5.20
Cirrosi II: Fisiopatologia
La cirrosi è una lesione epatica cronica progressiva causata da infiammazione prolungata, rimodellamento fibrotico eccessivo e rigenerazione compromes…
La cirrosi inizia con lesioni ripetute al fegato, che scatenano tre processi principali: infiammazione, attivazione del sistema immunitario e morte cellulare.
Insieme, questi processi causano danni epatici progressivi.
L'infiammazione attira le cellule immunitarie al fegato, stimolando il rilascio di citochine infiammatorie, come il fattore di necrosi tumorale alfa e l'interleuchina-1.
Queste citochine stimolano il rilascio del fattore di crescita beta trasformante, principale fattore promotore della fibrosi.
L'attivazione del sistema immunitario fa sì che le cellule stellate epatiche si attivino e producano un eccesso di collagene e proteine della matrice extracellulare.
L'attivazione continua porta all'accumulo di dense bande fibrose all'interno del tessuto epatico, distorcendo la sua normale architettura e ostacolando il flusso sanguigno.
L'apoptosi e la necrosi epatocitarie si verificano parallelamente a questi cambiamenti, scatenando una rigenerazione disorganizzata con il progredire della fibrosi.
Questa rigenerazione disordinata porta alla formazione di noduli delle cellule epatiche circondati da tessuto fibrotico denso.
La distorsione risultante aumenta la resistenza al flusso sanguigno portale, causando ipertensione portale.
View the full transcript and gain access to JoVE Core videos
Q1: What three main processes drive cirrhosis development?
Cirrhosis develops through inflammation, immune system activation, and hepatocyte death. Inflammation recruits immune cells that release cytokines like tumor necrosis factor-alpha and interleukin-1, triggering transforming growth factor-beta production. These processes activate hepatic stellate cells, stimulate collagen production, and cause liver cell death, collectively driving progressive liver damage and fibrosis.
Q2: How do hepatic stellate cells contribute to cirrhosis?
Hepatic stellate cells normally store vitamin A in a quiescent state. When activated by inflammatory signals, they transform into myofibroblasts and produce excess collagen and extracellular matrix proteins. Continuous activation leads to dense fibrous tissue accumulation that replaces normal liver tissue, distorting the liver's architecture and impairing its function.
Q3: What happens to the liver's structure as fibrosis progresses?
As fibrosis progresses, dense fibrous bands accumulate within liver tissue, distorting normal architecture. Hepatocyte death triggers disorganized regeneration, creating regenerative nodules—clusters of liver cells surrounded by fibrous tissue. These nodules further distort vascular and biliary structures, increasing resistance to portal blood flow and leading to portal hypertension.
Q4: How does cirrhosis lead to portal hypertension?
Fibrosis and regenerative nodules in the liver distort normal vascular architecture, increasing resistance to portal blood flow. This elevated pressure in the portal vein causes portal hypertension, which can trigger serious complications including ascites, splenomegaly, and bleeding from esophageal or gastric varices.
Q5: What role does inflammation play in cirrhosis pathophysiology?
Chronic liver injury triggers inflammation that recruits immune cells and promotes oxidative stress and reactive oxygen species production. Inflammatory cytokines damage liver tissue, disrupt cellular balance, and initiate fibrogenesis. This sustained inflammation accelerates hepatocyte injury and perpetuates the cycle of liver damage and fibrotic remodeling.
Q6: How does impaired liver regeneration affect cirrhosis progression?
Hepatocyte apoptosis and necrosis accelerate liver damage, prompting regeneration attempts. However, surrounding fibrosis disrupts this regenerative process, resulting in disorganized regeneration and regenerative nodules rather than normal tissue repair. This impaired regeneration perpetuates structural distortion and progressive functional decline in the liver.
Q7: What metabolic complications can result from advanced cirrhosis?
Advanced cirrhosis reduces the liver's ability to detoxify substances, allowing toxins like ammonia to accumulate and cause hepatic encephalopathy. The liver's diminished metabolic capacity also leads to kidney dysfunction, hormonal problems, and potential multi-organ failure in severe cases of decompensated cirrhosis.