Alcoholic hepatitis pathophysiology: Difference between revisions
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== Pathophysiology== | == Pathophysiology== | ||
* The amount and duration of alcohol (EtOH) necessary to damage the liver is variable and relates to host factors. | * The amount and duration of [[alcohol]] (EtOH) necessary to damage the [[liver]] is variable and relates to host factors. | ||
* Most patients with established liver disease continuously consume 60-80 g/day of ETOH (about 8 beers, one liter of wine, or half a pint of liquor) for 10 to 20 years. After 20 years of such behavior, most will have fatty changes, but only half will have [[Cirrhosis|cirrhosis]]. | * Most patients with established [[liver disease]] continuously consume 60-80 g/day of ETOH (about 8 beers, one liter of wine, or half a pint of liquor) for 10 to 20 years. After 20 years of such behavior, most will have fatty changes, but only half will have [[Cirrhosis|cirrhosis]]. | ||
*:* [[Cirrhosis]] occurs in women at ~40gm EtOH/day for >10 years | *:* [[Cirrhosis]] occurs in women at ~40gm EtOH/day for >10 years | ||
*:* [[Cirrhosis]] occurs in men at ~80gm EtOH/day for >10 years | *:* [[Cirrhosis]] occurs in men at ~80gm EtOH/day for >10 years | ||
* Diffuse focal liver cell necrosis with polymorphonuclear, mononuclear, fatty | * Diffuse focal liver cell necrosis with polymorphonuclear, mononuclear, fatty infiltration. Neutrophilic infiltration in particular is unusual for other forms of [[hepatitis]]. | ||
* | * [[Mallory bodies]] | ||
*:* Perinuclear eosinophilic inclusions from intermediate filaments found in alcohol liver disease that can also be seen in [[Ddx:Fatty Liver|fatty liver]], [[Primary Biliary Cirrhosis|primary biliary cirrhosis]], [[Hepatitis C|hepatitis C]], [[Obesity|obesity]]. | *:* Perinuclear eosinophilic inclusions from intermediate filaments found in alcohol liver disease that can also be seen in [[Ddx:Fatty Liver|fatty liver]], [[Primary Biliary Cirrhosis|primary biliary cirrhosis]], [[Hepatitis C|hepatitis C]], [[Obesity|obesity]]. | ||
* | * Perivenular inflammation | ||
* “Ballooning” of hepatocytes results from the accumulation of fat and water. | * “Ballooning” of [[hepatocytes]] results from the accumulation of fat and water. | ||
* Swollen hepatocytes and collagen deposition leads to increased sinusoidal pressures, and perhaps portal hypertension. | * Swollen hepatocytes and [[collagen]] deposition leads to increased sinusoidal pressures, and perhaps [[portal hypertension]]. | ||
* Perisinusoidal fat cells transform into fibroblasts. | * Perisinusoidal fat cells transform into [[fibroblasts]]. | ||
* Other non-essential changes that might be present include bridging necrosis, bile duct proliferation, and cholestasis. | * Other non-essential changes that might be present include bridging necrosis, [[bile duct]] proliferation, and [[cholestasis]]. | ||
=== Molecular Biology === | === Molecular Biology === | ||
Potential mechanisms of alcohol associated liver disease include: | Potential mechanisms of alcohol associated liver disease include: | ||
* ETOH generates excess NADH, which slows gluconeogenesis, increasing lactate production, and leading to fatty acid accumulation. | * ETOH generates excess [[NADH]], which slows [[gluconeogenesis]], increasing [[lactate]] production, and leading to [[fatty acid]] accumulation. | ||
* Acetaldehyde is a toxic metabolite that can impair hepatocyte function | * [[Acetaldehyde]] is a toxic metabolite that can impair [[hepatocyte]] function | ||
* Alcohol metabolism consumes oxygen and contributes to centrilobular hypoxia | * Alcohol metabolism consumes oxygen and contributes to centrilobular hypoxia | ||
* Neutrophil infiltration – perhaps in association with reactive oxygen species | * [[Neutrophil]] infiltration – perhaps in association with reactive oxygen species | ||
* Other minor pathways of alcohol metabolism are upregulated in alcoholics, which may produce more dangerous oxygen intermediates. A microsomal pathway has been called the microsomal enzyme oxidation system (MEOS). Polymorphisms of enzymes in this system (P4502E1 in particular) may contribute to the predisposition of some individuals to alcohol associated liver damage. P4502E1 also appears to increase acetominophen metabolism to toxic metabolites, and may play a role in acetominophen associated liver disease in patients who drink alcohol. | * Other minor pathways of alcohol metabolism are upregulated in alcoholics, which may produce more dangerous oxygen intermediates. A microsomal pathway has been called the microsomal enzyme oxidation system (MEOS). Polymorphisms of enzymes in this system (P4502E1 in particular) may contribute to the predisposition of some individuals to alcohol associated liver damage. P4502E1 also appears to increase [[acetominophen]] metabolism to toxic metabolites, and may play a role in acetominophen associated liver disease in patients who drink alcohol. | ||
* Inflammation and collagen deposition in the perivenular (zone 3) region of the hepatic sinusoids and the space of Disse, impede flow, increasing pressure. Perivenular cell necrosis may be found. | * Inflammation and collagen deposition in the perivenular (zone 3) region of the hepatic sinusoids and the space of Disse, impede flow, increasing pressure. Perivenular cell necrosis may be found. | ||
