NASH

NNon-on-AAlcoholic lcoholic FFatty atty LLiver iver DDisease isease (NAFLD) (NAFLD)

• An epidemic of new milleniumAn epidemic of new millenium..• A new consequence of A new consequence of the obesity epidemicthe 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

NNon-on-AAlcoholic lcoholic FFatty atty LLiver iver DDiseaseisease(NAFLD) (NAFLD)

Fatty liver (Steatosis)

SteatohepatitisSteatohepatitis - inflammation- inflammation - fibrosis - fibrosis

Cirrhosis Cirrhosis

Normal liver Normal liver

The Brief History of NAFLD The Brief History of NAFLD

Fatty Liver Disease: NASH and Related DisordersFatty Liver Disease: NASH and Related DisordersBlackwell Publishing, 2005 Blackwell Publishing, 2005

19791979 ~8 papers published~8 papers published19981998 First NIH conferenceFirst NIH conference19991999 First Clinical Trials First Clinical Trials20022002 ~60 papers published~60 papers published20042004 Release of first book on NAFLD/NASHRelease of first book on NAFLD/NASH20052005 ~354 papers published~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

NAFLD NAFLD

1. 1. Most commonMost common of all liver disorders. of all liver disorders.2. Frequent cause of chronic liver disease.2. Frequent cause of chronic liver disease.3. Present in 3% of children and >50% of 3. Present in 3% of children and >50% of obese children.obese children.

Fatty Liver Disease: NASH and Related DisordersFatty Liver Disease: NASH and Related DisordersBlackwell Publishing, 2005 Blackwell Publishing, 2005

Prevalence of NAFLD In General Population In Asian Pacific Region

Name of the Percentage NAFLD inCountry AdultsJapan 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% NAIndonesia 52% 47% 56%

Aetiological Classification

• 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

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.

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.

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.

Pathophysiology

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

Two-hit Hypothesis

Fatty Liver11stst Hit Hit

Damaged Liver

22ndnd Hit HitOxidative StressOxidative Stress

ToxinsToxinsInflammatoryInflammatoryMoleculesMolecules

SusceptibilitySusceptibility

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

DietDietFFAFFA

BurnedBurnedVLDL-TGVLDL-TG

Liver DamageLiver Damage

22ndnd Hit Hit

Liver DamageLiver DamageSat FASat FA

22ndnd Hit Hit

ApoptosisApoptosis

Hepatocyte Mass Hepatocyte Mass

Fatty Liver 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

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

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

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

Natural history and clinical outcomes of NASH

20% 30—40% NASH CIRRHOSIS Liver related Death

Sub acute HCC Post-OLTX Failure recurrance

Diagnosis

• 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

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

• 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

Histology

• 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

Histology

• 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%

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

• 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.

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.

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

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

Betaine• 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

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