Liver Disease (1): Alcohol Related

• formation of glycogen from glucose
• breakdown of glycogen into glucose
• synthesis of glucose from certain amino acids, lactate, or glycerol.

• protein metabolism, synthesis as well as degradation
• liver produces albumin
• amino acid synthesis

• cholesterol synthesis,
• lipogenesis, and the production of triglycerides,

• production of clotting factors,
• red blood cell production (fetal)
• production for thrombopoietin; regulates the production of platelets
• liver synthesizes angiotensinogen

• emulsifying fats and help the
• absorption of vitamin K from the diet

• breakdown of insulin/ hormones
• bilirubin
• breaking down or modifying toxic substances (drugs)
• breaks down ammonia into urea

• glucose (in the form of glycogen),
• vitamin A (1–2 years’ supply),
• vitamin D,
• vitamin B12
• vitamin K,
• iron, and copper.

• mononuclear phagocyte system of the liver contains many immunologically active cells, acting as a ‘sieve’ for antigens carried to it via the portal system

• In response to high alcohol consumption; the Liver up-regulates expression of enzymes needed in the breakdown of ethanol

• However, there is a “max-level”
  • As the alcohol level exceed the maximum, it becomes toxic to the liver cells and inflicts injury on the cell

3 Stages in alcohol liver disease:

Steatosis, also called fatty change, is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm.

When the vesicles are large enough to distort the nucleus, the condition is known as macrovesicular steatosis; otherwise, the condition is known as microvesicular steatosis.

While not particularly detrimental to the cell in mild cases, large accumulations can disrupt cell constituents, and in severe cases the cell may even burst.

necrosis of minute clusters of hepatocytes;

usually in association with lymphocytes, in which liver-cell plates are disrupted or replaced by small groups of lymphocytes and macrophages.

Limiting plate separates the portal track & hepatocytes

• Usually perivenular (around venules)
• portal tracts may be either normal in size or expanded

(most of the infiltrating cells in acute hepatitis small T lymphocytes, plasma cells; a few neutrophils and eosinophils.)

ballooning degeneration of hepatocytes, is a form of liver parenchymal cell death.

The cells undergoing this form of cell death increase in size (balloon).

“pink-cotton aggregates”

• Cytoplasmic irregular pink material
• Usually in already ballooned hepatocytes

• Cytokeratin filaments
• Hallmarks of Alcoholic hepatitis (but not exclusive)
  • Can also occur in tumours, NASH

Immuno-histochemistry can help to identify Mallorys hyaline (stain)

• Ubiquitin: highlights mallorys –>

(Around the venules)

• Stains for detecting connective tissues

Pericellular Fibrosis

(around the cells)

“Chicken wire” appearance (pink →)

Ultimate liver failure (affects)

• Coagulopathy,
• Nutrient Metabolism,
• Bile metabolism

Ascites: abnormal accumulation fluid in the peritoneal cavity. The most common cause of ascites is cirrhosis of the liver.

• Portal hypertension causes systemic shunts (> to eso.)
• Esophageal varices “most fatal feature”

• Hypocoagulability: significant/fatal hemorrhage

– increased long term risk hepatocellular carcinoma

(5-15% of patients with alcoholic cirrhosis),

Risk Factors

susceptibility to alcoholic liver disease

1. Dose duration and pattern of alcohol consumption
2. Drinking outside mealtimes (on empty stomach)
3. Drinking multiple different alcoholic drinks

1. Female susceptibility >> males
2. Obesity and increased BMI- increased risk (fatty liver disposition)

Alcohol & Hepatitis C

Additive effect on liver degeneration

Without antiviral treatment, HCV-related inflammation of the liver persists, causing fibrosis (scarring) of the liver

• Alcohol: accelerates progression of HCV liver disease (fibrosis spread)
• Alcohol: important potentiating factor for Hepatitis C virus associated hepatocellular carcinoma (HCC)

• Study: cumulative occurrence rate of HCC in 80.7% of patients with alcoholic cirrhosis and who were HCV positive compared with 18.5% in those with alcoholic cirrhosis alone

Other drugs and alcohol

Impact in Metabolism

1. Liver enzyme expression increases: Increase Metabolism
   
   1. Drugs 1st pass metabolism; more drugs needed to get same amount into blood

1. Hepatocytes destroyed: Decreased Metabolism

So, giving medication at the normal amount might be: too little / too much (toxic) …

Examples:

• Increased CYP2E1 cytochrome:
  • Increased metabolism of other agents eg paracetamol

• Paracetamol (therapeutic): injury in chronic alcoholics
  • Overdose cause serious liver damage and possibly death. Paracetamol overdose is one of the leading causes of liver failure.

• Chronic low dose alcohol: potentiate effect of other drugs in therapeutic doses- cryptogenic cirrhosis (drug interaction differs!)

Is Cirrhosis Reversible?

Studies now show that abstinence can prolong survival in alcoholic cirrhosis

• Study: 68% of cirrhotics who abstained survived 5 years compared with 41% of those who continued to drink (just stops further damage; unknown if damage was reversed)

Studies in animal models showed some reversal of cirrhosis were caused by carbon tetrachloride

• Yet to be conclusively that alcohol related cirrhosis is reversible in humans

Portal Hypertension

Increased intravascular pressure in all portal / systemic vascular networks

Results in:

• Oesophageal varices → fatality
• Rectal hemorrhoids → visual que
• Caput medusae (abdomen) → visual que

glycogen, interface hepatitis

• Stains glycogen in hepatocytes

• Useful to highlight steatosis- fat spaces prominent

• Useful to highlight interface hepatitis- irregular limiting plate

1. Reticulin: silver stain; fine reticulin -condensation and collapse early in architectural abnormality

2. HVG haematoxylin van gieson: fibrosis

3. Massons trichrome: fibrosis

Haemochromatosis, or iron overload disorder.

• Iron is not normally seen in liver
• Accumulation: hepatocytes, bile ductule cells

Grading: 1-4(granule size)

• 57% patients show mild siderosis (deposition in tissues)
• 7%-grade 3-4 iron

Blue granules: Iron