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Liver Fibrosis

Pathophysiology

  • Activation of hepatic stellate cells
  • Release of ECM
  • Deposition of fibrin in space of Disse
  • Loss of Endothelial Fenestration
  • Increase in Fibril forming collagen (Type I, III, IV)
  • HSC —> Myofibroblasts —> Fibrosis

Figure 7.1: Matrix and Cellular Alteration in Hepatic Fibrosis

Normal Liver Parenchyma:

  • Epithelial Cells: The liver parenchyma primarily consists of hepatocytes, which are responsible for most of the liver's metabolic functions.
  • Nonparenchymal Cells:
    • Fenestrated Sinusoidal Endothelium: The endothelial cells lining the sinusoids are fenestrated (i.e., have small pores) to facilitate the exchange of substances between blood and hepatocytes.
    • Hepatic Stellate Cells (HSCs): Located in the space of Disse, these cells store vitamin A in their quiescent state.
    • Kupffer Cells (KCs): These are liver-resident macrophages involved in immune surveillance and clearance of pathogens and debris.

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A. Normal Sinusoidal Structure:

  • Space of Disse: This space separates the sinusoids from hepatocytes, containing a low-density basement membrane-like matrix that ensures efficient metabolic exchange.
  • Metabolic Exchange: The normal structure, with fenestrated endothelium and hepatocyte microvilli, facilitates bidirectional metabolic exchange between the portal venous blood and hepatocytes.

B. Hepatic Fibrosis and ECM Deposition:

  • HSC Activation: Upon liver injury, HSCs become activated, transforming into myofibroblast-like cells that secrete large amounts of extracellular matrix (ECM).
  • ECM Deposition: The increased ECM leads to thickening of the septa (connective tissue partitions in the liver).
  • Pathological Changes:
    • Loss of Endothelial Fenestrations: The deposition of ECM in the space of Disse causes the endothelial cells to lose their fenestrations, hindering the free flow of substances.
    • Loss of Hepatocyte Microvilli: The increased ECM and loss of microvilli impair the normal exchange of metabolites, worsening liver function.
    • Portal Hypertension: The structural alterations in the liver, particularly the thickened septa and loss of fenestrations, contribute to the development of portal hypertension.

Summary: Hepatic fibrosis leads to significant structural changes in the liver, including the activation of hepatic stellate cells and the deposition of extracellular matrix in the space of Disse. These changes result in the loss of endothelial fenestrations and hepatocyte microvilli, impairing metabolic exchange and contributing to the development of portal hypertension.

Figure 7.2: Pathways of Cellular Injury and Fibrosis

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Figure 7.2: Pathways of Cellular Injury and Fibrosis

Overview:

  • The diagram illustrates the key pathways leading to cellular injury and fibrosis in the liver, focusing on the roles of different factors like alcohol, nonalcoholic steatohepatitis (NASH), viral infections (HBV, HCV), and bile acid injury.

Main Causes of Chronic Liver Injury:

  • Alcohol:
    • Promotes gram-negative bacterial overgrowth in the small intestine.
    • Reduces gut integrity, leading to increased lipopolysaccharide (LPS) levels in portal blood.
    • LPS activates Kupffer cells, which produce tumor necrosis factor-alpha (TNF-α), leading to increased mitochondrial oxidative stress in hepatocytes, making them more prone to apoptosis.
  • Nonalcoholic Steatohepatitis (NASH):
    • Causes damage to hepatocytes, promoting oxidative stress.
    • Sensitizes hepatocytes to apoptosis due to increased intracellular oxidative stress.
    • Free fatty acids contribute to this oxidative stress, exacerbating cellular injury.
  • Viral Infections (HBV, HCV):
    • Similar to NASH, these infections cause oxidative stress, leading to hepatocyte damage and apoptosis.
  • Cholestatic Conditions:
    • Injury from bile acids can contribute to fibrosis, although bile acids also inhibit hepatic stellate cell (HSC) activation through the farnesoid X receptor (FXR) pathway.

Pathways of Fibrosis Development:

  • Hepatic Stellate Cells (HSCs):
    • Central to liver fibrogenesis; when activated (aHSCs), they produce extracellular matrix (ECM) components leading to fibrosis.
    • Quiescent HSCs (qHSCs) become activated in response to liver injury.
  • Kupffer Cells:
    • Activated by LPS, these liver macrophages produce reactive oxygen species (ROS) and TNF-α, contributing to hepatocyte apoptosis.
    • Kupffer cells also promote the accumulation of inflammatory cells and neutrophils, further stimulating HSC activation.
  • Oxidative Stress:
    • Caused by various factors (alcohol, NASH, viral infections), it leads to mitochondrial dysfunction in hepatocytes, making them more susceptible to damage and apoptosis.
  • Farnesoid X Receptor (FXR) Pathway:
    • Bile acids inhibit HSC activation via this pathway, although their overall role in liver injury can still contribute to fibrosis through other mechanisms.

