Alcoholic hepatitis pathophysiology

https://https://www.youtube.com/watch?v=RudR2_VVoaw%7C350}}

Alcoholic hepatitis Microchapters
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Alcoholic hepatitis from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Alcoholic hepatitis pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Alcoholic hepatitis pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Alcoholic hepatitis pathophysiology
CDC on Alcoholic hepatitis pathophysiology
Alcoholic hepatitis pathophysiology in the news
Blogs on Alcoholic hepatitis pathophysiology
Directions to Hospitals Treating Alcoholic hepatitis
Risk calculators and risk factors for Alcoholic hepatitis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S

Pathophysiology

• The pathogenesis is multifactorial.
• Alcoholic Hepatitis is caused by interplay between alcohol metabolism, inflammation and innate immunity.
• The Alcohol metabolism leads to a reduced ratio of the nicotinamide adenine dinucleotide (NAD) to NADH."Alcoholic Hepatitis - StatPearls - NCBI Bookshelf".
• The NAD depletion inhibit fatty acid oxidation; therefore, it cause fat accumulation in hepatocytes and lipogenesis.
• Due to increased intestinal permeability in patients with Alcoholic Hepatitis, high levels of Endotoxemia is recognized.
• Endotoxin binds to lipopolysacchride and translocate from intestine to hepatocytes.
• In hepotocytes, lipopolysacchride bindes to CD14 molecule on surface of Kupffer cells which activates Kupffer cells.
• This activation release tumor necrosis factor-alpha (TNF alpha), interleukin-8, monocyte chemotactic protein 1 (MCP-1), and platelet-derived growth factor (PDGF) which are responsible for characterized symptoms including malaise, fever, and peripheral neutrophil leukocytosis. "Interleukin-8 in alcoholic liver disease - PubMed".

• 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 occurs in women at ~40gm 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 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.
• 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.
• 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.

If chronic liver disease is also present:

• Fibrosis
• Cirrhosis - a progressive and permanent type of fibrotic degeneration of liver tissue.

References