Liver Anatomy and Injury

Lobular Anatomy

• The liver includes a lobular model, indicating that the terminal hepatic vein sits at the center of a lobule.
• Portal tracts are at the periphery in the lobular model.
• Pathologists often refer to the regions of the parenchyma as "periportal and centrilobular."
• The liver includes an acinar model, with three zones defined by blood flow.
• Zone 1 is the closest to the blood supply
• Zone 3 is the farthest
• Each zone differs based on metabolic processes and susceptibility to hepatic injury.

Mechanisms of Hepatic Injury/Repair

• Liver injury can cause reversible changes like lipid vacuoles or steatosis accumulation.
• Cellular death can occur due to necrosis from hypoxia, ischemia, or apoptosis from viral, autoimmune, drug, or toxin-induced causes.
• Regeneration occurs via mitosis of adjacent hepatocytes in acute instances.
• Stem cell proliferation and differentiation manages regeneration in chronic cases.
• Severe acute liver injury leads to scarring.
• Chronic injury more often results in scar formation.
• Hepatic stellate cells can transform into myofibroblasts.
• Systemic inflammation alters metabolic activity and biosynthesis, elevating acute phase reactants like CRP and serum amyloid.
• CD4 and CD8 cells are involved in Inflammation/immunologic response

Liver Failure

• Acute liver failure is liver disease that produces hepatic encephalopathy in less than 6 months.
• Chronic liver failure is typically morphologically changed.
• Cirrhosis does not always lead to end-stage liver disease.
• Not all chronic liver disease ends in cirrhosis (i.e. chronic biliary tract disease).
• Some cirrhosis doesn't lead to end-stage liver disease, particularly if hepatitis C is treated or autoimmune hepatitis is managed.
• Acute-on-chronic liver failure describes well-compensated disease that develops acute liver failure.

Liver Failure: Symptoms

• Acute: Jaundice, Icterus, Cholestasis, Portal Hypertension, Ascites, Coagulopathy due to decreased clotting factors, and Hepatic Encephalopathy including asterixis and elevated ammonia levels.
• Chronic: Severe jaundice, icterus, pruritus (possibly from elevated bile salts), hepatorenal syndrome resulting from decreased renal perfusion, portal hypertension, and an increased risk of hepatocellular carcinoma.
• Hepatorenal syndrome causes systemic vasodilation reduces systemic vascular resistance lowers renal perfusion and decreases urine output while increasing BUN/Cr.
• Portal hypertension can cause porticosystemic shunts and congestive splenomegaly

Hepatitis

• Hepatitis A is transmitted via the fecal-oral route, often through contaminated food or water.
• Hepatitis A has an incubation period of 2–6 weeks.
• Hepatitis A does not cause chronic liver disease and is usually a benign, self-limited infection.
• Hepatitis B is transmitted via parenteral, perinatal, or sexual routes.
• The incubation period for Hepatitis B is 2-26 weeks, with an average of 8 weeks.
• 5–10% of Hepatitis B cases lead to chronic liver disease.
• Hepatitis B outcomes vary widely.
• Host response primarily determines Hepatitis B outcomes
• Hepatitis B outcomes include acute hepatitis with recovery/viral clearance, non-progressive chronic hepatitis, progressive chronic disease with cirrhosis, fulminant hepatitis with massive necrosis, and asymptomatic carrier status.
• Hepatitis C is transmitted parenterally.
• Intranasal cocaine use increases risk
• Hepatitis C has an Incubation period of 4-26 weeks, average of 9 weeks
• More than 80% of Hepatitis C infections cause chronic liver disease.
• Acute Hepatitis C infection is often asymptomatic.
• Persistent infection and chronic hepatitis are hallmarks of Hep C

Alcohol-Induced Liver Disease

• Alcoholic Liver Disease is commonly caused by a fatty liver.
• Consuming 80 g of ETOH daily can cause Alcoholic Liver Disease .
• 5-6 beers or 8-9 oz of 80-proof liquor equate to 80g of ETOH daily
• Binge drinking carries a higher risk than steady consumption.
• Hepatic steatohepatitis occurs in 90–100% of cases, involving lipid biosynthesis and decreased lipoprotein secretion, resulting in intracellular lipid accumulation.
• Alcoholic hepatitis occurs in 10–35% of cases.
• Acetaldehyde disrupts the cytoskeleton and membrane function.
• ETOH impacts mitochondrial function and membrane fluidity.
• ROS damages membranes/proteins during ETOH oxidation.
• Cirrhosis occurs in 8–20% of cases, typically after 10 years.
• Cirrhosis can be expedited by concurrent Hep C infection
• Approximately 30% of alcoholics have Hep C.

