Nonalcoholic Fatty Liver Disease

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Nonalcoholic Fatty Liver Disease

• Clinical Implication and Related Biochemical
  Studies

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Nonalcoholic Fatty Liver Disease

• a growing worldwide problem.
• may be the most common disease encountered
• in general medical practice
• and in health check up.

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Nonalcoholic Fatty Liver Disease

• affects 10 to 24 of the general population in
  various countries
• 57 to 74 in obese persons
• 2.6 of children
• 22.5 to 52 of obese children

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Nonalcoholic Fatty Liver Disease

• mistaken as
• non-progressive or
• of nothing previously

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Nonalcoholic Fatty Liver Disease

• simple steatosis,
• steatohepatitis,
• fibrosis,
• cirrhosis

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Progression of Disease

• Progression of fibrosis
• histologically in 32 to 37 of NASH.
• Risk of developing liver complications within 7
  years
• NASH/advanced stage fibrosis
• Mortality, liver related
• 12 to 25 within 7 to 10 years in cirrhotic N

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Progression of Disease

• Cirrhosis
• Age
• Activity of NASH
• Mortality, liver related
• 12 to 25 within 7 to 10 years in cirrhotic N

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Progression of Disease

• Cryptogenic cirrhosis
• Many cryptogenic cirrhosis are probably NAFLD
• Liver transplant
• Account for 4 to 10 of liver transplant in
  America End Stage of NAFLD

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Clinical Condition Related to NAFLD

• Obesity
• T2DM
• Hyperlipidemia
• Insulin Resistant
• Impaired glucose tolerance
• Cardiovascular Disease
• Celebrovascular Disease
• Endocrine Disease

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Nonalcoholic Fatty Liver Disease

• Lugwig coined the term nonalcoholic
  steatohepatitis (NASH) in 1980
• Angulo P. nonalcoholic fatty liver disese in New
  England Journal of Medicine 2002

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Pathogenic Relationships

• Metabolic studies in human and animals
• Inextricable relationships between vieral
  adiposity (central obesity), steatosis and
  insulin resistance

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Insulin Resistance

• In peripheral tissues, muscle and adipose,
  decreased uptake of glucose
• In liver, failure of insulin to stimulate
  glycogen synthesis and suppress gluconeogenesis?
  failure of insulin to downregulate hepatic
  glucose production

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Steatosis before hepatic IR

• Sequence of steatosis before hepatic IR
• By several studies in animals.
• Samuel VT. J Biol Chem 2004, Kraegen EW. Diabetes
  1991
• Correction of steatosis reverses hepatic IR in
  leptin-deficient ob/ob mice.
• Friedman J. Nature 2002 415268

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Steatosis (in human, current focus)

• Mitochondrial defects as primary cause of
  steatosis
• Impaired B-oxidation of fatty acid
• Possibly have a genetic basis, worsened by aging
  and environmental factors
• Lowell BB. Science 2005 307. Browning JD. J Clin
  Invest 2004 114.

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Steatosis cause hepatic IR
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Peripheral IR a role with NASH

• Nearly universal association of NASH, usually
  with two of more features of metabolic syndrome
• Recurrent of NASH after liver transplant?
  metabolic milieu rather then primary hepatic
  defect

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Key Issue in NASH

• Whether hepatic IR ?cellular injury and hepatic
  inflammation
• Or inflammation and steatosis? hepatic IR
• Recent studies latter by block hepatic insulin
  receptor signaling

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Hepatic and peripheral insulin receptor signaling

• IR? intracellular accumulation of fatty acids
  and their metabolites? activate protein kinase C
  isoforms
• Protein kinase C catalyzes serin/threonine
  phosphorylation of the insulin receptor
  substrate IRS-1 and IRS-2? impair the tyrosine
  phophorylation required for signaling
• IRS-2 are critical in liver

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Other serine/threonine kinases

• Inhibitor of kappaB kinase IKKB-ß
• C-Jun N-terminal kinase
• Both can be activated by oxidative stress or
  indirectly by engagement of the TNFa type 1
  receptor
• Cytokines induce suppressors of cytokine
  signaling (SOCS)?another family protein? mediate
  hepatic IR

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Hepatic Expression of Cytochrome P450 (CYP)2E1
Creates Oxidative Stress

• Associate with impaired insulin receptor
  signaling in both NASH and some forms of
  experimental steatohepatitis

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TNFa

• Activation of IKK-B or c-Jun N-terminal kinase,
  induction IL-6 which induce SOCS3? womorsening
  hepatic insulin resistance
• A candidate molecule in the transition of
  steatosis to steatohepatitis

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Peripheral Insulin Resistance and failure of
humoral mediator

• Resulting in steatosis and NASH
• Increased fatty acid uptake and synthesis
  (lipogenesis), suppression of mitochondrial
  B-oxidation, and impaired TG seretion as VLDL
• Alternatively, steatosis and NASH coud be
  attributable to the combined effect of severe
  peripheral IR and relative failure of humoral
  (adipokine) mediators that combat the effects of
  high insulin levels and fasting hyperglycemia on
  hepatic lipid turnover.

