NONALCOHOLIC STEATOHEPATITIS (NASH), NAFLD, ASH

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NONALCOHOLIC STEATOHEPATITIS(NASH), NAFLD,
ASH

• J. Horák
• Department od Medicine I
• Third Faculty of Medicine
• Charles University

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HEPATIC STEATOSIS

• macrovesicular
• in long-standing disorders of hepatic lipid
  metabolism (obesity, DM type II, alcohol)
• microvesicular
• impaired ß-oxidation of FA abnormal
  metabolism of VLCFA, LCFA, DCA and other
  substrates for peroxisomal FA-CoA oxidase that
  activate PPAR-a (peroxisome proliferator-activated
  receptor)

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NASH

• First described by Ludwig et al. (Mayo Clin.
  Proc. 55, 1980, 434 - 438)
• NASH is a part of Nonalcoholic Fatty Liver
  Disease (NAFLD)
• Defined clinically (alcohol intake lt 20 g/day)
  and histologically liver biopsy is necessary for
  reliable diagnosis
• Predisposing factors obesity, adult age,
  diabetes mellitus type II, female sex
• Lab AST gt ALT, hypertriacylglycerolemia

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NAFLD

• Is a result of insulin resistance
• Histological findings
• Simple steatosis
• Steatosis plus inflammation
• Steatosis plus balloon degeneration
• Steatosis, sinusoidal fibrosis and
  polymorphonuclear cell infiltrate, sometimes
  together with Malloryho hyaline
• Only stages 3 and 4 correspond with NASH

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PREVALENCE

• Whole population
• NAFLD 20
• NASH 2 3
• The highest occurrence of NAFLD
• 5th 6th decade, females (65 83), diabetes
  mellitus type II (28 55), obesity (60 95),
  hyperlipidemia (20 92)

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THE METABOLIC SYNDROME AND NAFLD

• 67 patients with NAFLD and 88 with NASH have MS
• MS increases risk of NASH (OR 3.2) and hepatic
  fibrosis (OR 3.5)
• prevalence of MS in NAFLD increases with BMI
• in NAFLD prevalence of NASH increases with BMI
• 66 patients with NAFLD have hypertriacylglycero
  lemia

Marchesini et al, Hepatology 2003
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CAUSES OF NAFLD

• Metabolic syndrome
• Insulin resistance is an important part of NAFLD
  and is found also in patients with normal weight
  and glucose tolerance
• NAFLD increases exponentially pribývá
  exponenciálne with type II DM, hyperlipidemia,
  visceral obesity and hypertension
• Drugs (steroids, amiodaron, diltiazem)
• Chronic inflammation
• Total parenteral nutrition
• Short-bowel syndrome
• Inborn errors of lipid metabolism
  (abetalipoproteinemia etc.)

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ETIOPATHOGENESIS OF NASH (1)

• Defined causes
• The initial lesion is simple steatosis episodes
  of steatohepatitis lead to cirrhosis (cirrhosis
  prevalence up to 25)
• Insulin resistance of any cause
• Rapid weight loss in obesity
• Total parenteral nutrition
• Drugs and other toxins
• Jejunoileal bypass
• TNF-a polymorfisms
• Copper intoxication

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ETIOPATHOGENESIS OF NASH (2)

• NASH might be due to liver lesion in frame of a
  systemic disease
• Industrial toxins
• dimetylformamid
• toxic oil syndrome

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ETIOPATHOGENESIS OF NASH (3)

• Drugs
• amiodaron
• perhexillin
• dilthiazem, niphedipin
• synthetic estrogens, tamoxiphen
• chloroquine
• salicylates
• glucocorticoids (high doses)
• tetracycline

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ETIOPATHOGENESIS OF NASH (4)

• Others
• Gluten-sensitive enteropathy
• Abetalipoproteinemia
• Wilson disease
• Colon diverticulosis

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PATHOGENESIS OF NASH

• insulin resistance
• simple hepatic steatosis
• reactive oxygen species
• lipid peroxidation
• NASH

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HISTOLOGY OF NASH

• steatosis (100)
• balloon degeneration of hepatocytes (100)
• mild diffuse infiltration by PMNs (56 100)
• perivenular and perisinusoidal collagen
  deposition (41 100)
• cirrhosis (0 26)
• Mallory hyaline (0 90)
• glycogen nuclei (35 100)
• focal necroses (25 57)

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MINIMAL DEMANDS FOR DIAGNOSIS

• mainly macrovesicular steatosis
• mild lobular infiltration by PMNs and
  mononuclears
• balloon degeneration of hepatocytes
  with a maximum around steatotic hepatocytes in
  zone 3

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CLINICAL AND LABORATORY FINDINGS

• Asymptomatic course - in 45 100
• Symptomes right epigastric pain, abdominal
  dyscomfort, fatigue, malaise
• Objective findings hepatomegaly (12 75),
  abnormal liver fubction tests, precoccious
  atherosclerosis in NASH
• US, CT, NMR hepatic steatosis
• In advanced cases hepatic cirrhosis
  (cryptogenic)

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NAFLD MORTALITY
Adams et al, Gastroenterology, 2005, 129113-121
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TREATMENT OF NASH (1)

• treatment of associated conditions (metabolic
  syndrome, obesity, hyperglycemia, hyperlipidemia)
• aerobic exercise
• avoid suspected drugs
• in terminal stage of cirrhosis liver
  transplantation

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TREATMENT OF NASH (2)

• UDCA (Ursofalk), N-acetylcystein (ACC),
  a-tocoferol
• statines
• sibutramin (Meridia), orlistat (Xenical)
• metformin
• thiazolidindiones pioglitazone - Actos,
  rosiglitazone - Avandia

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TREATMENT OF NASH (3)

• anti-TNF drugs pentoxiphyllin, adiponectine
• phenofibrate
• In extreme obesity (BMI gt 40 or BMI
  gt 35 risk factors) bariatric surgery
  

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NASH before and after treatment with
pioglitazone vitamin ESanyal et al, Clin
Gastroenterol and Hepatol, Dec 2004
Pre treatment (10 X)
Post treatment (10 X)