Liver and Gallbladder

Liver Disorders

  • Jaundice

  • Hepatitis

  • Cirrhosis

  • Cholecystitis

Anatomy and Physiology of the Liver and Functions

  • Blood Flow
      - Aorta to hepatic artery and portal vein to liver.
      - Then liver to hepatic vein to inferior vena cava.

  • Hepatic Sinusoids
      - Lined by endothelial cells and Kupffer cells (a type of phagocytic macrophage).

  • Functions of the Liver
      - Fat digestion
      - Carbohydrate storage
      - Blood detoxification
      - Protein production

Pathophysiology of Liver Disorders and Related Manifestations

  • Liver failure is life-threatening if more than 80% of liver is destroyed.

  • Portal Hypertension (Portal HTN)
      - Caused by obstruction in blood flow.
      - Results in a rise in portal venous pressure proximal to blockage.

  • Hepatocellular Failure

  • Manifestations of Liver Failure
      - Jaundice
      - Muscle wasting
      - Ascites (fluid in abdomen)
      - Excess bleeding
      - Deficient plasma proteins (e.g., hypoalbuminemia leading to low serum oncotic pressure and edema).
      - Deficient vitamins
      - Altered glucose balance
      - Decreased hormone production
      - Decreased clotting factors

  • Hypoalbuminemia leads to low serum oncotic pressure, resulting in edema.

  • Hyperglycemia/Hypoglycemia
      - Abnormal storage and release of glucose in the form of glycogen.

Effects of Liver Dysfunction

  • Decreased Bile Salts
      - Results in decreased absorption of fat-soluble vitamins.

  • Decreased Vitamin D
      - Can lead to osteomalacia.

  • Decreased Vitamin K
      - Poor blood clotting factor production.

  • Altered Lipoprotein Processing
      - Can lead to hypertriglyceridemia.

  • Decreased Clearance of Drugs and Toxins.

  • Impaired Conversion of Ammonia to Urea
      - May result in hepatic encephalopathy.

  • Impaired Bilirubin Metabolism
      - Leads to jaundice.

Bilirubin Metabolism

  • Free unconjugated bilirubin results from the lysis of old or damaged red blood cells (RBCs).

  • The bilirubin released in plasma binds to albumin (lipid soluble) and is transported to the liver.

  • In the liver, bilirubin is conjugated and excreted into bile ducts as a component of bile, then converted to urobilinogen which is excreted in urine and feces.

  • Elevated Unconjugated Bilirubin
      - Indicates significant hemolysis.

  • Elevated Conjugated Bilirubin
      - Indicates biliary obstruction.

Jaundice

  • Symptoms
      - Yellow/green pigmentation of skin due to hyperbilirubinemia.

  • Mechanisms
      - Obstructive jaundice: due to common bile duct occlusion or hepatocyte malfunction leading to obstructed bile flow.
        - Conjugated bilirubin (H2O soluble) cannot flow into duodenum, accumulates in the liver/enters bloodstream, causing hyperbilirubinemia.
      - Hemolytic jaundice: excessive hemolysis of RBC leading to increased levels of unconjugated bilirubin (not H2O soluble).
        - Kernicterus: elevated bilirubin in the CNS.

  • Clinical Manifestations (CM) of Jaundice
      - Dark urine
      - Pale (light-colored) stools due to obstruction of bile flow.
      - Yellow sclera & skin
      - Pruritus (itching due to bilirubin accumulation in skin)
      - Anorexia
      - Malaise
      - Fatigue

Mechanisms of Jaundice

  • Intrahepatic obstructive jaundice due to hepatocyte damage or obstruction of bile canaliculi.

  • Extrahepatic obstructive jaundice due to bile duct obstruction (cholestasis).

  • Impaired conjugation and excretion of bilirubin leading to conjugated biliribun accumulation in liver and bloodstream.

  • Light-colored stools and urine may show both conjugated and unconjugated hyperbilirubinemia resulting in bilirubin deposition in tissues (jaundice).