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Adiponectin

• Adiponectin transport of fatty acids into
  mitrochondria for B-oxidation and hepatic fatty
  acid synthesis? countering the effect of high
  insulin
• Low serum adiponectin distinguishes NASH from
  simple steatosis
• Decreased adiponectin before T2DM and
  cardiovasular disease

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Adiponectin

• Adiponectin transport of fatty acids into
  mitrochondria for B-oxidation and hepatic fatty
  acid synthesis? countering the effect of high
  insulin
• Low serum adiponectin distinguishes NASH from
  simple steatosis
• Decreased adiponectin before T2DM and
  cardiovasular disease

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Adiponectin

• Administer adiponectin reverse steatohepatitis by
  combating release of TNF-a
• Masaki T. Hepatology 2004 4019
• A potential therapeutic targets in NASH
• Larter C. J Hepatol 2006 44253

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Transition of Steatosis to Steatohepatitis
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Lipotoxicity

• Capacity of hepatocytes to safely store fat is
  overwhelmed by
• Continued uptake
• Impaired egress of fatty acids
• Fatty acid become toxic?lipotoxicity

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Lipotoxicity

• Cause cell death by
• Direct effects of lipid mediators on apoptosis
• Alternatively, liberation of oxidized lipids and
  their peroxidation products
• ?recruiting and perpetuating the inflammatory
  response

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The First Hit

• Steatosis
• Fatty liver predisposed to forms of injury that
  involve oxidant stress

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The Second Hit

• TNFa
• Oxidative Stress
• Cytokines
• Chemokines

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The Second Hit

• Exaggerated release of TNFa in rodent models of
  steatosis
• Over-express CYP2E1 in animal model and in NASH
  human
• Increased CCL2/MCP-1 (CC-chemokine ligand/
  Monocyte chemoattractant protein) in NASH
• Haukeland JW. J of Hepatol 2006 441167

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The Second Hit

• Recent data TNFa may not be essential
• Oxidative stress may recruit inflammation via
  activcation of nuclear factor-kappa B

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Grading for steatohepatitis

• Grade 1, mild
• Grade 2, moderate
• Grade 3, severe

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Staging for fibrosis

• Stage 1 zone 3 perivenular, perisinusoidal, or
  pericellular fibrosis focal or extensive
• Stage 2 as above, with focal or extensive
  periportal fibrosis
• Stage 3 bridging fibrosis, focal or extensive
• Stage 4 cirrhosis

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Possible Topics

• Prospective observation of NAFLD with different
  biochemical marker
•  Cohort studies of NAFLD with different
  biochemical marker
• Controversy in leptin in NAFLD
• Inflammatory mediators in NAFLD other than TNF
•  

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• IR in NAFLD and its relation with clinical
  parameter
•  Prevalence of NAFLD in type II DM
•  Impaired glucose tolerance vs NAFLD (normal ALT/
  abnormal ALT?)
•   Differences between Metabolic syndrome or type
  II DM with or without NAFLD

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• The influence of steatosis in the treatment with
  chronic hepatitis C
• Predictor of type II DM
• Predictor of fibrosis
• Treatment with Metformin or other insulin
  sensitizer

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Health Control

• Normal BMI
• Normal fasting blood sugar, TG, cholesterol,
  normal OGGT
• Normal AST/ALT/Bilirubin/rGT
• No evidence of hepatitis including HBV, HCV,
  autoimmune disease
• Alcohol consumption lt20g/day

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Essential Recording

• Age, Gender
• Body weight, body height, waist circumference,
  hip circumference, BMI
• Alcohol consumption (amount/frequency, at least
  g/day)
• History of liver disease, including HBV, HCV,
  autoimmune disease, DM, hyperlipidema
• Family History of above mentioned (at least first
  degree)

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NAFLD and Related Biochemical Studies Including
OGTT and, IR

• Arthrometry BMI, Wait/hip ratio
• AST/ALT, rGT, Bilirubin, ALP
• Cholesterol, HDL, TG, UA
• SBP/DBP
• OGTT
• Insulin Resistance
• ANA, Ferritin

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Ultrasound

• Increased echogenicity, increased L/K contrast
• Attenuation
• Lost of detail
• Sandford, NL. Walsh, P. Matis, C, et
  al.Gastroenterology 1985 89 186-91. Is
  Ultrasonography useful in the assessment of
  diffuse parenchyma liver disease.
• Yang PM. Huang, GT. Lin, JT, et al. J Formosan
  Med Asoc 1988 87 966- 77
• Riley TR, Mendoza A, Bruno MA. Bedside ultrasound
  can predict nonalcoholic fatty liver disease in
  the hands of clinicians using a prototype image.
  Dig Dis Sci 2006 51(5) 982- 985
• Needleman L, Kurtz AB, Rifkin MD, et al.
  Sonography of diffuse benign liver disease
  Accuracy of pattern recognition and grading. AJR
  1986 1461011- 1015
• Riley TR, Kahn A. Risk factors and ultrasound can
  predict chronic hepatitis caused by nonalcoholic
  fatty liver disease. Dig Dis Sci 2006 51(1) 41-
  44

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HOMA

• Homa index insulin concentration (µU/ml)x
  fasting glucose concentration (mmol/l)/22.5
• Cutoff level 2.5 for adult
• Cutoff level 3.16 for aldolescent
• Keskin M, et al. Padiactric 2005 March

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