Non alcoholic steatohepatitis (NASH)

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Non alcoholic steatohepatitis(NASH)

• Raika Jamali M.D.
• Gastroenterologist and hepatologist
• Tehran University of Medical Sciences

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Steatohepatitis

• Is an intermediate stage in the spectrum of non
  alcoholic fatty liver disease (NAFLD),
• Simple fatty liver --gt Steatohepatitis --gt
  Cirrhosis
• Shows the same histopathology but occurs in the
  absence of excess alcohol consumption (lt20 gr/day)

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• Associated with the metabolic syndrome
  (insulin-resistant state)
• Truncal obesity,
• Type 2 DM,
• Hypertension
• Dyslipidemia (high TG and low HDL levels).
• Though strongly associated with obesity, NASH has
  also been demonstrated in 3 of lean individuals
  (generalized lipodystrophy)

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Epidemiology

• The prevalence varies based on the diagnostic
  test used
• Population-based surveys of adults gt18 y with US
  have demonstrated fatty liver disease in 20 of
  the populations of Japan, Western Europe, and the
  US
• MRI 34 in the general population gt18 y
• Hispanic Americans (50), Whites (33), African
  Americans (25) have fatty livers

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• 80 of individuals with steatosis by MRI have
  normal ALT levels,
• Indicating that blood tests are the least
  sensitive tool for diagnosis
• Prevalence of fatty liver disease falls to 8 if
  elevations in ALT are used for screening

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• NASH is the main cause of elevated liver enzymes
  in the Western world
• The true prevalence of NASH is unknown
• because neither imaging tests nor blood tests
  reliably differentiate steatosis from more
  advanced stages of fatty liver disease (NASH and
  cirrhosis)
• and because liver biopsy studies show that NASH
  or cirrhosis sometimes occurs in individuals with
  normal ALT levels,

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• Liver biopsy studies suggest
• Steatosis is twice as common as NASH
• at least 10 of patients with NASH progress to
  cirrhosis over time
• in the adult U.S. population
• Fatty liver (34)
• Steatohepatitis (17)
• Cirrhosis (2)

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• The prevalence of NAFLD in Iran was
• 2.04 in a population based study in Golestan
  province. (2006)
• 2.1 in autopsies from forensic medicine of
  Tehran. (2006)
• 2.35 in healthy blood donors in Tehran. (2005)

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Pathobiology

• In the early stages of non alcoholic fatty liver
  disease (NAFLD), fat accumulates within
  hepatocytes when mechanisms that promote lipid
  removal (by oxidation or export) cannot keep pace
  with mechanisms that promote lipid import or
  biosynthesis.
• Although alcohol consumption has long been known
  to promote lipid biosynthesis while inhibiting
  lipid export, it has been appreciated only
  recently that the molecular mechanisms involved
  are very similar to those that promote steatosis
  in nonalcoholic fatty liver disease.

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• Factors that modulate the evolution of NAFLD
• Fatty acids
• Tumor necrosis factor-a (TNF-a)
• Adiponectin
• Fatty acids routinely traffic between the liver
  and adipose tissue.
• Fat and the liver are also important sources of
  TNF-a and adiponectin.
• Adiponectin reduces lipid accumulation within
  hepatocytes
• by inhibiting fatty acid import and increasing
  fatty acid oxidation and export.
• It is also a potent insulin-sensitizing agent.

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• TNF-a antagonizes the actions of diponectin
• promotes hepatocyte steatosis
• increases mitochondrial generation of reactive
  oxygen species, which induce insulin resistance.
• promotes hepatocyte apoptosis and recruits
  inflammatory cells to the liver.
• generates oxidative and apoptotic stress that
  sometimes overwhelms antioxidant and
  antiapoptotic defenses and leads to
  steatohepatitis.
• Thus the relative risk for the development of
  NASH correlates with increases in TNF-a or
  decreases in adiponectin levels

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Fatty acids within hepatocytes
Inhibitor ? kinase-ß
Nuclear transcription factor NF?B
TNF-a and IL-6
insulin resistance

• Therefore, like adipose tissue, fatty livers also
  make soluble factors that circulate to distant
  tissues and contribute to systemic insulin
  resistance (the metabolic syndrome).

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• NASH can develop in nonobese individuals.
• The mechanism of liver damage in nonobese and
  obese individuals may be similar
• excessive exposure of hepatocytes to fatty acids
• fatty acidinducible inflamma-tory mediators
  (TNF-a)
• reactive oxygen species.
• Intestinal microflora help regulate intestinal
  uptake of diet-derived lipids, in addition to
  hepatic fatty acid synthesis,
• the gut bacteria of some nonobese individuals
  might promote excessive hepatic accumulation of
  fatty acids, as well as exposure to other
  bacterial factors (e.g., lipopolysaccharide) that
  trigger hepatic TNF production

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• The role of intestinal flora in the pathogenesis
  of alcohol-induced fatty liver disease has been
  well demonstrated
• Experimental animals housed under germ-free
  conditions or treated with poorly absorbed oral
  antibiotics are protected from alcohol-induced
  hepatotoxicity.
• Products from intestinal bacteria are thought to
  injure the liver by increasing hepatic production
  of TNF-a and reactive oxygen species
• because mice that are genetically deficient in
  either TNF-a or certain enzyme that generate
  reactive oxygen species are also protected from
  the alcoholic liver damage

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• Progression from fatty liver disease to cirrhosis
  is predominately dictated by the severity of
  oxidant stress and the consequent
  necro-inflammation.
• However, findings in animal models of
  steatohepatitis cast some doubt on this
  assumption because mice in which severe
  steatohepatitis develops do not uniformly
  progress to cirrhosis
• In fact, progression to cirrhosis is also poorly
  predicted by the gravity of the injurious insult
  in human fatty liver disease
• For example, although there is no doubt that
  alcohol is hepatotoxic, most lifelong heavy
  drinkers do not become cirrhotic
• Similarly, although obesity clearly increases
  exposure to fat-derived inflammatory mediators
  and is an independent risk factor for progression
  of alcoholic fatty liver disease to cirrhosis,
  some morbidly obese individuals have normal
  livers at the time of gastric bypass surgery

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• Individuals in whom just steatosis develops
  despite constant bombardment with inflammatory
  factors might be better at repairing their liver
  damage without the development of fibrosis than
  those in whom NASH or cirrhosis develops.
• In this regard, leptin, angiotensin, and
  norepinephrine
• promote the proliferation of hepatic stellate
  cells
• upregulate their expression of profibrogenic
  cytokines (TGF ß)
• induce collagen gene expression.
• Conversely, adiponectin appears to inhibit the
  activation of hepatic stellate cells and decrease
  liver fibrosis.
• Angiotensin is an independent risk factor for
  advanced liver fibrosis in NASH and the
  suggestion,that angiotensin receptor blockade
  might decrease liver fibrosis and slow disease
  progression in patients with NASH and arterial
  hypertension.

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