Hepatitis

  • Definition
      - Inflammation of the liver.

  • Causes
      - Most commonly viral infections (Hepatitis A, B, C, D, E, G), drug reactions, Alcoholism (ETOH), malaria, mononucleosis.

Pathophysiology of Viral Hepatitis

  • Virus invades host DNA and replicates, damaging the liver.

  • Causes hepatic cell necrosis, infiltration with phagocytes, leading to scarring.

  • Leads to:
      - Proliferation of Kupffer cells (hyperplasia)
      - Inflammation of portal ducts (disrupts bilirubin excretion)
      - Inflammation of bile ducts (cholestasis and obstructive jaundice)

  • Liver may regenerate after 2-3 months or, if without regeneration, can be fatal.

Clinical Course of Hepatitis

  • Phases of Hepatitis
      1. Prodromal Phase (Preicterus)
        - Lasts ~2 weeks after exposure and ends with appearance of jaundice.
        - Symptoms: anorexia, nausea/vomiting (N/V), fatigue, malaise, headache (HA), arthralgia, low-grade fever, mild abdominal pain, distaste for smoking.
        - Very transmissible.
      2. Icteric Phase
        - Begins 1-2 weeks after prodromal phase, lasts about 2-6 weeks.
        - Symptoms: jaundice, dark urine, clay-colored stools, hepatomegaly, pruritus.
      3. Recovery Phase (Convalescent)
        - Begins with resolution of jaundice about 6-8 weeks after exposure.
        - Symptoms: reduced symptoms, liver remains enlarged and tender.
        - Liver function tests (LFTs) normalize 2-12 weeks after jaundice onset.

Hepatitis Syndromes

  • Asymptomatic

  • Acute

  • Carrier state (asymptomatic but harbors virus)

  • Chronic hepatitis (inflammation lasting > 3-6 months, persistence of symptoms and liver inflammation, abnormal LFTs > 6 months, presence of Hepatitis B surface antigen [HBsAg])

  • Fulminating hepatitis - massive liver necrosis and failure (rare).

Hepatitis A

  • Characteristics
      - More benign (RNA virus).
      - Replicates in the liver, enters bile, excreted in bile.
      - Shed in feces (~2 weeks before symptoms).
      - Transmission: fecal/oral route (poor sanitation, contaminated food/water, infected food handlers).
      - Most common in children < 6 years (often asymptomatic).

  • Incubation Period
      - 2-4 weeks (15-45 days).
      - Illness duration: 4-8 weeks; often mild symptoms without jaundice.

  • Management
      - Bedrest, nutrition, avoid alcohol and acetaminophen.

  • Prevention
      - Vaccine, improved hygiene and sanitation, handwashing.

Hepatitis B

  • Characteristics
      - Major cause of chronic hepatitis (DNA virus).
      - Transmission: via serum, blood, semen, saliva, and transplacental.
      - Risk populations: IV drug users, risky sexual behavior.

  • Incubation
      - Infectious: 2 weeks to 6 months (28 to 180 days).
      - Communicable: 2-7 weeks before symptoms.

  • Survives on dry surfaces for up to 7 days.

  • Chronic infection characterized by the presence of HBsAg.

  • Management
      - Bedrest, restrict protein, increase fluids, isolation if indicated, interferon treatment, antiemetics, avoid alcohol and acetaminophen.

  • Convalescence may take 3-4 months.

  • Prevention
      - Vaccination, screening, use of disposable needles, needleless systems, gloves, condoms, HBIG (Hepatitis B immune globulin).

Hepatitis C

  • Characteristics
      - Similar to Hepatitis B but is an RNA virus.
      - Most common cause of chronic hepatitis, cirrhosis, and liver cancer (CA).
      - Milder than B but with a greater risk of chronicity.

  • Transmission
      - Blood-borne, parenteral, and via blood transfusions prior to 1990; potential sexual transmission.

