Liver Pathophysiology (Exam 2 Material)

1) What is the largest visceral organ in the body?

2) Which lobe of that organ is the largest?

3) What percent of blood supply is from the vein?

1) Liver is the largest visceral organ

2) Right lobe is the largest lobe

3) 75-85% of blood supply is from portal vein

What are the 6 functions of the liver?

• Metabolism

• Storage

• Excretory/Secretory

• Protective

• Circulatory

• Coagulation

Describe the metabolic functions of the liver.

• Carbohydrate metabolism

  • Gluconeogenesis: Synthesizing new glucose

  • Glycogenolysis: Breaking down glycogen to produce glucose (glycogen stores glucose → when broken down, releases glucose)

  • Glycogenesis: Synthesizing new glycogen

• Synthesis of fatty acids, lipoproteins, and cholesterol

• Ketogenesis (break down of fatty acids to ketones)

• Protein metabolism

• Synthesis of plasma proteins (albumin, globulin, fibrinogen)

• Urea synthesis (ammonia to urea)

• Hormone metabolism

• RBC production

  • In fetal livers during the first trimester of pregnancy

What are the storage functions of liver?

• Glycogen → stores glucose

• Vitamins:

  • A, D, E, K → lipid soluble

  • B12 (water soluble)

• Minerals store iron and copper

Excretory/secretory functions:What primary hormone/growth factor, class of macromolecules, and major fluid secretion are produced and excreted/secreted by the liver?

• Growth Factor: Insulin-like Growth Factor 1 (IGF-1)

• Proteins: Mostly blood proteins

• Bile (and its key components): Water, cholesterol, bile pigments (bilirubin and biliverdin), bile acid anions, phospholipids (mainly lecithin), and bicarbonate and other ions

• Lipids: Cholesterol and fatty acids

What are the protective functions of the liver? Specifically, what specialized resident macrophages reside in the liver, and what is their primary protective role?

• Purification, clearance, transformation

  • REMEMBER: PCT, like PCR

  • Endogenous: Hormones, ammonia, etc.

  • Exogenous: Drugs and chemicals

• Kupffer cells (residential macrophages)

  • Phagocytose and clear bacteria and other foreign materials arriving via the portal blood supply

What nickname describes the liver's circulatory role regarding blood coming from the GI tract, and which major vessel delivers this nutrient-rich blood to the liver?

1) Antechamber of the heart

2) Hepatic portal vein

What are the coagulation factors produced by the liver?

• Fibrinogen I

• Prothrombin II

• Factors (V, VII, IX, X, XI)

• Protein C

• Protein S

• Antithrombin

What are the two types of liver enzymes and two examples of each?

• Transaminases (from damaged/dead hepatocytes)

  • Aspartate aminotransferase (AST or SGOT)

  • Alanine aminotransferase (ALT or SGPT)

• Cholestatic Enzymes (from injured biliary epithelial cells)

  • Alkaline phosphotase (ALP)

  • Gamma-glutamyl transferase (GGT)

Microstructure of Liver Hepatic Lobule (come back to this)

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What are the key histopathological differences between acute and chronic hepatitis? What is the key distinguishing feature between both?

Acute hepatitis: Inflammatory infiltrates, hepatocyte ballooning degeneration, apoptosis, and necrosis

• Inflammatory infiltrate: Immune cells accumulate in the liver in response to injury (initial stages of immune response or normal immune response)

• Ballooning Degeneration: Hepatocytes swell due to cellular injury

• Apoptosis: Programmed death of damaged hepatocytes

• Necrosis: Hepatocyte death caused by injury and inflammation (if inflammation isn’t resolved)

• Macrophage aggregates: Macrophages accumulate to clear dead cells and debris

Main idea: Acute hepatitis is characterized primarily by active inflammation and hepatocyte injury.

Chronic Hepatitis: Persistent inflammation, lymphoid aggregates, and fibrosis

KEY DISTINGUISHING FEATURE: FIBROSIS (may progress bridging fibrosis)

Persistent inflammation, lymphoid aggregates, and fibrosis (KEY distinguishing feature), which may progress to bridging fibrosis.