Nonalcoholic Fatty Liver Disease

• Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, obesity, type 2 diabetes, dyslipidemia, and hypertension.
• NAFLD can show changes similar to alcoholic liver disease.
• Steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis are all changes similar to alcoholic liver disease.
• Features of steatohepatitis, such as hepatocyte ballooning, Mallory-Denk bodies, and neutrophilic infiltration, are less prominent in NAFLD than in alcohol-related injury.
• Pediatric NAFLD is increasingly recognized as the obesity epidemic spreads, though it has a distinct histologic pattern from adults.
• 80% of NAFLD cases have isolated fatty liver which has minimal progression to cirrhosis
• There is no increased risk of death compared to the general population with isolated fatty liver
• 11% of cases progress to NASH cirrhosis over 15 years.
• There is significant variability with progression to NASH cirrhosis
• 31% will experience decompensation over 8 years with NASH cirrhosis
• 7% will develop HCC over 6.5 years with NASH cirrhosis

Drug and Toxin-Induced Liver Injury

• The liver is susceptible to Drug and Toxin-Induced Liver Injury because it main drug-metabolizing and detoxifying organ.
• Predictable (intrinsic) reactions to the liver affect individuals via a dose-dependent pattern.
• A toxic agent damages centrilobular regions that can extend to lobules
• A classic example of Predictable (intrinsic) reactions to to the liver is from excessive acetaminophen.
• Unpredictable (idiosyncratic) reactions to the liver depend on the amount of an individual's immune response to antigenic stimuli and how fast the agent can be metabolized.
• Chlorpromazine can cause cholestasis in slow metabolizers.
• Halothane is responsible for a fatal immune-mediated hepatitis when repeatedly exposed.

Inherited Metabolic Liver Diseases

• Hemochromatosis causes excessive absorption of iron, which deposits into parenchymal organs, especially the liver and pancreas.
• Heredity and parenteral administration (transfusions) cause Hemochromatosis.
• Hepcidin levels or function diverse mutations can cause in Hemochromatosis.
• Intestinal iron absorption is directly related to Hepatic Injury
• Hepatic injury occurs after 20g of stored Fe has accumulated.
• Lipid peroxidation, Collagen formation from stellate cell activation and DNA damage by ROS lead to hepatic injury.
• Symptoms include hepatomegaly, abdominal pain, skin pigmentation, impaired glucose tolerance, cardiac dysfunction, and atypical arthritis.
• Men are more susceptible to hemochromatosis than women due to menstrual blood loss.
• Wilson Disease is caused by an autosomal recessive mutation in the ARP7B gene.
• Wilson Disease leads to reduced copper excretion into the bile.
• Secondary accumulation of toxic levels of copper occur in tissues and organs because of Wilson Disease
• Individuals with Wilson disease may have compromised livers
• Neuropsychiatric complications from copper in basal ganglia contribute to symptoms of Wilson Disease
• Diagnostics for Wilson Disease includes reduced serum ceruloplasmin, elevated hepatic copper content, and elevated urinary copper excretion
• In α1-Antitrypsin Disease, Normal a1AT inhibits proteases released by neutrophils.
• α1-Antitrypsin Disease is autosomal recessive, and autosomal recessive mutations misfold α1AT.
• People with α1-Antitrypsin Disease have decreased levels of circulating a1-anti-trypsin
• Symptoms of α1-Antitrypsin Disease include lung injury, pulmonary emphysema, neonatal hepatitis, cholestatic jaundice
• Adolescents with α1-Antitrypsin Disease may demonstrates hepatitis attacks causing failure+ cirrhosis.
• Adults with α1-Antitrypsin Disease may show no signs until cirrhosis is discovered.

Cholestatic Syndromes

• Hepatic bile serves 2 functions, emulsification of intraluminal fat via detergent action of bile salts, and elimination of bilirubin, cholesterol, xenobiotics, and other substances.
• Disturbing bilirubin production or clearance equilibrium can cause issues
• Increased bilirubin, hepatocyte dysfunction, and bile obstruction can cause disturbed bilirubin production or clearance equilibrium
• Bilirubin is the end-product of heme degradation.
• 85% of heme degrades in the spleen, liver, and bone marrow by macrophages.
• 15% of hepatic heme or hemoproteins degrade
• Conjugated bilirubin is water-soluble, non-toxic, loosely bound to albumin, and excreted in urine vs Unonjugated Bilirubin
• Unconjugated bilirubin is mostly bound to albumin, and has unbound fraction
• Via hemolytic disease excess unbound fraction can be cause in Conjugated Bilirubin
• Via protein binding drugs bile acids, and bilirubin can be displaced
• Hemolytic disease of newborn (erythroblastosis fetalis) causes injury to the brain (kernicterus).
• Predominantly unconjugated hyperbilirubinemia includes excess production of bilirubin in both hemolytic anemias and resorption of blood in the liver.
• Reduced Hepatic Uptake and Impaired Bilirubin Conjugation are associated with Predominantly unconjugated hyperbilirubinemia
• Physiologic jaundice of the newborn and Diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis and cirrhosis) can impair bilirubin conjugation
• Decreased Hepatocellular Excretion, drug-induced canalicular membrane dysfunction (e.g., oral contraceptives and cyclosporine.
• Predominantly Conjugated Hyperbilirubinemia can include Impaired Intrahepatic or Extrahepatic Bile Flow

