Etiology:

The liver tolerates low levels of alcohol consumption.  However, daily consumption of 30-50 grams of alcohol can cause alcoholic liver in approximately 5 years.

FYI:  The definition of 1 alcohol drink is 13.7 grams alcohol (i.e. the equivalent of 12oz. 5% alcohol beer, or 8oz 7% alcohol liquor, or 5oz 12% alcohol wine, or 1.5oz 40% hard-liquor).

Risk Factors:

Non-modifiable risk factors: include:  genetic, metabolic, and immunological

Modifiable risk factors include: high-fat diet and at-risk drinking behaviours

At risk drinking behaviours include:

• Males: over 14 drinks per week or more than 4 drinks per occasion
• Females and adults over 65ys old: over 7 drinks per week or more than 3 drinks per occasion

“Definitions of significant drinking from a liver toxicity standpoint are as below (this history is essential to differentiate non-alcoholic fatty liver disease (NAFLD)  from alcoholic fatty liver disease (AFLD)

• Men: more than 21 drinks per week
• Women: over 14 drinks per week”

Reference for above information:  https://www.ncbi.nlm.nih.gov/books/NBK546632/

Pathogenesis – Steps of Development:   

1. Stage One of Alcoholic Fatty Liver Disease (AFLD) is “Fatty Liver” or “Hepatic Steatosis” (steatos is Greek for fat)
   1. Alcohol metabolism increases triglyceride (lipid) formation which accumulates in liver cells (hepatocytes)
   2. Lipolysis decreases during alcohol consumption and fat droplets increase inside hepatocytes.
   3. Hepatomegaly; hepatocytes accumulate triglyceride fat in vacuoles as they are no longer able to process it.
   4. Asymptomatic and reversible with reduced alcohol intake
   5. Hepatocytes normally turn over every 5 months, making the liver fairly regenerative, however, when the amount of damage exceeds the ability of the hepatocytes to regenerate, damage becomes permanent.
2. Stage Two of Alcoholic Fatty Liver Disease (AFLD) is “Alcoholic Hepatitis” (hepatitis = liver inflammation)
   1. As hepatocytes become less functional and injured, WBCs are activated
   2. Neutrophils begin to attack hepatocytes and the Inflammatory response is triggered by Mast Cells and Basophils. Inflammation and cell necrosis occurs.
   3. Fibrous (collagen scar) tissue formation (scarring replaces hepatocytes)—irreversible change
   4. Mild symptoms – anorexia, nausea, liver tenderness; bout of heavy alcohol consumption can lead to liver failure, encephalopathy & death
3. Stage Three of Alcoholic Fatty Liver Disease (AFLD) is End-Stage Cirrhosis
   1. Depicted by increased necrosis of hepatocytes and scarring (fibrosis). Liver shrinks in size
   2. Little normal function of liver remains
   3. Extensive diffuse fibrosis interferes with blood supply ; Bile may back up; Loss of lobular organization (nodules of regenerated hepatocytes may appear, but are not functional due to distorted blood vessels & biliary ducts)
   4. Degenerative changes may be asymptomatic until disease is well advanced (80-90% of liver destroyed).
   5. Signs of portal hypertension (e.g. ascites), impaired digestion & absorptions

Why Portal Hypertension?

• Portal Hypertension occurs because the fibrosis within the liver impinges the blood vessels within the liver creating resistance to blood flow. 
• Therefore the portal vein becomes engorged and exhibits high pressure.
• The portal vein carries blood from the esophagus, stomach, small & large intestines, spleen, pancreas and gallbladder meaning that the engorgement and hypertension builds up within those tissues as well.
• This leads to: varices (engorged veins) which can rupture and bleed.
• Engorged blood vessel cause splenic congestion and enlargement of the spleen (splenomegaly) and
  • esophageal varices (which are easily torn by food passage, causing hemorrhaging).
• Congestion of spleen increases hemolysis (RBC lysis) and drop in WBC and platelet numbers.
• Congestion in intestinal walls & stomach Impairing digestion & absorption.
• Decreased blood volume into kidneys
  • stimulates activation of renin, aldosterone and ADH, leading to increase Na+ and water retention,
  • contributing to increases in blood volume and portal hypertension, leading to ascites.
• Blocked lymphatics as well as decreased liver’s synthesis of plasma protein albumin contribute to decreased plasmas osmotic pressure,
  • which increase fluid shift from blood into peritoneal cavity creating more ascites.