Key Molecular Players:

  • TNF-α (Tumor Necrosis Factor-alpha): Sensitizes hepatocytes to apoptosis.
  • ROS (Reactive Oxygen Species): Result from oxidative stress, contributing to cellular injury.
  • EGFR (Endothelial Growth Factor Receptor): Involved in signaling pathways that might contribute to liver fibrosis.
  • ERK-1 (Extracellular Signal-Regulated Kinase-1): Part of the signaling pathways activated during liver injury.

Summary: The pathways depicted in this figure highlight how different factors—alcohol, NASH, viral infections, and bile acids—lead to liver fibrosis. Central to this process is the activation of hepatic stellate cells (HSCs), driven by oxidative stress, inflammation, and apoptosis of hepatocytes. Understanding these pathways is crucial for developing targeted therapies to prevent or mitigate liver fibrosis.

Functions of HSC in Normal and Diseased Liver

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Hepatic Stellate Cells

  • Store vit A
  • Activation in inflammation
  • VEGF, TGF B1 , CTGF, Angiotensin II and Leptin
  • Accumulation of actin - Hepatic Myofibroblast
  • Portal Fibroblast/Bone marrow derived fibroblast
  • help in Regeneration and if not then cause Fibrosis

FIBROGENESIS

  • Stellate cells = hepatic myofibroblasts → TGF B1
  • Type IV collagen replaced by Type 1 and III
  • Continuous Basement membrane
  • reduction of sinusoidal fenestration (capillarization)
  • Cross linking resistant to MMP
  • Decreased Level of MMP 1, MMP 8 & 13 and increased MMP -2
  • Increase in TIMP 1/2

DIAGNOSIS

  • Liver Biopsy is Gold Standard
  • Knodell - histology activity index score
  • Ishak scoring
  • METAVIR - Hepatitis C ( fibrosis+inflammation)
  • NAFLD = Centrilobular / BRUNT / KLEINER

Assessment:

  • Non contrast CT - assessment of steatosis = we look for HU = LAI with cut off values
  • MR elastography, MR Fat Fraction

Biochemical Assays

  • FIB-4 Index
  • ELF Test (Enhanced Liver Fibrosis)
  • FibroTest
  • HepaScore
  • Collagen Propeptides

Stiffness Assessment

  • Fibroscan:
    • Vibration Controlled Transient Elastography (VCTE) or MR Elastography.
    • Measures stiffness in kPa (more accurate than biopsy).
    • Early stage liver fibrosis can be detected.
    • Limitations:
      • Obesity
      • Ascites
      • Acute Hepatitis
      • Jaundice
    • Controlled Attenuation Parameter (CAP): Assesses fat content in the liver.

Liver Attenuation Index (LAI)

  • Non-Contrast CT Scan:
    • Compares Hounsfield Units (HU) of the liver and spleen.
    • Steatotic liver appears dark (lower attenuation).
    • LAI:
      • 0 to +5: Indicates a normal liver.
      • 0 to -5: Indicates 30-40% steatosis.

Treatment

  • Fibrosis can be reversed

  • remove etiological agent

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  • Drugs

    • Antioxidants = Silmyerin ,VIT E , S adenosyl methionine
    • Imatinib and Sorafenib = Antifibrotic

Doctutorials ( Liver Physiology)

Hepatic Fibrogenesis

Key Points

  1. Major Signal:
    • The major signal driving hepatic fibrogenesis is TGF-β1.
  2. Collagen Replacement:
    • In the space of Disse, collagen type IV is replaced by types I and III during fibrosis.
  3. Hepatic Stellate Cells (HSC):
    • HSCs play a major role in hepatic fibrogenesis.
    • HSCs transform into hepatic myofibroblasts (HMF) during fibrosis.
    • Activated HSCs lose retinoid stores and develop markers of skeletal muscle, such as α-smooth muscle actin and desmin.
  4. Collagen and Parenchymal Mass:
    • The total amount of collagen increases up to sixfold, while the parenchymal mass (e.g., hepatocytes) is progressively diminished.
  5. T-Helper Cells:
    • Th2 cells are profibrogenic in liver injury, whereas Th1 cells (via IFN-γ, TNF-α, and IL-2) are antifibrogenic.
  6. Hepatic Myofibroblasts (HMF):
    • HMFs have decreased vitamin A stores and develop markers of skeletal muscle.

Multiple Choice Question

Answer:

  • Correct Answer: E.Th2 cells are profibrogenic, not antifibrogenic. Th1 cells are antifibrogenic.

Additional Note:

  • The CD4-positive T lymphocytes called T-helper cells are involved in hepatic fibrogenesis. The humoral immunity mediated by T-helper 2 cells (Th2) is profibrogenic in liver injury, whereas the cell-mediated immunity by Th1 cells via IFN-γ, TNF-α, and IL-2 is antifibrogenic.
  • In a healthy liver, HSCs are quiescent cells containing cytoplasmic retinoid droplets, representing the major storage site for vitamin A in the body, and expressing markers like desmin and glial fibrillary acidic protein.
  • When activated, HSCs lose retinoid stores and develop actin, becoming hepatic myofibroblasts (HMF), characterized by α-smooth muscle actin and desmin expression.
  • Angiotensin II, a vasoconstrictive peptide expressed by activated HSCs in chronically injured livers, induces hepatic inflammation and stimulates fibrogenic actions of HSCs, including cell proliferation, migration, secretion of proinflammatory cytokines, and collagen synthesis.

