NAFLD, NASH

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Information about NAFLD, NASH

Published on July 31, 2009

Author: Shatdal

Source: slideshare.net

Description

This presentation is meant for MBBS students

DR. Shatdal Chaudhary MD NAFLD

NAFLD

N on- A lcoholic F atty L iver D isease (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

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

N on- A lcoholic F atty L iver D isease (NAFLD) Fatty liver (Steatosis) Steatohepatitis - inflammation - fibrosis Cirrhosis Normal liver

The Brief History of NAFLD Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005 1979 ~8 papers published 1998 First NIH conference 1999 First Clinical Trials 2002 ~60 papers published Release of first book on NAFLD/NASH 2005 ~354 papers published

1979 ~8 papers published

1998 First NIH conference

1999 First Clinical Trials

2002 ~60 papers published

Release of first book on NAFLD/NASH

2005 ~354 papers published

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

“ 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

NAFLD 1. Most common of all liver disorders. 2. Frequent cause of chronic liver disease. 3. Present in 3% of children and >50% of obese children. Fatty Liver Disease: NASH and Related Disorders Blackwell Publishing, 2005

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%

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%

Prevalence of NAFLD In High Risk Population In Asian Pacific Region Name of the Diabetes Obesity Dyslipidemia country Japan 40-50% 50-80% 42-58% China 35% 70-80% 57% Korea 35% 10-50% 26-35% India 30-90% 15-20% NA Indonesia 52% 47% 56%

Name of the Diabetes Obesity Dyslipidemia

country

Japan 40-50% 50-80% 42-58%

China 35% 70-80% 57%

Korea 35% 10-50% 26-35%

India 30-90% 15-20% NA

Indonesia 52% 47% 56%

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

Primary NAFLD : associated with metabolic syndrome.

Secondary NAFLD : includes fatty liver diseases with a proximate causes.

Types of NAFLD Primary Secondary 1 Insulin resistance 1 severe weight loss Obesity jejunoileal bypass Diabetes gastric bypass Hypertriglyceridemia severe starvation Hypertension 2 total parenteral nutrition 3 Iatrogenic Amiodarone Diltiazem Tamoxifen Steroids HAART 3 Refeeding syndrome 4 Toxic exposure Hydrocarbon , yellow phosphorus 5 Disorders of lipid metabolism Abetalipoproteinemia Hypobetalipoproteinemia Andersen’s disease Weber –christian syndrome

Primary Secondary

1 Insulin resistance 1 severe weight loss

Obesity jejunoileal bypass

Diabetes gastric bypass

Hypertriglyceridemia severe starvation

Hypertension 2 total parenteral nutrition

3 Iatrogenic

Amiodarone

Diltiazem

Tamoxifen

Steroids

HAART

3 Refeeding syndrome

4 Toxic exposure

Hydrocarbon , yellow phosphorus

5 Disorders of lipid metabolism

Abetalipoproteinemia

Hypobetalipoproteinemia

Andersen’s disease

Weber –christian syndrome

Morbid Obesity Four studies evaluating > 600 morbidly obese patients undergoing gastric bypass All patients underwent intraoperative liver biopsies Prevalence of NAFL ranged from 30-90% and NASH was documented in 33-42%.  > 2/3 of morbidly obese patients undergoing gastric bypass surgery have NAFL/NASH Abrams GA, et al.  Hepatology 2004;40:475-483; Frantzides CT, et al.  J Gastrointest Surg 2004;8:849-855; Dallal RM, et al. Obes Surg 2004;14:47-53; Beymer C, et al.  Arch Surg 2003;138:1240-1244.

Four studies evaluating > 600 morbidly obese patients undergoing gastric bypass

All patients underwent intraoperative liver biopsies

Prevalence of NAFL ranged from 30-90% and NASH was documented in 33-42%. 

> 2/3 of morbidly obese patients undergoing gastric bypass surgery have NAFL/NASH

Type 2 Diabetes Mellitus Recent study surveyed 100 patients with type 2 DM and used U/S to screen for NAFLD Detected fatty liver in 50% of patients Performed subsequent liver biopsy in those with NAFLD: NAFL: 13% NASH: 86% Fibrosis: 22% Gupte, et al.  J Gastro Hepatol 2004;19:854-858.

Recent study surveyed 100 patients with type 2 DM and used U/S to screen for NAFLD

Detected fatty liver in 50% of patients

Performed subsequent liver biopsy in those with NAFLD:

NAFL: 13%

NASH: 86%

Fibrosis: 22%

Dyslipidemia Canadian study used U/S to screen 95 adults with dyslipidemia Detected fatty liver in 50% Steatosis was particularly common in individuals with moderate to severe hypertriglyceridemia or mixed dyslipidemia Hypertriglyceridemia and mixed dyslipidemia increased the risk for hepatic steatosis by ~5-fold Assy N, et al. Dig Dis Sci 2000;45:1929-1934.