  • Incubation
      - Average 2 months; infectious before symptoms appear.

  • Treatment
      - Interferon, ribavirin, liver transplant, avoid alcohol and acetaminophen.

  • No vaccine currently available.

Hepatitis D

  • Requires Hepatitis B virus for its survival and replication.

  • Increases the severity of HBV.

  • Transmission: blood, body fluids, sexual contact.

  • Prevention: vaccine for HBV.

Hepatitis E

  • Transmission: fecal/oral route, similar to Hepatitis A.

Hepatitis G

  • Transmission is through blood and sexually.

  • Incubation period unknown; usually has a benign course with uncertain long-term significance.

Table of Different Types of Hepatitis Virus

  • Hepatitis A:
      - Major Routes of Transmission: Fecal-oral; also parenteral, sexual.
      - Special Characteristics: Often mild and self-limited.
      - Prevention: Hygiene, safe water and food, immune globulin (passive), vaccine (active).

  • Hepatitis B:
      - Major Routes of Transmission: Parenteral, sexual, perinatal.
      - Special Characteristics: May become chronic and lead to cirrhosis and/or hepatocellular carcinoma.
      - Prevention: Blood and body fluid precautions, safe sex, needle exchange programs, pretransfusion blood screening, immune globulin (passive), HBV vaccine (active).

  • Hepatitis C:
      - Major Routes of Transmission: Parenteral; also sexual, perinatal.
      - Special Characteristics: Often asymptomatic; may become chronic and lead to cirrhosis and hepatocellular carcinoma.
      - Prevention: Blood and body fluid precautions, safe sex, needle exchange programs, pretransfusion blood screening.

  • Hepatitis D:
      - Major Routes of Transmission: Parenteral, sexual.
      - Special Characteristics: Requires concurrent HBV infection; concurrent infection with HBV and hepatitis D virus increases risk of fulminant liver failure.
      - Prevention: Blood and body fluid precautions, safe sex, needle exchange programs, pretransfusion blood screening, HBV vaccine (active).

Blood Tests in Hepatitis

  • Immunoglobulins
      - IgM: Increased for ~6-8 weeks (acute stage of infection).
      - IgG: Increased several weeks after initial infection; may stay elevated for years (reflects chronic state).

  • Specific Antibodies and Antigens
      - Anti-HAV IgM: Indicates acute phase of hepatitis A infection.
      - Anti-HAV IgG: Indicates previous infection with hepatitis A virus; lifelong immunity.
      - HBsAg: Hepatitis B surface antigen; indicates recent acute infection or chronic carrier state (appears within 2 weeks, peaks after 6 months).
      - HBcAg: Hepatitis B core antigen; only found in those infected (not vaccinated); differentiates between infected vs. vaccinated.
      - Anti-HBs: Antibody to surface antigen; indicates immunity to HBV, + response to vaccine or immune globulin.
      - Anti-HBc: Antibody to core antigen; indicates past infection.
      - Anti-HCV: Antibody to hepatitis C virus; reflects past infection, appearing 2-6 months after exposure at illness onset.
      - Anti-HDV: Antibody to hepatitis D; indicates past/present infection.
      - Anti-HEV: Antibody to hepatitis E.

Other Blood Tests

  • AST (SGOT)

  • ALT (SGPT)

  • Alkaline Phosphatase

  • LDH

  • Bilirubin levels

Complications of Chronic and Acute Hepatitis

  • Liver cancer (especially with HCV).

  • Liver failure (fulminant hepatitis, especially with HBV).

  • Coagulopathy.

  • Encephalopathy.

  • Potentially fatal outcomes.

Cirrhosis

  • Definition
      - Defined as the end stage of liver disease.
      - Requires at least 10% of liver function to maintain bodily function.

  • Characteristics
      - Irreversible inflammation disrupting liver structure and function, causing obstruction of bile channels and distortion of liver tissue.
      - Results in diffuse fibrosis and nodular regeneration intermixed with fibrous tissue.
      - Develops slowly over years (progressive condition).

