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					Nonalcoholic Fatty Liver Disease
    NAFLD—Presentation Outline
•   Definition
•   Prelevance
•   Risk Factors
•   Pathogenesis
•   Natural History
•   Clinical Features
•   Diagnosis
•   Treatment
                   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
• Absence of serologic evidence of hepatitis B or hepatitis C.
 NAFLD—Spectrum of Disease


Steatohepatitis (NASH)

NASH with Fibrosis

         NAFLD—Why 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%)
               NASH—Risk Factors

Diabetes             34 to 75

High TG                     20 to 80

Obesity                         69 to 100

           0    10     20       30     40    50   60   70

                            Prevalence (%)
               NAFLD—Risk Factors
                                    Diabetes Mellitus
                                     *Diabetes Mellitus*
Acquired Metabolic Disorders
in 38%
                               Total Parenteral Nutrition ,Rapid
                                weight loss, Acute starvation
                                      Jejunoileal Bypass
                                 Extensive Small Bowel Loss
                                  Corticosteroids; Estrogens
                                   Methotrexate; Tamoxifen
                                     Diltiazem; Nifedipine
                                       Organic Solvents
Occupational Exposures
                               Wilson's dis,Abetalipoproteinemia
                                     Jejunal diverticulosis
                                 Hepatic iron, leptin,
                                 anti-oxidant deficiencies,
                                 and intestinal bacteria

                                   Second Hit
First Hit            Steatosis                        NASH
Insulin resistance
 Fatty acids


• Lipid Peroxidation and Hepatic Lipotoxicity

• Cytokine Activation and Fibrosis

• Adiponectin and Leptin (Adipocytokines)

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

  1. Peripheral lipolysis

  2. Triglyceride synthesis

  3. Hepatic uptake of fatty acids
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)
     Cytokine Activation and Fibrosis
• Lipoperoxide induce expression of inflammatory cytokines

• Cytokine level elevation, especially TNF-α has been well
  described in NAFLD.
 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
           NAFLD—Natural 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
    Independent predictors of fibrosis

•   Diabetes mellitus,
•   Low initial fibrosis stage
•   Higher body mass index.
•   Elevated liver enzymes
Predictors of More Severe Histology
              in NASH
•   Age >40–50 y
•   Female gender
•   Degree of obesity or steatosis
•   Hypertension
•   Diabetes or insulin resistance
•   Hypertriglyceridemia
•   Elevated ALT,AST, γ-GT level
•   AST:ALT transaminase ratio >1
•   Elevated immunoglobulin A level

  GI bleeding
   RUQ pain
                0   10   20     30     40      50   60   70

                              Prevalence (%)
           NAFLD—Exam Findings






               0   5   10   15    20    25   30   35   40

                            Prevalence (%)
     NAFLD—Laboratory 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
 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
 Current non-invasive modalities are unable to detect NASH
                  with or without fibrosis
A. Demonstrates a heterogeneous-appearing echotexture
―bright liver‖
B. Relatively hypodense liver compared to the spleen
(liver-to-spleen ratio <1)
                   NAFLD—Histological Spectrum
Time Progression


                           Lobular Inflammation

                          Macrovesicular Steatosis

>5%–10% macrosteatotic hepatocytes
NASH (without fibrosis)
(stage 4)   Early stage 3
  Liver biopsy in NASH, Indications
1. Peripheral stigmata of chronic liver disease

2. Splenomegaly

3. Cytopenia

4. Abnormal iron studies

5. Diabetes and/or significant obesity in an individual
   over the age of 45
                 How to Treat?
Insulin Sensitizers                  Antioxidants
Antihyperlipidemics                  Cytoprotectants

                                        Second Hit
 First Hit
                           Steatosis                  NASH
Insulin resistance                     Lipid
 Fatty acids                          peroxidation

                     Weight Loss
            Weight reduction
• Can lead to sustained improvement in liver
  enzymes, histology, serum insulin levels, and
  quality of life.
• Improvement in steatosis following bariatric
• Should not exceed approximately 1.6 kg per week
  in adults .
            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 >10% 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
            Insulin Sensitizers

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
• 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 .
• 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
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
             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
                    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
               Vitamin E
• An increase in mortality with vitamin E
• The weak evidence supporting its benefit in
• Vitamin E supplementation cannot be
  recommended in patients with NASH
                Other drugs
•   Betaine
•   Losartan
•   Pentoxifylline
•   Orlistat
            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.
Limitations of Studies

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

• Insulin sensitizers, cytoprotectants, antioxidants may play
  role in future for those who fail conservative therapy
                    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
            NAFLD—Risk Factors
• Metabolic syndrome in 304 consecutive patients with
  NAFLD (38%) of whom 120 were diagnosed with NASH
• 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
             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
•   Medications
•   Parenteral nutrition and malnutrition
•   Total parenteral nutrition
•   Kwashiorkor
•   Celiac disease
•   Miscellaneous
     Wilson disease
     Toxins (CCl4, perchloroethylene, phosphorous, ethyl bromide,
Simple steatosis: The patient is a 47-year-old woman with
mild obesity and an idiopathic, neurodegenerative disease
and hepatomegaly. The biopsy specimen showed only
minimal inflammation and no fibrosis. No inciting agents
were identified to
explain the liver condition
     Classification and Stages of Non

Fibrosis Stages of NASH (Brunt et al. (23))
• Stage 1: Zone 3, pericentral vein, sinusoidal or pericellular
• 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
• Type 4: Steatosis, inflammation, ballooned cells, and Mallory
  hyaline or fibrosis (NASH)
  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
• 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
• Resistance to leptin in the CNS rather than the liver may be
  important in the pathogenesis of NASH.
               Insulin Sensitizers

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

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