Canadian study used U/S to screen 95 adults with dyslipidemia

Detected fatty liver in 50%

Steatosis was particularly common in individuals with moderate to severe hypertriglyceridemia or mixed dyslipidemia

Hypertriglyceridemia and mixed dyslipidemia increased the risk for hepatic steatosis by ~5-fold

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

Two-hit Hypothesis Fatty Liver 1 st Hit Damaged Liver 2 nd Hit Oxidative Stress Toxins Inflammatory Molecules Susceptibility Donnelly et al. J. Clin. Invest. 113: 1343, 2005 Day and James. Gastroenterol. 114: 842, 1998 Diet FFA Burned VLDL-TG

Liver Damage 2 nd Hit Liver Damage Sat FA 2 nd Hit Apoptosis Hepatocyte Mass Fatty Liver

Pathophysiology Other factors involved in NASH pathogenesis Bacterial overgrowth Increased hepatic oxidative stress Production of ethanol and TNF- α Direct activation of inflammatory cytokines and liver macrophages via release of lipopolysaccarides Leptin Obesity gene Regulates food intake and body composition Leads to hepatic steotosis by promoting insulin resistance or by modulating insulin signalling in hepatocytes

Other factors involved in NASH pathogenesis

Bacterial overgrowth

Increased hepatic oxidative stress

Production of ethanol and TNF- α

Direct activation of inflammatory cytokines and liver macrophages via release of lipopolysaccarides

Leptin

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 β 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

Serum and liver iron

Mitochondrial β 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

Pathophysiology: others TNF- α Corelates with obesity Derives from adipose tissue Decrease phosphorylation of insulin receptor Reduce expression of GLUT-4 Contributes toward insulin resistence Also causes chemotaxis, activation of stellate cells, Mallory hyaline formation, collagen synthesis

TNF- α

Corelates with obesity

Derives from adipose tissue

Decrease phosphorylation of insulin receptor

Reduce expression of GLUT-4

Contributes toward insulin resistence

Also causes chemotaxis, activation of stellate cells, Mallory hyaline formation, collagen synthesis

Clinical Presentation Variable clinical presentation Typically asymptomatic, but may have hepatomegaly and abdominal discomfort Liver enzymes may be normal in >75% of cases, making them insensitive in detecting NAFLD When increased, usually only modestly and limited to aminotransferases ALT upper limits of normal: <30 in M, <20 in F

Variable clinical presentation

Typically asymptomatic, but may have hepatomegaly and abdominal discomfort

Liver enzymes may be normal in >75% of cases, making them insensitive in detecting NAFLD

When increased, usually only modestly and limited to aminotransferases

ALT upper limits of normal: <30 in M, <20 in F

Natural history and clinical outcomes of NASH 20% 30—40% NASH CIRRHOSIS Liver related Death Sub acute HCC Post-OLTX Failure recurrance

20% 30—40%

NASH CIRRHOSIS Liver related Death

Sub acute HCC Post-OLTX

Failure recurrance

Diagnosis Cf h/o Disturbed liver enzymes Radioimaging Biopsy

Cf

h/o

Disturbed liver enzymes

Radioimaging

Biopsy

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

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 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

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

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

Liver biopsy A liver biopsy and histopathological examination are required to establish the diagnosis. The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use).

Liver biopsy

A liver biopsy and histopathological examination are required to establish the diagnosis.

The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use).

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

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

Histologic diagnosis of NAFL requires presence of ≥ 5% steatosis

Indistinguishable from alcoholic fatty liver

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

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

Ballooning

Mallory bodies

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

Histologic evidence of steatohepatitis may disappear with progression to cirrhosis

Thus, significant proportion of cryptogenic cirrhosis is likely related to unrecognized NASH

COMPLICATION Cirrosis Risk- 8 to 15% Hepatocellular carcinoma Risk: 1-2%

Cirrosis

Risk- 8 to 15%

Hepatocellular carcinoma

Risk: 1-2%

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

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

Clues for severe NASH Old age(>50 yrs) Presence of diabetes Pesence of obesity AST/ALT > 1 ALT >2 times of normal TG >1.7m mol/L

Clues for severe NASH

Old age(>50 yrs)

Presence of diabetes

Pesence of obesity

AST/ALT > 1

ALT >2 times of normal

TG >1.7m mol/L

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 transplants Matteoni C, et al. Gastroenterology 1999;116:1413-1419.

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 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

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.

Treatment Lifestyle modification Diet and exercise Weight reduction Insulin sensitizers Metformin Troglitazone Rosiglitazone Pioglitazone Lipid Lowering agents Antioxidants Vitamin E Vitamin C Hepatoprotective agents Betaine Ursodeoxycholic acid Pentoxyfylline Angiotensin-converting enzyme inhibitors Probucol

Lifestyle modification

Diet and exercise

Weight reduction

Insulin sensitizers

Metformin

Troglitazone

Rosiglitazone

Pioglitazone

Lipid Lowering agents

Antioxidants

Vitamin E

Vitamin C

Hepatoprotective agents

Betaine

Ursodeoxycholic acid

Pentoxyfylline

Angiotensin-converting enzyme inhibitors

Probucol

Treatment (cont.) Beneficial according to preliminary studies: Insulin sensitizers: TZD > metformin Benefit unproven by preliminary studies Lipid lowering agents Antioxidants Probiotics (animal models only) Not beneficial Ursodiol

Beneficial according to preliminary studies:

Insulin sensitizers: TZD > metformin

Benefit unproven by preliminary studies

Lipid lowering agents

Antioxidants

Probiotics (animal models only)

Not beneficial

Ursodiol

Betaine Metabolite of Choline increases S-adenosylmethionine levels (SAM) protect against steatosis and decrease oxidative stress.

Metabolite of Choline

increases S-adenosylmethionine levels (SAM)

protect against steatosis and decrease oxidative stress.

Pentoxifylline Production of tumour necrosis factor-alpha is one of the primary events in many types of liver injury Patients with NASH have been shown to have higher levels of TNF-alpha. Biochemical improvement was demonstrated in certain study

Production of tumour necrosis factor-alpha is one of the primary events in many types of liver injury

Patients with NASH have been shown to have higher levels of TNF-alpha.

Biochemical improvement was demonstrated in certain study

Probucol Probucol is a lipid-lowering drug with potent antioxidant properties that tends to accumulate in fatty tissues Significant improvement in ALT levels with normalization of aminotranferases

Probucol is a lipid-lowering drug with potent antioxidant properties that tends to accumulate in fatty tissues

Significant improvement in ALT levels with normalization of aminotranferases

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