• Lymphoid aggregates: Collections of lymphocytes indicating persistent inflammation

• Periportal fibrosis: Scar tissue develops around the portal tract

• Bridging fibrosis: Fibrous scar tissue connects different regions of the liver, such as portal tracts and central veins

• Bridging necrosis: Areas of hepatocyte death connect different regions of the liver

• Ground-glass hepatocytes: Characteristic finding associated with hepatitis B

Main idea: Chronic hepatitis involves ongoing inflammation and injury that can lead to progressive fibrosis (scarring).

What is the fundamental difference in how HAV/HEV vs HBV/HCV damage hepatocytes, and what class of drugs is used to cure Hepatitis C? (come back im confused)

Mechanism of Hepatocyte Damage:

• HAV & HEV: Directly cytopathic, meaning the virus itself directly disrupts and kills hepatocytes via apoptosis

• HBV & HCV: The damage is primarily caused by body’s own immune system attacking the infected liver cells

Hepatisis C (HCV) Characteristics & Treatment

• Roughly 75% of HCV cases are asymptomatic

• Treated and cured in most individuals within 8-12 weeks using oral direct-0acting antiviral (DAA) medications

  • DAA Meds: glecaprevir/pibrentasvir (Mavyret), sofosbuvir/velpatasvir (Epclusa), and sofosbuvir/ledipasvir (Harvoni)

Hepatitis B Prevention:

• HBV prevalence remains lower in the US primarily due to widespread vaccine administration

Does DILI have a high incidence? What percent of ADR’s lead to DILI’s?

What are the two primary clinical injury patterns of Drug-Induced Liver Injury (DILI) with their classic examples, and what is the #1 most common drug associated with DILI?

• Has a high incidence

• 10% adverse drug reactions lead to DILI

• Injury Patterns and Examples:

  • Hepatocellular → Central lobular necrosis

    • EX: Tylenol

  • Cholestatic → Often characterized by bile plugs and feathering changes

    • EX: Methyl testosterone

• #1 Most Common Drug for DILI: Amoxicillin/clavulanate

  • Other drugs down the list in order: Diclofenac, Azathiopurin, infliximab, nitrofurantoin

What are the major etiologies of chronic liver injury?

• Obesity

• Alcohol:

• Drugs:

• Viral:

• Autoimmune:

Less Critical Etiologies:

• Iron overload

• Copper overload: Wilson’s disease (hepatolenticular degeneration)

• Alpha1-antitrypsin deficiency

• Autoimmune-bililary

  • PSC-progressive sclerosing cholangitis

  • PBC-progressing biliary cholangitis

What is the most common cause of abnormal liver enzyme tests, and what are the potential complications?

• Fatty Liver Disease

• Steatosis: Accumulation of fat within hepatocytes

• Hepatitis: Inflammation and injury of liver cells

• Lean NASH (Nonalcoholic Steatohepatitis): Steatohepatitis can occur in individuals who are not obese

• NASH involves fat accumulation PLUS inflammation and hepatocyte injury (steatohepatitis)

  • Affects 30-40% population in developed countries

• Progression of Disease: Hepatic steatosis (fat accumulation) → steatohepatitis (fat + inflammation/injury) → fibrosis (scarring) → cirrhosis) (advanced scarring) → increased risk of HCC (liver cancer)

• Affects 2-3% of children (35-50% of obese children)

What are the three key histopathological features of ASH and MASH/NASH, and how do they differ?

• ASH: Alcoholic steatohepatitis

  • Caused by harmful alcohol exposure

  • Steatosis + inflammation + ballooning

    • Steatosis: Fat accumulates inside hepatocyte

    • Inflammation: Immune cells accumulate in the liver due to injury

    • Hepatocyte ballooning: Injured hepatocytes become swollen and enlarged

• MASH: Metabolic dysfunction associated steatohepatitis

  • Associated with metabolic risk factors, such as obesity and insulin resistance

• NASH: Non-alcoholic steatohepatitis

Remember: Steatosis alone ≠ steatohepatitis.

