1. Alcoholic Liver Disease

2. Alcoholic Liver Disease
Alcohol Effects
Alcohol through action of alcohol DH & acetaldehyde DH  excess NADH + H+  increased lipid biosynthesis
Impaired assembly & secretion of lipoproteins + increased peripheral fat catabolism  fatty liver
Impaired hepatic methionine catabolism  dec. intrahepatic glutathione (GSH) levels  inc. sensitivity to oxidative injury

3. Alcoholic Liver Disease
Alcohol Effects
Induction of cytochrome P450
(a) CYP2E1  inc. alcohol catabolism in ER & inc conversion of other drugs to toxic metabolites
(b) production of reactive O2 species  damage membrane hepatocellular dysfunction
Impaired microtubular and mitochondrial function
Alcohol  acetaldehyde  (+) lipid peroxidation  disrupt cytoskeletal and membrane function

4. Alcoholic Liver Disease
Alcohol Effects
Become a major caloric source  displace other nutrients  (+) malnutrition and vitamin deficiencies
Lead to chronic gastritis, intestinal mucosal damage and pancreatitis  impaired digestive function
Induce release of bacterial endotoxin into portal circulation from gut  (+) liver inflammation
Induce release of endothelins from sinusoidal endothelial cells  (+) vasoconstriction & contraction of stellate cells  dec. hepatic sinusoidal perfusion  regional hypoxia

6. DIAGNOSIS OF ALCOHOL ABUSE
The diagnosis of alcohol abuse is based on a history of heavy alcohol intake and the presence of other organ system damage or an excessive frequency of falls, lacerations, and fractures.
Biomarkers of alcohol abuse:
1- The most specific of these biomarkers is carbohydrate-deficient transferrin (CDT).CDT levels increase in serum with ingestion of 50 to 80 g/day of ethanol for two to three weeks and decline gradually during abstinence, with a half-life of approximately 15 days.
2-Increased Mean corpuscular erythrocyte volume (MCV),increased serum gamma glutamyl transpeptidase (GGTP) levels, and the ratio of mitochondrial aspartate aminotransferase (AST) to total AST (mitochondrial AST/total AST) and combinations of these markers have been touted as more accurate measures of alcohol abuse.

7. Alcoholic Liver Disease
Hepatic Steatosis
Alcoholic fatty liver
Moderate alcohol intake  microvesicular
Chronic alcohol intake  macrovesicular
Enlarged, soft, yellow, greasy liver
Completely reversible

8. Alcoholic Liver Disease
Alcoholic Hepatitis
Characteristics:
Hepatocyte swelling & necrosis  ballooning due to accumulation of fat, water & proteins
Mallory bodies – eosinophilic cytoplasmic inclusions in degenerating hepatocytes
Neutrophilic reaction – accumulate around degenerating hepatocytes (“satellitosis”)
Fibrosis – (+) activation of sinusoidal stellate cells & portal tract fibroblasts

9. Histological features of alcoholic hepatitis
Histological features of alcoholic hepatitis. (A) Low- power view demonstrating the cardinal features of steatosis, fibrosis, inflammation, and hepatocellular injury.

10. Histological features of alcoholic hepatitis.
(B) (Black arrows) Mallory bodies are irregular eosinophilic cytoplasmic structures with a rope-like appearance. (Open arrow) Ballooning degeneration of hepatocytes.

11. Histological features of alcoholic hepatitis
Histological features of alcoholic hepatitis. (c) (Open arrow) Pericellular fibrosis, also termed 'chicken-wire' fibrosis surrounds individual degenerate hepatocytes; (Black arrow) Perivenular fibrosis extends from the central vein.

12. Histological features of alcoholic hepatitis
Histological features of alcoholic hepatitis. (d) The unit lesion (also termed satellitosis) comprises a degenerating hepatocyte with (arrow) a surrounding cuff of neutrophils. Marked steatosis is also evident.

13. Alcoholic Liver Disease
Alcoholic cirrhosis
Final, irreversible; 10 – 15% of alcoholics
Micronodular with scattered larger nodules  “hobnail” appearance of liver surface
Broad expanses of tough, pale scar tissue due to ischemic necrosis & fibrous obliteration of nodules  Laennec cirrhosis

15. Liver enzymes
Serum AST levels are almost always less than 300 to 500 U/L and typically are associated with trivial elevation of serum ALT levels, resulting in an AST/ALT ratio greater than 2, which is characteristic of alcoholic liver disease, in part because of deficiency of pyridoxal 5′ phosphate (a cofactor of aminotransferases) in alcoholic patients.

16. Alcoholic Liver Disease
Short-term ingestion of up to 80 gm of alcohol (~8 beers) over one to several days  FATTY LIVER
daily intake of gm in female and gm in male for 7 years  alcoholic cirrhosis .
Daily intake of 160 gms or more for years  SEVERE INJURY

17. Gynecomastia due to alcoholic cirrhosis
A 32 year old male patient with normal secondary sex characteristics, no testicular mass, no hystory of drug ingestion, no other endocrine abnormalities and a normal neurological examination. Nevertheless, he had a history of more than 15 years of large amounts of alcohol intake and a liver biopsy confirm alcoholic cirrhosis (Laennec's Cirrhosis).

18. Alcoholic Liver Disease
Cause of death:
Hepatic coma
Massive gastrointestinal hemorrhage
Intercurrent infection
Hepatorenal syndrome following alcoholic hepatitis
Hepatocellular carcinoma

19. Metabolic Disorders
Non-alcoholic Fatty Liver Disease
(NAFL)
Occurs in patients who are not heavy drinkers
Strong association with obesity, dyslipidemia and insulin resistance, and overt type 2 DM
May present only with elevated serum amino- transferases and/or GGT
(+) accumulation of triglycerides within hepatocytes
Progress to non-alcoholic steatohepatitis (NASH)  CIRRHOSIS

21. Obesity is the condition most often reported in association with NAFLD(overweight (defined as a body mass index [BMI] > 25 kg/m2) , obese (BMI > 30 kg/m2) and morbidly obese patients (BMI > 35 kg/m2) ).
NAFLD also is strongly associated with type 2 diabetes mellitus and glucose intolerance, with or without superimposed obesity. Type 2 diabetes mellitus, hyperglycemia, or glucose intolerance has been described in 20% to 75% of adult patients with NASH and may increase the risk of NASH more than twofold compared with that for nondiabetic persons.
NAFLD is now recognized as the hepatic component of the metabolic syndrome, which includes hyperlipidemia, glucose intolerance, obesity, and systemic hypertension. The risk and severity of NAFLD increase with the number of components of the metabolic syndrome.

22. Liver enzymes
Two- to fourfold elevation of serum ALT and AST levels.  AST/ALT ratio less than 1 in most patients.
The serum ALT level usually is greater than the AST level, in contrast with the pattern of alcoholic hepatitis, in which the AST level is at least twofold higher than the ALT level .