Nonalcoholic Fatty Liver Disease NAFLD

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Nonalcoholic Fatty Liver Disease (NAFLD)
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NAFLDPresentation Outline

• Definition
• Prelevance
• Risk Factors
• Pathogenesis
• Natural History
• Clinical Features
• Diagnosis
• Treatment

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Defining NAFLD

• A liver biopsy showing moderate to gross
  macrovesicular fatty change with or without
  inflammation (lobular or portal), Mallory bodies,
  fibrosis, or cirrhosis.
• Negligible alcohol consumption (less than 40 g of
  ethanol per week)
• History obtained by three physicians
  independently.
• Random blood assays for ethanol should be
  negative.
• If performed, desialylated transferrin in serum
  should also be negative.
• Absence of serologic evidence of hepatitis B or
  hepatitis C.

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NAFLDSpectrum of Disease

• Steatosis
• Steatohepatitis (NASH)
• NASH with Fibrosis
• Cirrhosis

NAFLD
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NAFLDWhy Study it?

• Prevalence of NAFLD 13-18 and that of NASH
  specifically 2-3 (1.2-9)
• Is the leading cause of cryptogenic cirrhosis
• Is a disease of all sexes, ethnicities, and age
  groups (peak 40-59)
• Occurs more frequently in females (65 to 83)

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NASHRisk Factors
34 to 75
20 to 80
69 to 100
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NAFLDRisk Factors
Obesity
Diabetes Mellitus
Hypertriglyceridemia
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NAFLDPathogenesis
Hepatic iron, leptin, anti-oxidant
deficiencies, and intestinal bacteria
Second Hit
Steatosis
First Hit
NASH
Lipid peroxidation
Insulin resistance ? Fatty acids
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NAFLDPathogenesis

• TRIGLYCERIDE ACCUMULATION
• INSULIN RESISTANCE
• Lipid Peroxidation and Hepatic Lipotoxicity
• Cytokine Activation and Fibrosis
• Adiponectin and Leptin (Adipocytokines)
• Abnormal Lipoprotein Metabolism

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TRIGLYCERIDE ACCUMULATION

• The normal liver contains less than 5 lipid by
  weight
• Excessive importation of FFA
• Obesity
• Rapid weight loss,excessive
• conversion of carbohydrates and proteins to
  triglycerides
• Impaired VLDL synthesis and secretion
• Abetalipoproteinemia,
• Protein malnutrition,
• Choline deficiency
• Impaired beta-oxidation of FFA to ATP
• Vitamin B5 deficiency,
• Coenzyme A deficiency

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INSULIN RESISTANCE

• Increased
• Peripheral lipolysis
• Triglyceride synthesis
• Hepatic uptake of fatty acids

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Lipid Peroxidation Hepatic Lipotoxicity

• Free radicals initiate the process derived from
  fat metabolism, in the setting of preexisting
  defects in mitochondrial oxidative
  phosphorylation.
• Free radical attack on unsaturated fatty acids
• The products of the reaction are another free
  radical and a lipid hydroperoxide, forms a second
  free radical and, amplifies the process.
• Imbalance between pro- and antioxidant substances
  (oxidative stress)

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Cytokine Activation and Fibrosis

• Lipoperoxide induce expression of inflammatory
  cytokines
• Cytokine level elevation, especially TNF-a has
  been well described in NAFLD.

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Adiponectin and Leptin (Adipocytokines)

• Adoponectin
• A hormone secreted by adipose tissue
• Enhance both lipid clearance from plasma and
  beta-oxidation of fatty acids in muscle.
• Direct anti-inflammatory effects,
• Suppressing TNF-alpha production in the liver
• Leptin
• Coded for by the obesity gene govern satiety
  through action at the hypothalamus
• Elevated levels in NASH were attributed to
  factors involved in production.
• No difference in leptin level was seen between
  patients with worsening injury or those without

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NAFLDNatural History

• Steatosis generally follows a benign course
• Steatosis can progress to NASH fibrosis
• NASH with fibrosis has increased liver-related
  morbidity and mortality
• A study of 103 patients who underwent serial
  liver biopsies (mean interval between biopsies of
  3.2 years) found
• Fibrosis stage progressed in 37 percent
• Remained stable in 34 percent
• Regressed in 29 percent