Cirrhosis

Key Points

  1. Fetor Hepaticus:
    • Characteristic ammoniacal smell occurs due to exhaled thiols seen in portovenous shunting.
  2. Spider Nevi:
    • Superficial, tortuous, arterial skin lesions with a central arteriole and numerous small radiating vessels.
    • Usually found in the vascular territory of the superior vena cava (arms, face, and upper torso).
    • More than two or three spider nevi are likely to be abnormal.
  3. Jaundice:
    • Can usually be observed when the bilirubin level is above 43 μmol/L.
  4. Features of Chronic Liver Disease (CLD):
    • Hippocratic fingers (clubbing), white nails (Terry nails), koilonychia, and asterixis are all features of CLD.

Summary:

  • Fetor Hepaticus: Caused by exhaled thiols, indicative of portovenous shunting.
  • Spider Nevi: Central arteriole with radiating vessels, typically in the superior vena cava territory.
  • Jaundice: Visible when bilirubin > 43 μmol/L.
  • CLD Features: Clubbing, Terry nails, koilonychia, and asterixis.

Multiple Choice Question

Answer:

  • Correct Answer: B. Spider nevi have a central arteriole with numerous small radiating vessels, not a venule.

Additional Note:

  • Spider Nevi: These are most commonly associated with chronic liver disease and are a result of increased estrogen levels, which cause the dilation of arterioles. They are typically located in areas drained by the superior vena cava, such as the face, neck, upper chest, and arms. The central arteriole and the radiating small vessels resemble a spider, hence the name.

Fibroscan and Serum Surrogate Markers for Cirrhosis

Key Points

  1. Serum Surrogate Markers for Cirrhosis:
    • AST-Platelet Ratio Index (APRI): Based on AST and platelet count.
    • Forns Index: Includes age, platelet count, cholesterol, and GGT.
    • FibroTest: Includes α-2-macroglobulin, GGT, apolipoprotein A1, haptoglobin, bilirubin, age, and gender.
    • FIB-4 Index: Utilizes age, AST, ALT, and platelet count.
    • Enhanced Liver Fibrosis (ELF) Test: Measures markers of fibrosis.
    • HepaScore120: Includes measurements of collagen propeptides.
  2. Fibroscan:
    • Not a serum test: Fibroscan is an imaging test that measures liver elasticity and steatosis.
    • KiloPascals (kPa): Measurement of liver elasticity, indicating the degree of liver fibrosis.
    • Controlled Attenuation Parameter (CAP): Measurement of hepatic steatosis.

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Summary:

  • Serum Surrogate Markers: APRI, Forns Index, FibroTest, FIB-4, ELF Test, HepaScore.
  • Fibroscan: Imaging test, not a serum test.
    • Liver Elasticity (kPa): Indicates fibrosis stage.
    • Hepatic Steatosis (CAP): Indicates fatty change percentage.

Multiple Choice Question

Answer:

  • Correct Answer: D. Fibroscan

Additional Note:

  • Fibroscan: Provides non-invasive assessment of liver stiffness and hepatic steatosis, helping to determine the stage of fibrosis and the extent of fatty change in the liver. It is an essential tool for evaluating liver disease progression and guiding clinical management.

Staging Systems for Liver Fibrosis

Commonly Used Staging Systems

  1. Knodell:
    • Used for cirrhosis.
  2. Ishak:
    • Used for cirrhosis.
  3. Metavir:
    • Specifically used for HCV infection.
    • Stages:
      • F0: No fibrosis can be detected.
      • F1: Fibrosis with expansion of portal zones.
      • F2: Fibrosis with expansion of most portal zones and occasional bridging.
      • F3: Fibrosis with expansion of most portal zones, marked bridging, and occasional nodules.
      • F4: Presence of cirrhosis.
  4. Brunt/Kleiner:
    • Used for NAFLD (Non-Alcoholic Fatty Liver Disease).
    • Kleiner Staging:
      • 0: Absence of fibrosis.
      • 1: Portal/perisinusoidal fibrosis.
      • 2: Perisinusoidal and portal/periportal fibrosis.
      • 3: Septal or bridging fibrosis.
      • 4: Cirrhosis.
  5. Ludwig's:
    • Used for PBC (Primary Biliary Cirrhosis).
    • Stages:
      • Stage 1 (Portal Stage): Inflammation limited to portal triads with mononuclear infiltration.
      • Stage 2 (Periportal Stage): Inflammation beyond portal triads, piecemeal necrosis, small granulomas, and small duct proliferation may be seen.
      • Stage 3 (Septal Stage): Bridging fibrosis connecting the portal tracts.
      • Stage 4 (Cirrhosis): Regenerative nodules surrounded by fibrosis.

Multiple Choice Question

Answer:

  • Correct Answer: C. Metavir

Additional Note:

  • Metavir Staging System: This system is highly specific for HCV infection and is widely used due to its simplicity and reliability in assessing the degree of fibrosis and necroinflammatory activity. It helps guide treatment decisions and predict outcomes in patients with HCV.