  • Scarring affects biliary and vascular flow, leading to bile stasis and portal hypertension (portal HTN).

Causes of Cirrhosis

  1. Alcoholic (Laennec's cirrhosis).

  2. Biliary cirrhosis (intrahepatic or extrahepatic obstruction of bile flow due to gallstones, tumors, or pancreatitis).

  3. Postnecrotic cirrhosis (resulting from HAV or HCV infection, drugs, or autoimmune conditions).

  4. Metabolic cirrhosis (due to metabolic defects).

  5. Cardiac cirrhosis (related to right heart failure).

Alcoholic Cirrhosis (Laennec’s)

  • Mechanism
      - Ethanol is converted to acetaldehyde, impairing hepatocyte function.
      - Mitochondrial function is impaired.
      - Decreases oxidation of fatty acids resulting in fatty liver disease.
      - Alters enzyme and protein synthesis.
      - Leads to cellular damage, inflammation, necrosis, and excess collagen deposition causing fibrosis and scarring.
      - Fibrosis and liver damage become irreversible.

Clinical Manifestations of Cirrhosis

  • Depend on disease duration and severity of damage.

  • Symptoms include:
      - Hepatomegaly
      - Jaundice
      - Weight loss
      - Ascites
      - Abdominal pain (dull ache usually in epigastric or right upper quadrant).
      - Portal hypertension (leading to splenomegaly).
      - Risk of bleeding (due to decreased clotting factors).
      - Portosystemic shunt: formation of esophageal and anorectal varices or caput medusae.
      - Weakness, anorexia, and digestive complaints (DC).

Complications of Cirrhosis

  • Liver inflammation

  • Pain and fever

  • Liver necrosis

  • Decreased bilirubin metabolism leading to hyperbilirubinemia (jaundice).

  • Hepatic fibrosis and scarring causing portal hypertension.

  • Symptoms of liver failure may include nausea, vomiting, anorexia, and fatigue.

  • Hormonal changes may lead to increased androgens and estrogens causing gynecomastia, loss of body hair, and menstrual dysfunction.

  • Biochemical alterations include elevated AST, ALT, and bilirubin; low serum albumin; and prolonged prothrombin time.

Portal Hypertension

  • Definition
      - Increased resistance to hepatic blood flow (affects pre-hepatic, intra-hepatic and post-hepatic areas).

  • Clinical Manifestations
      - Increased abdominal distention, weight gain, increased girth, dyspnea, increased respiratory rate, peripheral vasodilation, increased ADH and aldosterone levels.

  • Ascites
      - Fluid accumulation in peritoneal cavity due to decreased serum albumin and capillary pressures.

  • Complications
      - Esophageal varices (risk of bleeding; major determinant for bleeding is the size).

Treatment for Portal Hypertension

  • Octreotide (synthetic hormone analogous to somatostatin).

  • Prophylactic antibiotics.

  • Acid suppression therapies.

  • Endoscopic sclerotherapy and banding may be required for varices.

Surgical Interventions for Portal Hypertension

  • Peritoneovenous Shunt

  • Transjugular Intrahepatic Portosystemic Shunt (TIPS).

Esophageal Varices

  • Development and Rupture
      - Portal vein pressure increases, leading to formation of large collateral channels between portal and systemic veins with flow reversal.
      - Thin walled varicosities are formed in submucosa of the esophagus.
      - Rupture can cause hemorrhage.

  • Management
      - Beta blockers (to decrease portal venous pressure).
      - Vasoconstrictors.
      - Balloon compression and shunt procedures between portal and systemic venous systems.

Ascites

  • Definition
      - Accumulation of fluid in the peritoneal cavity.

  • Pathophysiology
      - Caused by portal hypertension, decreased serum albumin levels, increased capillary filtration pressure, and renal retention of sodium and water.

