Chapter 18 part 1--Liver failure, cirrhosis Flashcards
General features of Liver Disease–most common primary diseases
-viral hepatitis, alcohol related liver disease, nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC)
General features of Liver disease–most common secondary diseases
- secondarily affected by common disorders like congestive heart failure and metastatic cancer
- lab testing may show injury but an enormous functional hepatic reserve masks clinical impact of early damage
General features of Liver disease–symptoms
- Most liver disease is insidious with symptoms of decompensation developing over weeks to years
- but disrupted bile flow or progressive disease=life threatening
Tests that measure hepatocyte integrity
- Cytosolic hepatocellular enzymes:
- Serum aspartate aminostransferase (AST)
- Serum alanine aminotransferase (ALT)
- Serum lactate dehydrogenase (LDH)
Tests that measure Biliary excretory function
- substances normally secreted in bile:
- Serum bilirubin (Total=unconjugated + conjugated, direct=conjugated only, delta=covalently linked to albumin)
- urin bilirubin
- serum bile acids
- Plasma membrane enzymes (from damage to bile canaliculus)–serum alkaline phosphatase, serum GGT, serum 5’-nucleotidase
Tests that measure hepatocyte function
- Proteins secreted into blood:
- Serum albumin
- Prothrombin time (factors V, VII, X, prothrombin, fibrinogen)
- Hepatocyte metabolism:
- Serum ammonia
- Aminopyrine breath test (hepatic demethylation)
- Galactose elimination (IV injection)
Elevation vs. decrease in liver tests
- Elevation implicates disease
- Decrease also implicates liver disease
Mechanisms of injury and repair–hepatocyte and parenchymal responses—reversible degenerative changes include:
- fat accumulation (steatosis) and bilirubin buildup (cholestasis)
- when injury is not reversible, hepatocytes die by necrosis or apoptosis
Hepatocyte necrosis
-predominant mode of death in ischemic-hypoxic injury and responses to oxidative stress: defective osmotic regulation leads to cell swelling and rupture, also marked by local macrophage accumulation
Hepatocyte apoptosis
-typical of cell death associated with acute and chronic hepatitis and is marked by hepatocyte shrinkage, nuclear chromatin condensation (pyknosis), fragmentation (karyorrhexis), and cellular fragmentation into acidophilic bodies
Vascular insults and liver disease
-Even in diseases where hepatocytes are the principal targets of attack (e.g., hepatitis), vascular insults via inflammation or thrombosis–lead to confluent zones of parenchymal necrosis
Hepatocyte regeneration
- occurs primarily by proliferation of hepatocytes adjacent to those that have died
- stem cell replenishment is usually not a significant part of parenchymal repair
- In severe liver injury, the canal of Hering–the primary intrahepatic stem cell niche–can be activated but unclear how much they contribute to healing
- With chronic disease, hepatocytes can reach replicative senescence, at which point stem cell activation leads to formation of ductular reactions that can contribute to parenchymal restoration
scar formation and regression–hepatic stellate cell–what is it?
-lipid (vitamin A) storing cell is responsible for liver scar deposition
how are stellate cells activated?
- can be activated by:
- 1) inflammatory cytokines like TNF, lymphotoxin, and IL-1B and lipid per oxidation products
- 2) cytokine and chemokine production by Kupffer cells, endothelial cells, hepatocytes and bile duct epithelial cells
- 3)in response to disruption of ECM
- 4) direct stimulate of stellate cells by toxins
What happens after stellate cells are activated? how does further fibrogenesis occur?
- activation causes stellate cells to develop into highly fibrogenic and contractile myofibroblasts
- subsequent fibrogenesis is driven by cytokines released by Kupffer cells and lymphocytes (TGF-B)
- stellate cell contraction stimulated by endothelin1 (ET-1)
Portal fibroblasts
-Also contribute to scar deposition with ductular reactions leading to activation and recruitment of such fibrogenic cells
What happens if the chronic injury leading to scar formation is interrupted (clearance of hepatitis virus infection, cessation of alcohol use)?
- then stellate cell activation ceases and fibrosis can be fragmented by metalloproteinases produced by hepatocytes
- so in this way, scar formation can be reversed!!
Inflammation and Immunity
- Innate and adaptive immune systems involved in liver injury and repair
- TLRs detect molecules derived from foreign invaders like bacteria and viruses
- lead to pro inflammatory cytokines
- adaptive immunity plays critical role in viral hepatitis by destroying infected hepatocytes
Liver failure
- occurs when greater than 80-90% of hepatic function lost
- without liver transplantation, mortality rate is 80%
- Although occasionally caused by massive acute destruction (fulminant hepatic failure), more commonly bc of successive waves of injury or progressive chronic damage
- Pts with marginal function can also go into failure when intercurrent dz places a greater demand on hepatic fnx
Stellate cell activation and liver fibrosis
- Kupffer cell activation leads to secretion of multiple cytokines
- PDGF and TNF activate stellate cells and contraction of activated stellate cells is stimulated by ET-1
- Fibrosis is simulated by TGF-B
- Chemotaxis of activated stellate cells to areas of injury is promoted by PDGF and monocyte chemotactic protein-1 (MCP-1)