Cholangiopathy and Cholestasis

• Cholestasis is caused by obstructed bile channels that are intrahepatic, extrahepatic, inflammatory, or mechanical, with defects occurring in hepatocyte bile excretion.
• Cholestasis symptoms - jaundice, pruritus, skin xanthomas, elevated alkaline phosphatase (alk phos), elevated gamma-glutamyl transferase (GGT enzymes within membranes of hepatocytes and cholangiocytes).
• Neonatal Cholestasis is Prolonged conjugated hyperbilirubinemia
• Neonatal Cholestasis Includes Biliary atresia (complete or partial obstruction of the extrahepatic biliary tree), and Neonatal hepatitis causes and cluster of disorders.
• Primary Biliary Cholangitis used to previously be calls primary biliary cirrhosis
• Primary Biliary Cholangitis causes destruction of intrahepatic bile ducts
• Primary Biliary Cholangitis has characteristic anti-mitochondrial antibodies
• Primary Biliary Cholangitis is mostly diagnosed when asymptoms
• Women are more susceptible to Primary Biliary Cholangitis
• Primary Sclerosing Cholangitis includes fibrosis in the intrahepatic ducts.

Cirrhosis

• Cirrhosis is caused by a series of factors and conditions, including, Virus (hepatitis), Wilson's, Hemochromatosis, Alpha-1, PSC, PBC, Etoh, NASH

Circulatory Disorders of the Liver

• Impaired Blood Inflow via portal vein obstruction causes splenomegaly.
• Impaired Intrahepatic Blood Flow via Cirrhosis causes Hepatic Vein Outflow Obstruction
• Hepatic Vein Outflow Obstruction such as Budd-Chiari syndrome causes symptoms such as jaundice

Liver Tumors

• Includes Hepatocellular Adenoma, Hepatocellular Carcinoma, and Cholangiosarcoma
• Hepatocellular Adenoma develops from hepatocytes.
• Hepatocellular Adenoma is subclassified on the basis of molecular changes
• Hepatocellular Adenoma presents with pain from liver capsule distension
• Hepatocellular Adenoma develops from Oral Contraceptives and Anabolic steriods
• Cessations of sex hormones can often regress tumors
• Hepatocellular Carcinoma is driven by Hep B and C, Alcoholic Cirrhosis and Hemochromatosis
• Hepatocellular Carcinoma can recapitulate normal liver formations
• Hepatocellular Carcinoma includes both Hepatic Adenoma and Low Grade Dysplasia
• Cholangiosarcoma involves tumors in the intrahepatic or extrahepatic bile ducts
• Cholangiosarcoma Risk factors include Chronic inflammation and cholestasis

Gallbladder

• Gallbladder can be diagnosed by Gallstones, Acute calculous/acalculous cholecystitis, Chronic Cholecystitis and Cancer
• Cholesterol gallbladder stones is a Western issue.
• Suparsaturation and exceed cholestrol amounts causes cholestrol to crystallize out of bile's solution
• pigment gallbladder stones is an Asian issue.
• biliary tree unconjugated bilirubin causes biliary tree to precipitate in salts
• The risk factors for Cholesterol Stones includes advancing years, female sex hormones. and pregnancy
• 90% of obstructions happen gallbladder's neck when dealing with gallstones
• Biliary pain occurs for more than 6 hours
• RUQ pain radiates radiation
• Bacterial superinfection can lead to cholangitis
• Most common reason for a cholecystectomy is gallstones
• Charcots Triad includes pain in RUQ causes jaundice, and causes fever
• Patients often experience acute cholecystitis when there's dehydration present
• acute patients have increased chance of having bacterial infections
• comorbid conditions and acute dehydration often lead to complications
• Cholecystis includes attacks that lead to cancerous cells

Pancreatic Disease

• Pancreatic Diseases Includes Agenesis Pancreas Divisum, Ectopic Pancreas Congenital Cysts
• The exocrine pancreas breaks down because of longs tanding complications
• The loss of pancreas breaks even down further down when breaking down is handled
• Etiology in which long standing can create new issues and long term issues with the long term function

Acute Pancreatitis

• Acute Pancreatitis symptoms range, from focal edema to widespread hemorrhagic necrosis
• Causes for Acute Pancreatitis include mutations within trypsinogen and trypsin
• Shock and Acute Pancreatitis cause atherosclerosis
• Systemic damage can occur if the patient isn't treated
• Full blown pancreatitis often ends poorly for all associated