  • Clinical Manifestations
      - Abdominal discomfort, dyspnea, and increased abdominal girth.

  • Treatment
      - Paracentesis, low sodium diet (2 g/day), diuretics (Spironolactone and furosemide), 25% albumin infusion may be beneficial.

Hepatic Encephalopathy

  • Definition
      - Biochemical alterations affect neurotransmission due to liver dysfunction.

  • Mechanism
      - Collateral circulation shunts blood around liver allowing toxins absorbed from the GI tract to circulate freely (including ammonia).
      - Ammonia interferes with cerebral energy metabolism and neurotransmission.

  • Clinical Manifestations
      - Personality changes, irritability, confusion, memory loss, asterixis (flapping tremor), diminished alertness, lethargy, stupor, impaired speech, sleep disturbances, seizures, coma, and potentially death.

  • Diagnosis
      - History and Physical examination (H & P), EEG, blood chemistry showing increased serum ammonia levels.

  • Treatment
      - Correct fluid and electrolyte imbalances.
      - Avoid precipitating drugs.
      - Decrease ammonia levels via dietary protein restriction and antibiotics (e.g., Neomycin).
      - Use Lactulose to promote ammonia conversion to non-absorbable ammonium ions.

Complications of Advanced Liver Disease

  • Hepatorenal syndrome characterized by progressive azotemia, increased serum creatinine, and oliguria due to decreased renal blood flow leading to renal failure.
      - Symptoms include oliguria, sodium/water retention, hypotension, and peripheral vasodilation, which can be fatal without liver transplantation.

Non-Alcoholic Fatty Liver Disease (NAFLD)

  • Definition
      - Non-alcoholic fatty liver disease includes fatty liver and non-alcoholic steatohepatitis (NASH).

  • Risk Factors
      - Metabolic syndrome (obesity, glucose intolerance, hypertension, dyslipidemia).

  • Causes
      - Insulin resistance leading to increased free fatty acid (FA) levels and hepatic fatty infiltration.

  • Clinical Manifestations
      - Asymptomatic or vague RUQ pain.
      - Advanced liver injury may lead to jaundice, anorexia, and pruritus.

  • Treatment
      - Lifestyle changes (diet, exercise, weight loss).
      - Avoiding hepatotoxins.
      - Addressing insulin resistance.

Pancreas Functions

  • Secretes insulin, somatostatin, and glucagon.

  • Releases digestive juices (amylase, lipase, trypsinogen) into gastrointestinal tract.

  • Stasis or decreased motility of pancreas increases risk for pancreatitis.

  • Risk factors include high spinal cord injuries, patients on TPN, diabetes mellitus, obesity, oral contraceptives, prolonged fasting, rapid weight loss, and pregnancy (men more often affected).

Pancreatitis

  • Definition
      - Inflammation of the pancreas, can be acute or chronic.

  • Causes
      - Alcoholism, trauma, peptic ulcer disease (PUD), biliary disorders; auto-digestion due to secretion alterations, increased secretion, or obstruction.

Acute Pancreatitis

  • Mechanism
      - Most commonly due to obstruction of the pancreatic duct by stones, leading to autodigestion.

  • Symptoms
      - Steady, boring pain in epigastric or left upper quadrant (LUQ), often radiating to the back; N/V, tenderness, reduced bowel sounds, low-grade fever, abdominal distension, steatorrhea.
      - Pain worsens in supine position and may improve when flexed. - Diagnosis is made via abdominal ultrasound (gold standard).

  • Laboratory Tests
      - Elevated serum amylase and lipase; lipase is more specific and remains elevated longer.
      - Elevated alkaline phosphatase and bilirubin hint at biliary obstruction.
      - Elevated WBC counts and decreased calcium levels; hyperglycemia may arise.

  • Diagnostics
      - Chest X-ray, ultrasound, CT scan, endoscopic retrograde cholangiopancreatography (ERCP) for duct issues.

