosis evolves, fibrous septa bridge portal and perivenous areas

COMPLICATION
Cirrosis
Risk- 8 to 15%

Hepatocellular carcinoma
Risk: 1-2%

Prognosis
Patients with bland steatosis (NAFL) have a benign liver-related prognosis
1.5% develop cirrhosis 1% die from liver-related causes over 10-20 years

Almost 30% of patients with NASH and fibrosis become cirrhotic within 5-10 years
Those with biopsy-proven NASH have a liver-related death rate of ~10%

NASH cirrhosis may develop into HCC

~13% of cases of all HCC are related to NASH cirrhosis Endstage NAFLD accounts for ~5-10% of liver Matteoni C, et al. Gastroenterology 1999;116:1413-1419. transplants

Treatment
Aim to improve insulin sensitivity and modify underlying metabolic risk factors
Diet and exercise Insulin Sensitizing Agents (metformin, TZD) Lipid lowering medications (statins, fibrates)

L-Carnitine supplementation

McCullough AJ. N Engl J Med 2006; 355: 2361-3.

TAKE HOME MESSAGE

One manifestation screen for all the rest Metabolic syndrome is a hidden volcano Evaluate every one >25 years of age for MS WC must be measured routinely like taking BP Remember MS is the PRE for T2DM and CVD We should not wait till these killers