Some signs and pathological changes in liver histology include: | Some signs and pathological changes in liver histology include: | ||
* [[Mallory body|Mallory's Hyaline]] - a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| location=Philadelphia| id=0-7216-7335-X}}</ref> | * [[Mallory body|Mallory's Hyaline]] - a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| location=Philadelphia| id=0-7216-7335-X}}</ref> | ||
* Ballooning degeneration - hepatocytes in the setting of alcoholic change often swell up with excess fat, water and [[proteins|protein]]; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary | * Ballooning degeneration - hepatocytes in the setting of alcoholic change often swell up with excess fat, water and [[proteins|protein]]; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby [[biliary duct]]s, leading to diffuse [[cholestasis]].<ref name="robspath"> </ref> | ||
* [[Inflammation]] - [[Neutrophil]]ic invasion is triggered by the necrotic changes and presence of cellular debris within the [[lobules]]. Ordinarily the amount of debris is removed by [[Kupffer cells]], although in the setting of inflammation they become overloaded, allowing other white cells to spill into the [[parenchyma]]. These cells are particularly attracted to hepatocytes with Mallory bodies.<ref name="robspath"> </ref> | * [[Inflammation]] - [[Neutrophil]]ic invasion is triggered by the necrotic changes and presence of cellular debris within the [[lobules]]. Ordinarily the amount of debris is removed by [[Kupffer cells]], although in the setting of inflammation they become overloaded, allowing other white cells to spill into the [[parenchyma]]. These cells are particularly attracted to hepatocytes with Mallory bodies.<ref name="robspath"> </ref> | ||
If chronic liver disease is also present: | If chronic liver disease is also present: | ||
* [[ | * [[Fibrosis]] | ||
* [[Cirrhosis]] - a progressive and permanent type of fibrotic degeneration of liver tissue. | * [[Cirrhosis]] - a progressive and permanent type of fibrotic degeneration of liver tissue. | ||
Revision as of 19:44, 15 February 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S
Pathophysiology
- The amount and duration of alcohol (EtOH) necessary to damage the liver is variable and relates to host factors.
- Most patients with established liver disease continuously consume 60-80 g/day of ETOH (about 8 beers, one liter of wine, or half a pint of liquor) for 10 to 20 years. After 20 years of such behavior, most will have fatty changes, but only half will have cirrhosis.
- Diffuse focal liver cell necrosis with polymorphonuclear, mononuclear, fatty infiltration. Neutrophilic infiltration in particular is unusual for other forms of hepatitis.
- Mallory bodies
- Perinuclear eosinophilic inclusions from intermediate filaments found in alcohol liver disease that can also be seen in fatty liver, primary biliary cirrhosis, hepatitis C, obesity.
- Perivenular inflammation
- “Ballooning” of hepatocytes results from the accumulation of fat and water.
- Swollen hepatocytes and collagen deposition leads to increased sinusoidal pressures, and perhaps portal hypertension.
- Perisinusoidal fat cells transform into fibroblasts.
- Other non-essential changes that might be present include bridging necrosis, bile duct proliferation, and cholestasis.
Molecular Biology
Potential mechanisms of alcohol associated liver disease include:
- ETOH generates excess NADH, which slows gluconeogenesis, increasing lactate production, and leading to fatty acid accumulation.
- Acetaldehyde is a toxic metabolite that can impair hepatocyte function
- Alcohol metabolism consumes oxygen and contributes to centrilobular hypoxia
- Neutrophil infiltration – perhaps in association with reactive oxygen species
- Other minor pathways of alcohol metabolism are upregulated in alcoholics, which may produce more dangerous oxygen intermediates. A microsomal pathway has been called the microsomal enzyme oxidation system (MEOS). Polymorphisms of enzymes in this system (P4502E1 in particular) may contribute to the predisposition of some individuals to alcohol associated liver damage. P4502E1 also appears to increase acetominophen metabolism to toxic metabolites, and may play a role in acetominophen associated liver disease in patients who drink alcohol.
- Inflammation and collagen deposition in the perivenular (zone 3) region of the hepatic sinusoids and the space of Disse, impede flow, increasing pressure. Perivenular cell necrosis may be found.
Some signs and pathological changes in liver histology include:
- Mallory's Hyaline - a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.[1]
- Ballooning degeneration - hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary ducts, leading to diffuse cholestasis.[1]
- Inflammation - Neutrophilic invasion is triggered by the necrotic changes and presence of cellular debris within the lobules. Ordinarily the amount of debris is removed by Kupffer cells, although in the setting of inflammation they become overloaded, allowing other white cells to spill into the parenchyma. These cells are particularly attracted to hepatocytes with Mallory bodies.[1]
If chronic liver disease is also present: