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NAFLD, NASH
 

NAFLD, NASH

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    NAFLD, NASH NAFLD, NASH Presentation Transcript

    • DR. Shatdal Chaudhary MD
      • 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
    • 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
    • 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 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%
    • 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%
    • 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 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
    • 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