Alcholic Liver Disease Flashcards
Stages of ALD
- Hepatic steatosis- fatty liver, perivenular fibrosis
- Alchoholic hepatitis - fatty changes, inflammation, Mallory bodies, necrosis of hepatocytes
- Alchoholic cirrhosis - loss of architecture, fibrosis, regenerating nodules
- mainly due to excessive ethanol consumption
Metabolism of ethanol
- site- liver
- formation of Acetaldehyde - toxic metabolite- plays etiological role in ALD
1. Alchohol dehydrogenase- cytoplasm
2. Cyp2e1 - microsomes - ROS - MEOS
3. Catalase- peroxisomes - formation of Acetic acid -mitochondrial respiratory chain
~ by aldehyde dehydrogenase in mitochondria of hepatocytes
Etiology of ALD
- Gender- females >
~ even with low intake- estrogen increases gut permeability to endotoxins - pro inflammatory cytokines mediators- injury to hepatocytes - Genetic - polymorphisms in the detoxifying enzymes like ALDH
- Association - Iron overload, infections with HCB, HCV
- Duration and amount of ethanol intake:
~ 80g short term - reversible steatosis
~ 80g daily - increase risk of cirrhosis
~ 160g daily for 10-20 years- severe cirrhosis
Pathogenesis of ALD
Mechanism of liver injury by ethanol
Ethanol —> Acetaldehyde —> Acetic acid
1. Oxidative stress:CYP2E1 metabolism-ROS - lipid per-oxidation of cell membrane
2. Chemical adducts: neoAg - stimulate immune system - autoimmune like response
3. Increased redox ratio:
~ dec NAD+ in cytoplasm and mitochondria
~inhibit fatty oxidation - accumulation of fat
~ lactic acidosis
~ mitochondrial dysfunction- acetic acid production
~ impaired glutathione transport
4. Pro inflammatory cytokines :
~ endotoxin - LPS from gram -ve bacteria- enter portal circulation- TNF a( kupffer)
~ impaired ubiquitin proteosome pathway- inefficient degradation of ubiquitin - accumulation of ubiquitin - Mallory bodies -IL 8,18
5. Protein adducts: directly hepatotoxic
6. Hypoxia - centrilobular area has lowest O2 tension, suspectible to HID
7. Reduced ADH, ALDH isoenzymes- cannot metabolise ethanol
8. Abnormal metabolism of methionine, SAM, folate- dec glutathione
9. Malunutrition, thiamine def, impaired digestive functions( gastric, intestinal mucosal damage, pancreatitis)
10. Induction of enzymes - CYP2E1 ( drugs - toxic metabolites)
Mechanism of fibrosis/ cirrhosis
~ Stellate/ Ito/ Perisinusoidal cells in Space of disse- quiescent cells- store VitA
~ Alcohol activates stellate cells —>myofibroblast contractile cells-fibrosis, lose VitA
~ constrict sinusoidal vascular channels
~ cytokine, chemokine- TGF b
~ inflammatory cytokines- TNF, IL 1b, lymphotoxin
~ oxidative stress
Mechanism of steatosis
~ inc catabolism of fat - fat deposited in liver
~ inc fatty acid synthesis
~ inc TG synthesis
~ impaired secretion / release of lipoproteins
~ dec oxidation of fatty acids
Morphology of hepatic steatosis / fatty liver
Gross: enlarged, soft, yellow, greasy :4-6 kgs
Micro : ~ microvesicular steatosis - small, clear vacuoles of lipid in cytoplasm of hepatocytes - acinar zone 3 (centrilobular), cytoplasm looks foamy
~ macrovesicular steatosis - large, clear lipid droplets, push nucleus to periphery
~no inflammation , no fibrosis
- reversible stage
Morphology of Alcoholic hepatitis
Gross : yellow, enlarged, firm
Micro:
~ Ballooning degeneration of hepatocytes - swollen hepatocytes with water, protein, fat, granular or clumped cytoplasm - centrilobular zone —> hepatic necrosis
~ Mallory body/ Mallory denk body/ Mallory hyaline :
*perinuclear region, characteristic, not significant
*Tangled skeins of intermediate cytokeratin filaments( 8,18)
