FATTY LIVERShahin Merat, M.D.Associate Professor of MedicineDigestive Disease Research Center, Tehran University of Medical Sciences,8th International Congress of Endocrine DisordersTehran, Oct 2009

FATTY LIVER (AKA STEATOSIS)

Any amount of fat in liver histology Mirovesicular or macrovesicular With or without inflammation With or without fibrosis Associated with other disease or not Alcohol related or not

Alcoholic fatty liver Non alcoholic fatty liver (NAFL)

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NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Defined as: Deposition of fat droplets in hepatocytes AND the absence of significant alcohol intake

Generally defined as less than 20gr ethanol per week

NAFLD is a range of conditions from near normal liver to cirrhosis

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OTHER TERMS Simple non-alcoholic fatty liver disease

(NAFLD) Only deposition of fat in liver No inflammation or fibrosis

Non-Alcoholic Steatohepatitis (NASH) NAFLD with inflammation (lobular or portal),

hepatocyte ballooning, or fibrosis Absence of serologic evidence of infection with

hepatitis B or hepatitis C, …

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NAFLD—SPECTRUM OF DISEASE

Steatosis

Steatohepatitis (NASH)

NASH with Fibrosis

Cirrhosis

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NAFLD

NAFLD, SIMPLE STEATOSIS

Fatty Liver Only deposition of fat in liver No inflammation No fibrosis Not believed to progress to cirrhosis Up to 25 % of some populations!

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NAFLD—STEATOSIS

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Source: Ibdah 2003

NAFLD—NASH (WITHOUT FIBROSIS)

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Source: Ibdah 2003

NAFLD—NASH (WITH FIBROSIS)

Source: Ibdah 2003

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MULTIPLE HIT THEORY

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Normal Liver

Fatty Liver

Steatohepatitis

Cirrhosis

Hit 1: ? Insulin resistance, endotoxins, …

Fat accumulation

Hit 2: ? Oxidative stress, … Inflammation

Hit 3: ? Oxidative stress, …

Fibrosis

May loose fat

NAFLD—HISTOLOGICAL SPECTRUM

Macrovesicular Steatosis

Lobular Inflammation

Fibrosis

Cirrhosis

Tim

e

Pro

gre

ssio

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IMPACT

Liver-related death rate: General population: 9.5/100,000 NASH: 11% !

Liver-related deaths were the second most common cause of death in NAFL

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NATURAL HISTORY

In various follow-up studies (4-18 years) Improved: 0-4%No change: 50-60%Progession: 40-45%

Fibrosis: 27% Cirrhosis: 19%

Much better than alcoholic hepatitisApproximately 38-50% progress to

cirrhosis over seven years14

NAFLD—CLINICAL PREDICTORS

Patients at risk to develop NASH with fibrosis:

A. Age > 45

B. Obesity (BMI > 31-32)

C. Diabetes

D. AST/ALT > 1

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SURVIVAL NASH (Hepatology 2001)

5-year all-cause survival: 67%10-year all-cause survival: 59%

Alcoholic hepatitis5-year survival: 38%10-year survival: 15%

Hepatitis C with compensated cirrhosis 384 cases (Gastroenterology 1997)5-year survival: 91%10-year survival: 79%

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HEPATITIS C (AS A COMPARISON) 222 cases of Hepatitis C and 377 controls

after 25 years of follow-up: (Hepatology 2001) All cause mortality in HCV: 67% In controls: 65% (not significant)

917 women with acute HCV due to contaminated anti-D immune globulin (Hepatology 2000) After 20 yrs: 0.4% cirrhosis

Shiraz liver transplant cases (n=207) (2005): Cryptogenic cirrhosis: 23% (most common cause) Hepatitis B: 17% Hepatitis C: 2%

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NASH, EPIDEMIOLOGY (WORLD)

The most common cause of elevated enzyme levels among asymptomatic patients

Only 10% of NAFLD have NASH Among patients who have had liver biopsies,

NASH is seen in approximately 7-9% in Western countries

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EPIDEMIOLOGY There are many indications that a large

number of patients labeled as cryptogenic cirrhosis have been cases of NASH who have lost indications of NASH.

There is evidence that the increased rate of cirrhosis and liver-related death in many conditions such as diabetics and malabsorbtion states (eg celiac disease) is due to NASH

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NASH, PREVALENCE IN IRAN NASH is considered as the hepatic

manifestation of the metabolic syndrome (syndrome X).

In a large scale study on 10,368 subjects in Tehran, the prevalence of the metabolic syndrome was found to be 30.1% (Azizi et al.)

This study did not look to the liver tests or its ultrasonographic appearance, but it can be considered a good estimation of the at-risk population in Iran.

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NASH, PREVALENCE IN IRAN An autopsy series on 895 consecutive deaths

from non-medical causes (Sotoudehmanesh et al) 283 (31.6%) had steatosis 19 (2.1%) had steatohepatitis 6.7% of cases of steatosis had steatohepatitis

Non had alcohol consumption or diabetes Post-mortem changes ?

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NASH, PREVALENCE IN IRAN 1959 blood donors

Subjects with abnormal liver enzymes were invided

Further studies performed Viral studies Ultrasonography

2.35% NASH

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NASH, PREVALENCE IN IRAN Only 2.2% of these cases had a BMI of less

than 25 Limitations:

The population studied was 75.1% male. No histologic confirmation Cases studied were among volunteer blood donors

obese subjects are more likely to donate blood high risk subjects are screened out.

Nevertheless, this is currently the only published study addressing the prevalence of NASH in Iran’s general population.

Another study on 6,000 randomly selected subjects from the general population is on the way

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NASH, DIAGNOSIS Poorly studied

Many doctors do not even believe in NASH! Benign compared to other hepatitis

One of the most common ways by which NAFLD comes to medical attention is its incidental report during abdominal ultrasonography.

Unfortunately some ultrasonographists don’t believe in NAFLD too!

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NASH, DIAGNOSIS Most patients are asymptomatic. Hepatomegaly is the most common physical

finding. ALT / AST > 1, usually not so high Ultrasound will demonstrate a fatty or “bright

liver.” In CT, the liver is darker than the spleen Liver biopsy is required

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DIAGNOSIS, ULTRASONOGRAPHY

Unfortunately many radiologists in Iran do not report mild steatosis Technically unsuitable equipment ? Simple negligence ? They don’t believe in it!

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DIAGNOSIS, ULTRASONOGRAPHY

Increased echogenecity of the liver parenchyma, white liver

Not the same as coarse echogenicity which is a sign of fibrosis

Can be staged to grade I, II, and III according to vascular blurring or visibility of the diaphragm

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DIAGNOSIS, CT

The liver and spleen usually have equal, or near-equal, density

In hepatic steatosis the liver is hypodense when compared to the spleen

You may see liver angiogram even without contrast injection

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SUMMARY (1/2)

It appears that about 30% of the adult population in Iran is at risk for NAFLD

The overweight, obese, and diabetic is more prone.

About 10% of these subjects, almost 2-3% of the general adult population, already have NASH.

In may be roughly estimated that 10% of NASH cases will progress to cirrhosis. 34

SUMMARY (2/2) The prevalence of NASH (2-3%) is

comparable to the prevalence of hepatitis B, and much larger than the prevalence of hepatitis C

Since hepatitis B is being vaccinated for, we will be seeing less of this disease in the future

But obesity is on the rise. (as is hepatitis C)

It can be concluded that in the near future, NASH and hepatitis C will be the major liver diseases we will be facing in Iran 35