Signs & Symptoms (and why each occurs):

Loss of hepatocyte function causes:

1. Ascites: due to portal hypertension, elevated renin, aldosterone and ADH levels, decreased serum albumin level and decreased plasma osmotic pressure, lymphatic obstruction in liver.
2. General edema: also due to elevated renin, aldosterone and ADH levels, decreased serum albumin level and decreased plasma osmotic pressure, lymphatic obstruction in liver
3. Esophageal varices and hemorrhoids (engorged blood vessels) and possible tears:  due to portal hypertension
4. Splenomegaly
5. Anemia, Fatigue
6. Anorexia, Indigestion, Weight Loss:
7. Leukopenia, Thrombocytopenia
8. Increased bleeding
9. Purpura
10. Hepatic encephalopathy, tremors, confusion, coma
11. Gynecomastia, impotence, irregular menses
12. Jaundice
13. Impaired conversion of protein breakdown product, ammonia to urea (to be excreted in urine)
14. Decreased inactivation of hormones and drugs
    • Drug dosages must be carefully monitored to avoid toxicity.
15. Decreased removal of toxic substances (ammonia, drugs)
16. Blood Chemistry is altered (abnormal electrolytes, amino acids, ↑ ammonia) causing hepatic encephalopathy, & increased clotting times (due to ↓ clotting proteins).

Signs & symptoms:

Initial manifestations often mild & vague:

• Fatigue, anorexia, weight loss, anemia, diarrhea
• Dull aching pain may be present in RUQ (right upper quadrant).

Advanced cirrhosis:

• Ascites & peripheral edema; pruritus
• ↑ bruising; ↓ healing & tissue maintenance
• Esophageal varices – May rupture, leading  to hemorrhage, circulatory shock, Jaundice
• Obstruction of bile ducts & blood flow by fibrous tissue causes:
• Reduction of bile entering the intestine  →  Impairs digestion and absorption!
• Backup of bile in the liver → Leads to obstructive jaundice (note that intrahepatic jaundice now co-exists with obstructive jaundice!)
• Sex hormone imbalance → spider nevi, testicular atrophy, impotence, gynecomastia, irregular menses.
• Acute encephalopathy (asterixis/hand-flapping, confusion, convulsions, coma) or
• Chronic encephalopathy (personality changes, memory lapses, irritability, disinterest in personal care)

Diagnostic Tools:

1. Imaging,
2. Blood tests for blood counts and abnormal presence of liver proteins/enzymes in blood (indicating hepatocyte death/dysfunction)

Treatments:

1. Avoid fatigue & exposure to infection
2. Avoidance of alcohol or specific cause
3. Supportive or symptomatic treatment
4. Dietary restrictions on protein & salt
5. Increased intake of carbohydrate & vitamin supplements
6. Balancing serum electrolytes (possibly with diuretics)
7. Paracentesis to remove excess fluid
8. Albumin transfusions to prevent third spacing
9. Antibiotics to reduce intestinal flora
10. Emergency treatment if esophageal varices rupture
11. Portocaval shunts to reduce portal hypertension
12. Liver transplantation (can be from living donors!)

3 Types of Jaundice:

Compare Prehepatic Jaundice, Intrahepatic Jaundice and Posthepatic Jaundice giving an example of a cause of each:

• Jaundice: The yellowish colour of sclera of eyes, skin & other tissues due to hyperbilirubinemia.
• Is a sign of a disease or disorder.

Three types of disorders can cause jaundice

1. Pre-hepatic jaundice:

• Caused by excessive destruction of red blood cells (& liver can’t keep up in breaking down of bilirubin – which is a breakdown product of hemoglobin’s heme pigment)
• • Characteristic of hemolytic anemias or transfusion reactions
  • Physiological jaundice of the newborn – common 2-3 days after birth …. Treated with phototherapy (bili light)
  • Prehepatic Jaundice is a result of: ↑ unconjugated bilirubin in serum

2. Intra-hepatic jaundice:

• Occurs with disease or damage to hepatocytes (can no longer uptake bilirubin and/or can no longer conjugate bilirubin) 

• • Hepatitis or cirrhosis
  • Intrahepatic jaundice results in ↑ unconjugated & conjugated bilirubin in serum

3. Post-hepatic jaundice:

• Caused by obstruction of bile flow into gall-bladder or duodenum & subsequent backup of bile into the blood… causes pruritus (itchiness) of the skin (due to bile salt deposits) and ↓ digestion.

1. • Caused by Tumor, or choledocholithiasis
   • Posthepatic Jaundice is due to ↑ conjugated bilirubin in serum