*Dense, eosinophilic ropey cytoplasmic inclusions/ clumps
~Neutrophilic infiltration-portal tracts are infiltrated c lymphocytes, macrophages
~ Alcoholic steatofibrosis- activation of stellate cells- sclerosis of central veins - perisinusoidal fibrosis - periphery of lobule - chicken wire fence pattern
~ Variable degree of steatosis
Morphology of alcoholic cirrhosis
- chronic, irreversible, end stage of ALD- diffuse process (entire liver)
- Laennec cirrhosis/ nutritional cirrhosis/ portal cirrhosis
Gross:
Early - 2kg, yellow, fatty, enlarged
Late-< 1kg, brown, non fatty, small and shrunken, diffuse nodular and firm
~ Capsular surface- nodular - pig skin texture
~ < 3 mm- micro nodular- Hobnail appearance
~ Nodules may coalesce - larger nodules
~ micro + marco nodular
Micro:
~Loss of architecture -hepatocytes injury and fibrosis
~Regenerating nodules- stimulate hepatocytes to regenerate and proliferate
~Fibrosis - central to portal regions, portal to portal tracts, broad scars/ delicate bands of fibres
~ Vascular reorganisation -new vascular channels, connect portal region to terminal hepatic veins
Clinical Features of all stages
- Fatty liver - hepatomegaly, reversible
- Alcoholic hepatitis- bout of heavy drinking - anorexia, weight loss, abdominal pain, malaise , tender hepatomegaly
- Alcoholic cirrhosis :
~initial -compensated, later -decompensated (portal hypertension, liver dysfunction)
~upper abdominal pain, anorexia, weight loss, weakness, hepatic failure , systemic infection, Gastro intestinal haemorrhage
Laboratory findings
- Alcoholic steatosis:
~ MODERATELY raised ALT
~ AST: ALT > 1
~ gamma glutamyl transpeptidase - increased
~ liver biopsy- accumulation of fat in perivenular hepatocytes - Alcoholic hepatitis
~ AST: ALT > 2
~ serum Bilirubin -raised
~ serum ALP -Mildy elevated
~ serum albumin -decreased
~ prothrombin time -prolonged
~ neutrophilic leucocytosis
~ Bilirubinuria - Alcoholic cirrhosis
Liver function tests:
~ hyperbilirubinemia - both conjugated +non-conjugated
~ Serum proteins: reversal of A:G ratio
~ serum transaminase: AST, ALT- raised , AST: ALT ratio >2
~ ALP- slightly elevated
~ prothrombin time -prolonged
Hemat: anaemia, acanthocytosis ( spur like projections on RBC), leucopenia, thrombocytopenia
Serological markers - HVB, HVC
BLOOD AMMONIA ESTIMATION -hepatic encephalopathy
Serum electrolytes - hyponatraemia, hypokalaemia, hypoMagniesemia, hypophosphataemia
Causes of death in ALD
~ hepatic coma
~ Gastro intestinal haemorrhage
~ infection
~ hepato-renal syndrome
~hepato cellular carcinoma
Mallory bodies seen in
~ alcoholic hepatitis
~ non-alcoholic fatty liver disease
~ primary biliary cirrhosis
~ Wilson disease
~ chronic cholestatic syndrome
~ hepato-cellular tumours
Classification of cirrhosis
- Morphological classification
~ depending on size of regenerating nodules
* micronodular: regular, small nodule, <3mm, fibrous tissue septa is thin , associated with alcoholic cirrhosis
* macronodular: irregular, large nodules, >3mm, fibrous tissue septa are broad, increased risk of carcinoma, associated with chronic hepatitis
* mixed: both micro and macro
~ active form: continued liver cell necrosis + inflammation
~ in active form: neither live cell necrosis+ nor inflammation - Aetiological classification.
~ alcohol
~ viral hepatitis B and C
~ haemochromatosis
~ non-alcoholic steatohepatitis
~ Wilson’s disease
~ autoimmune liver disease
~ Intra hepatic and extrahepatic obstruction
~ idiopathic
~ drugs and toxins
~ Indian childhood cirrhosis