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What is the molecular mechanism of MASH/NASH?

• First hit: Fat accumulation in the liver (steatosis)

  • Obesity

  • Long-term fasting

• Additional/parallel hit: Injury caused by the below factors leads to inflammation;

  • Drugs

  • Pathogens

  • Leaky gut (LPS)

  • Genetic abnormalities (PTEN, FXR, or other deficiency)

  • Oxidative stress

What are the four major mechanisms involved in the pathophysiology of alcoholic steatohepatitis (ASH)?

• Hepatic Fat Storage: Fat accumulates in hepatocytes (steatosis) →

• Inflammation: Gut-derived endotoxins (leaky gut due to alcohiol increasing intestinal permeability) activate Kupffer cells triggering proinflammatory factor release

• Oxidative stress: Induction of cytochrome P4502E1 which metabolized ethanol, producinqg toxic acetaldehyde and ROS

• ER Stress: Ethanol disrupts protein folding, causing misfolded proteins to accumulate

Describe the mechanism of ALD-Inflammation.

Innate Immunity:

• Gut-derived LPS (endotoxin) → TLR4 activation on Kupffer cells → ↑ proinflammatory cytokines (TNF-α, IL-1, IL-17)

• C3/C5 complement activation → ↑ proinflammatory cytokines

• Ethanol/acetate → acetyl-CoA → histone acetylation → ↑ cytokine expression

• IL-17 → stellate cells → ↑ chemokines (IL-8, CXCL1)

• Acetaldehyde/LPS/TNF-alpha → hepatocytes → NF-κB, JNK, AP-1 activation → ↑ chemokines

• Results: Cytokines + chemokines → recruitment of neutrophils and macrophages → inflammation

Adaptive Immunity:

• Alcohol → ↑ ROS → protein adduct formation

• Protein adducts → antigen presentation by dendritic cells/macrophages

• → T cell and B-cell activation/proliferation → lymphocyte infilitration

• Overall: Innate + adaptive immune activation → liver inflammation

What causes liver fibrosis, and what are its major consequences?

• Causes: Persistent activation of hepatic stellate cells (HSCs) → excess collagen/ECM deposition → fibrosis (scarring)

• Consequences: ↓ Hepatic blood flow (since there’s more tissue that disrupts liver structure), impaired liver function, and complications such as portal hypertension and cirrhosis

• Reversibility: Fibrosis can resolve, but advanced scarring may be difficult to reverse

  • Apoptosis: Activated stellate cells undergo programmed cell death

  • Inactivation: Activated stellate cells return to an inactive-like state

• Treatment: No therapeutic agents; advanced liver failure may require transplantation

What is cirrhosis? How is cirrhosis induced by MASH/NASH? What is burnt-out NASH?

Progression to Cirrhosis:

• Steatosis: Fat accumulation in hepatocytes

• MASH/NASH: Steatosis + inflammation + hepatocyte ballooning

• Fibrosis: Persistent injury → HSC activation → collagen deposition

• Cirrhosis: Advanced fibrosis → scar tissue surrounds regenerative hepatocyte nodules and disrupts liver architecture (irreversible)

Burnt-Out NASH

As MASH/NASH progresses to cirrhosis:

• Steatosis → May disappear

• Hepatocyte ballooning → May disappear

• Lobular inflammation → May disappear

• Perivenular/pericellular fibrosis → May remain

Advanced scarring and changes in liver tissue can make the original features of steatohepatitis less apparent

What does the histology show?