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Independent predictors of fibrosis progression

• Diabetes mellitus,
• Low initial fibrosis stage
• Higher body mass index.
• Elevated liver enzymes

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Predictors of More Severe Histology in NASH

• Age gt4050 y
• Female gender
• Degree of obesity or steatosis
• Hypertension
• Diabetes or insulin resistance
• Hypertriglyceridemia
• Elevated ALT,AST, ?-GT level
• ASTALT transaminase ratio gt1
• Elevated immunoglobulin A level

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NAFLDSymptoms
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NAFLDExam Findings
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NAFLDLaboratory Findings

• The AST/ALT ratio is usually less than 1(90)
• Antinuclear antibody positive in 30
• Increased IgA
• Abnormal iron indices in 20 to 60
• Elevated PT and low albumin with cirrhosis
• Alkaline phosphatase is less frequently elevated
• Hyperbilirubinemia is uncommon
• Normal labs do not rule out NAFLD

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NAFLDImaging

• Ultrasound
• Difficulty in differentiating fibrosis from fatty
  infiltration
• Misinterpretation of focal fatty sparing as a
  hypoechoic mass
• Poor detection if the degree of steatosis is less
  than 20 to 30
• As initial testing in a suspected case and for
  large population screening, it is a reliable and
  economical
• Computed Tomography
  
  Sensitivity and specificity of detecting fatty
  liver (with spleen-minus-liver attenuation of 10
  Hounsfield units) were 0.84 and 0.99
• M R Spectroscopy
  
  Correlation between liver fat concentration and
  1H-spectroscopy was 0.9

Current non-invasive modalities are unable to
detect NASH with or without fibrosis
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A. Demonstrates a heterogeneous-appearing
echotexture bright liverB. Relatively
hypodense liver compared to the spleen
(liver-to-spleen ratio lt1)
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NAFLDHistological Spectrum
Cirrhosis
Time Progression
Fibrosis
Lobular Inflammation
Macrovesicular Steatosis
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Steatosis
gt510 macrosteatotic hepatocytes
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NASH (without fibrosis)
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Cirrhosis (stage 4)
Early stage 3 (bridging fibrosis)
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Liver biopsy in NASH, Indications

• Peripheral stigmata of chronic liver disease
• Splenomegaly
• Cytopenia
• Abnormal iron studies
• Diabetes and/or significant obesity in an
  individual over the age of 45

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How to Treat?
Antioxidants
Insulin Sensitizers
Cytoprotectants
Antihyperlipidemics
Second Hit
First Hit
Steatosis
NASH
Insulin resistance ? Fatty acids
Lipid peroxidation
Weight Loss Diet/Exercise
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Weight reduction

• Can lead to sustained improvement in liver
  enzymes, histology, serum insulin levels, and
  quality of life.
• Improvement in steatosis following bariatric
  surgery
• Should not exceed approximately 1.6 kg per week
  in adults .

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Weight Loss/Exercise

• Palmer et al. Gastroenterology 1990
• --39 obese patients, no primary liver disease
• --Retrospective analysis after weight loss
• --Lower ALT seen in patients with gt10 weight
  loss
• Anderson et al. Journal Hepatology 1991
• --41 obese patients with biopsy-proven NAFLD
• --Low calorie diet (400 kcal/d) x 8 months
  then re-biopsied
• --Most improved, but 24 with worse
  fibrosis/inflammation
• --Histological worsening associated with rapid
  weight loss

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Insulin Sensitizers
Metformin

• Marchesini et al. Lancet 2001
• --20 patients, biopsy-proven NASH
• --14 metformin (500 tid) x 4 months 6 controls
• --ALT OGTT improved in metformin
• Nair et al. Gastroenterology (in press)
• --22 patients, biopsy-proven NASH
• --Received metformin 20 mg/kg/d x 12 months
• --Improvement in ALT insulin sensitivity
• --No improvement in liver histology

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Metformin

• Improvement in necroinflammation was observed
  more frequently in patients in the metformin
  group but results did not achieve statistical
  significance.
• Improvement was only transient in another open
  label study of 15 patients .