  • Treatment
      - NPO, NG tube suction, IV volume replacement (with electrolytes and protein), analgesics for 3-7 days, followed by gradual oral intake.
      - Pharmacologic treatments include analgesics, antacids, H2 inhibitors, antibiotics, anticholinergics, insulin.

Chronic Pancreatitis

  • Definition
      - Persistent symptoms leading to dysfunction over weeks to months.

  • Causes
      - Mostly related to chronic alcohol use.

  • Symptoms
      - Recurring bouts of acute pancreatitis with progressive dysfunction; epigastric pain often radiating to the back.
      - May present without pain but can lead to complications like diabetes mellitus and malabsorption leading to weight loss and steatosis (fat malabsorption).

  • Treatment
      - Abstinence from alcohol, pain management, addressing pancreatic insufficiencies, possible endoscopic drainage, biliary stents, Whipple procedure for serious cases.
      - Pancreatic enzyme replacements to address steatorrhea and chronic pain management; acid suppression and low-fat diet are recommended.

Complications of Pancreatitis

  • Hypovolemic shock.

  • Ileus.

  • GI bleeding.

  • Abscesses or fistulas.

  • Hypercoagulability with elevated platelets, factor VIII, and fibrinogen.

  • Hypocalcemia from tissue lipolysis leading to release of free fatty acids; high amylase leakage can occur in pleural effusion.

  • Pancreatic pseudocyst, CBD obstruction, PUD.

Gall Bladder Function

  • Modifies (concentrates) and stores bile produced in the liver.

  • Bile helps digest lipids, transports IgA, and detoxifies.

  • Bile exits through common bile duct and terminates at the Ampulla of Vater where digestive secretions enter the intestines.

  • Most bile is reabsorbed in the ileum; only 5% excreted in the colon.

  • High concentrations of bile predispose to gallstone formation.

Cholecystitis

  • Definition
      - Inflammation of the gallbladder wall.

  • Types
      - Chronic: characterized by intermittent biliary colic (RUQ pain), epigastric pain, and nausea/vomiting (may occur post-meal).
      - Acute: presents with severe RUQ pain, often radiating to the back, accompanied by abdominal tenderness and fever.

  • Pathophysiology
      - Causes include bacteria reaching the gallbladder via vascular or lymphatic routes.
      - Impaired venous/lymphatic circulation leads to bacterial presence, irritation, ischemia resulting in empyema, edema, and potentially necrosis.
      - Perforation can lead to bile leakage into the peritoneal cavity.
      - Risk factors: The 4 F’s - fair, fat, female, 40 years old.
      - Often associated with gallstones.

Cholecystitis Clinical Manifestations

  • Symptoms include:
      - Intermittent RUQ pain (biliary colic).
      - Pain radiating to the back, right shoulder, and epigastric area.
      - Nausea and vomiting.
      - Fever and leukocytosis.
      - Intolerance to fatty foods, heartburn, bloating, and flatulence.
      - Obstructive jaundice can lead to dark amber urine and clay-colored stools if ducts become obstructed.

  • Complications without treatment include gangrene of the gallbladder, empyema, peritonitis, and septic shock.

  • Diagnosis can be made via Ultrasound or HIDA scan to assess gallbladder secretion.

  • Treatment includes cholesterol-dissolving medications, lithotripsy, and surgical options (laparoscopic cholecystectomy or open cholecystectomy with T tube placement as needed).

Cholelithiasis

  • Definition
      - Formation of stones in the gallbladder, primarily composed of cholesterol (75%, hypersaturated).

  • Often asymptomatic for years but can lead to lodged stones in the cystic or common bile duct, causing cholecystitis or pancreatitis.

  • Risk factors include obesity, middle age, female sex, Native American descent, and conditions like Crohn’s disease or use of cholesterol-lowering medications.

Figures

  • Figure 59-4: Diagrams of Peritoneovenous (LeVeen) shunting for treatment of ascites.

  • Figures 38-22 and 38-23: Illustrations of gallstones.