• Pink regions: Hepatocytes

• Blue regions: Collagen/fibrosis/scar tissue

• Overall appearance: Thick fibrous bands surrounding hepatocyte nodules → characteristic of cirrhosis

🟠 What are the key histopathological features of HBV-associated cirrhosis, and what is its major complication? 🟠

• Regenerative nodules: Nodules of damaged and regenerating hepatocytes surrounded by fibrous bands

• Fibrous bands: Contain chronic inflammatory cell infiltrates/lymphocytes (dark purple dots)

• Micronodular cirrhosis: Nodules <3mm

• Macronodular cirrhosis: Nodules >3mm

• Major complication: Increased risk of hepatocellular carcinoma (HCC)

• Ground-glass cytoplasm (light colored surface Ag particles)

• Bile pigment accumulation (dark brown)

What are the three major hepatitis B virus (HBV) antigens, and what do they indicate?

• HBsAg - Surface Antigen: Most abundant antigens, detectable at onset of clinical symptoms

• HBcAg - Core Antigen: Marker of viral replication

• HBeAg - Antigen between nucleocapsid and lipid envelope, marker of viral replication

• Antibodies:

  • Anti-HBc IgM: Acute/recent infection or flare of chronic HBV

  • Anti HBc IgG: Previous exposure; persists in chronic or resolved infection

    • Present in chronic HBV infection

    • Also present after recovery from natural HBV infection

• HBV Structure:

  • HBV: Enveloped, partially double-stranded (relaxed) circular DNA virus

    • Relaxed: The DNA is not a completely closed, tightly wound double-stranded circle

  • Envelope: Outer lipid layer containing HBsAg

  • Nucleocapsid: Inner protein shell containing HBcAg and viral DNA

  • DNA polymerase: Enzyme involved in HBV replication; has reverse transcriptase activity

• HBsAg vs Anti-HBS vs. Anti-HBCL

  • HBsAg positive → Current HBV infection

    • HBsAg = Hepatitis B Surface Antigen

      • HBsAg is a protein found on the surface of HBV.

      • If HBsAg is detected in someone's blood → HBV is currently present.

      • Therefore, HBsAg (+) indicates a current HBV infection (acute or chronic).

  • Anti-HBS positive → Immunity to HBV (vaccination or recovery)

    • Anti-HBs = Antibody Against the Surface Antigen

  • Anti-HBc positive → Previous or current natural HBV infection (not produced by vaccination alone)

Describe the structure of Hepatitis C virus

• Made up of RNA

• Positive sense, single-stranded RNA virus from the Flavivirdae family → each particle contains a single RNA strand

What is gallstone disease?

• Cholesterol stones may form if there is an imbalance between the ratio of cholesterol and bile salts; normally the latter form micelles which have a hydrophilic exterior enclosing the hydrophobic cholesterol. Thus, gallstones can result from: an excess of cholesterol or a deficit of bile salts

• Bile pigment, cholesterol, or mixture of cholesterol and bile pigment

What are the risk factors for gallstone disease?

• Female

• Forties

• Fat

• Fertile

• FXR mutation?

What are some examples of benign liver tumors?

• Liver cell adenoma

• Angioma

• Bile duct hamartoma

• Focal nodular hyperplasia

What are some examples of malignant liver tumors?

• Primary:

  • Liver cell carcinoma

  • Cholangiocarcinoma

  • Angiosarcoma

  • Hepatoblastoma

• Secondary: Metastases from the GI, lung, and breast cancers

What is the difference between well differentiated and poorly differentiated HCC (hepatocellular carcinoma)?

• Well differentiated: Tumor cells resemble hepatocytes, form trabeculae, cords, and nests, and may contain bile pigment in cytoplasm

  • Trabeculae/cords: Tumor cells arrange themselves in rows or plates

  • Nests: Tumor cells form clusters.

• Poorly differentiated: Malignant epithelial cells are discohensive, pleomorphic anaplastic, and gain

  • Discohesive: Tumor cells lose normal cell-to-cell adhesion

  • Pleomorphic: Tumor cells vary in size and shape.

  • Anaplastic: Tumor cells lose normal differentiation and appear highly abnormal.

  • Giant cells: Abnormally large malignant cells may be present

• Cirrhosis can lead to HCC, but ~25% patients NEVER develop cirrhosis