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Thiazolidinediones

• Pioglitazone was associated with significant
  declines in serum aminotransferase levels,
  increased hepatic insulin sensitivity, and
  improvement in histology.
• Rosiglitazone was associated with significantThe
  mean global necroinflammatory score improvement
  in ten patients (45 percent) .
• There was also significant improvement is
  perisinusoidal fibrosis.
• Mean serum ALT levels showed corresponding
  improvement.

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Antihyperlipidemics

• Laurin et al. Hepatology 1996
• --16 patients biopsy-proven NASH
• --Received clofibrate 2 g/d x 12 months
• --No significant improvement in ALT or
  histology
• Basaranoglu et al. Journal Hepatology 1999
• --46 patients biopsy-proven NASH followed 4
  months
• --23 received gemfibrozil, 23 no treatment
• --74 patients in gemfibrozil group had lower
  ALT
• --30 patients no treatment group had lower ALT
• Naserimoghadam SSO - J Hepatol 2003
• Probucol was associated with a significant
  reduction in serum aminotransferases

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Ursodeoxycholic Acid

• Laurin et al. Hepatology 1996
• --24 patients with biopsy-proven NASH
• --Treated with UDCA 13-15 mg/kg/d x 12 months
• --63 had improved ALT and steatosis
• --No significant improvement in
  inflammation/fibrosis
• Lindor et al. Gastroenterology (in press)
• --Randomized controlled double-blind study
• --168 patients with biopsy-proven NASH
• --82 received UDCA and 86 no treatment x 12
  months
• --No significant improvement in ALT or histology

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Antioxidants
Vitamin E

• Hasegawa et al. Aliment Pharmacol Ther 2001
• --22 patients, 10 steatosis and 12 biopsy-proven
  NASH
• --6 months standard diet followed by Vitamin E
  100 IU tid x 12 mo
• --Steatosis group showed improvement in ALT
  after diet
• --NASH group showed improvement in ALT after
  Vitamin E
• --40 NASH patients had histological improvement
  after Vitamin E
• Kugelmas et al. Hepatology 2003
• --16 patients with biopsy-proven NASH followed
  for 3 mo
• --9 received diet/exercise and Vitamin E 800 IU
  qd
• --7 diet/exercise only
• --Vitamin E conferred no significant improvement
  in ALT

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Vitamin E

• An increase in mortality with vitamin E
  supplementation
• The weak evidence supporting its benefit in NASH
• Vitamin E supplementation cannot be recommended
  in patients with NASH

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Other drugs

• Betaine
• Losartan
• Pentoxifylline
• Orlistat

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Management Summary

• There is no proven effective therapy for NASH.
• Gradual, sustained weight loss is hallmark
  therapy
• Attempts should be made to modify potential risk
  factors (obesity, hyperlipidemia, and poor
  diabetic control).
• Rapid weight loss potentially worsening of liver
  disease
• Gemfibrozil, insulin sensitizers require
  further study
• Clofibrate ,UDCA Vitamin E is not useful in
  NASH.

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Limitations of Studies

• Few randomized trials
• Small study populations
• Short follow-up periods
• Minimal biopsy data

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Conclusions

• NAFLD affects up to 15 of the US population
• Steatosis is relatively benign, but NASH has
  significant morbidity/mortality risk
• Insulin resistance and cellular damage are the
  key pathogenetic mechanisms
• Sustained gradual weight loss and exercise are
  hallmark therapies
• Insulin sensitizers, cytoprotectants,
  antioxidants may play role in future for those
  who fail conservative therapy

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Defining NAFLD

• A liver biopsy showing moderate to gross
  macrovesicular fatty change with inflammation
  (lobular or portal) and with or without Mallory
  bodies, fibrosis, or cirrhosis indistinguishable
  from alcoholic hepatitis. It is possible that
  portal fibrosis alone may represent a variant of
  NASH .
• Convincing evidence of negligible alcohol
  consumption (less than 40 g of ethanol per week)
  including a detailed history obtained by three
  physicians independently and interrogation of
  family members and local medical practitioners.
• Random blood assays for ethanol estimation should
  be negative. If performed, assays for the
  presence of desialylated transferrin in serum, a
  marker of alcohol consumption, should also be
  negative
• Absence of serologic evidence of infection with
  hepatitis B or hepatitis C.
• In clinical practice, a meticulous history by
  three physicians is not usually practical we
  therefore feel that this is not mandatory for the
  diagnosis.

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NAFLDRisk Factors

• Metabolic syndrome in 304 consecutive patients
  with NAFLD (38) of whom 120 were diagnosed with
  NASH (14).
• Obesity has been reported in 69 to 100 percent of
  cases . Most patients are 10 to 40 percent above
  ideal body weight . NASH also occurs in obese
  patients who have undergone surgery for weight
  reduction it usually develops during the first
  12 to 18 months, the period in which weight loss
  is most rapid .
• Type 2 diabetes has been described in 34 to 75
  percent of patients with NASH .
• Hyperlipidemia (hypertriglyceridemia and/or
  hypercholesterolemia) has been reported in 20 to
  80 percent of patients with NASH

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Conditions Associated with Nonalcoholic Fatty
Liver

• Metabolic factors
• Bariatric (weight loss) surgery
• Jejunoileal bypass (no longer performed)
• Gastric bypass or gastroplasty (less frequent
  compared to jejunoileal bypass)
• Medications
• Parenteral nutrition and malnutrition
• Total parenteral nutrition
• Kwashiorkor
• Celiac disease
• Miscellaneous
• Wilson disease
• Toxins (CCl4, perchloroethylene,
  phosphorous, ethyl bromide, petrochemicals)

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Simple steatosis The patient is a 47-year-old
woman with mild obesity and an idiopathic,
neurodegenerative diseaseand hepatomegaly. The
biopsy specimen showed only minimal inflammation
and no fibrosis. No inciting agents were
identified toexplain the liver condition
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Classification and Stages of Non

• Fibrosis Stages of NASH (Brunt et al. (23))
• Stage 1 Zone 3, pericentral vein, sinusoidal or
  pericellular fibrosis
• Stage 2 Zone 3 sinusoidal fibrosis and zone 1
  periportal fibrosis
• Stage 3 Bridging between zone 3 and zone 1
• Stage 4 Regenerating nodules, indicating
  cirrhosis
• Types of NAFLD (Matteoni et al. (7))
• Type 1 Simple steatosis (no inflammation or
  fibrosis)
• Type 2 Steatosis with lobular inflammation but
  absent fibrosis or balloon cells
• Type 3 Steatosis, inflammation, and fibrosis of
  varying degrees (NASH)
• Type 4 Steatosis, inflammation, ballooned cells,
  and Mallory hyaline or fibrosis (NASH)

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Adiponectin and Leptin (Adipocytokines)

• Adoponectin is a hormone secreted by adipose
  tissue
• Enhance both lipid clearance from plasma and
  beta-oxidation of fatty acids in muscle.
• It has also has direct anti-inflammatory effects,
  suppressing TNF-alpha production in the liver
• Leptin is a circulating protein coded for by the
  obesity gene and produced primarily in white
  adipose tissue
• Its level is increased in cirrhosis .
• Its primary role is to govern satiety through
  action at the hypothalamus
• Human obesity is usually associated with elevated
  leptin levels .
• Elevated leptin levels in progressive NASH were
  attributed to factors involved in production no
  difference in leptin was seen between patients
  with worsening injury or those without on serial
  biopsy
• Resistance to leptin in the CNS rather than the
  liver may be important in the pathogenesis of
  NASH.

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Insulin Sensitizers
Thiazolidinediones

• Neuschwander et al. Journal of Hepatology 2003
• --30 patients biopsy-proven NASH and elevated
  ALT
• --Received rosiglitazone 4 mg bid x 6 months
• --Significant improvement of ALT and insulin
  sensitivity
• Azuma et al. Hepatology (in press)
• --12 patients biopsy-proven NASH
• --Received 15 mg qd pioglitazone x 3 months
• --Significant improvement in ALT