Hep C Discussion Forum

Hi all,

Today's 'lecture' is on the hepatic stellate cells (HSC's). These little fellows live in the liver in the space of Disse, between the hepatocytes and blood sinusoids. In a normal liver, they are quiescent, and their only function is to store Vitamin A as fat droplets in their cytoplasm. They are derived from mesoderm, and can secrete proteins from all three germ layers, so are thought to be germ cells. They have long projections, that wrap around the blood sinusoids.

When the HepC virus enters liver cells (hepatocytes) and begins to replicate, the hepatocyte is damaged and leaks various chemicals as a call for help. The typical inflammatory response occurs, with the arrival of white blood cells (neutrophils, lymphocytes and monocytes). As replication continues, hepatocytes begin to die and release further chemicals and debris. The liver has 'garbage-bag' cells called Kupffer cells (K. cells) that mop up all the debris. These K. cells release a host of chemokines and cytokines (chemicals). The names of these are not important but include TGF-alpha, beta1, MMP-9, TNF-alpha and various Interleukins. Some of the white cells also release these, particularly T-cell lymphocytes. All of these are pro-inflammatory.

These cytokines awake the HSC's from their sleeping state. The Vitamin A is dumped and the activated cells are transformed into myofibroblasts. They begin laying down layers of collagen (scar tissue)- initially Collagen Type3, then the stronger Type1. This is the typical response to injury.  Seal it up.  As the HCV continues to damage the liver, more and more collagen is formed, initially in the periportal areas, then spreading.  The long arms of the transformed HSC's are contractile, and they wrap around the blood sinusoids trying to decrease the portal vein flow.  The holes (sequestra) in the limiting plate are closed by the collagen, and the hepatocyte projections into the sinusoids are obliterated.  This 'protects' the hepatocyte from the nasties in the portal vein (virus and stuff from the gut).  This protective layer builds up, and this is why some of our antiviral drugs have poor access to hepatocytes.  As time passes, often years, of HCV replication, these collagen deposits spread through the liver.  Wherever hepatocytes are dying, the HSC's migrate and form collagen.  We know the different classifications of liver fibrosis.  F4 means there are sheets of collagen throughout the liver forming 'scars'.  Hepatocytes trying to replicate are trapped and form nodules, often without an adequate blood supply or bile drainage.  Meanwhile the HSC's keep squeezing the portal blood vessels, trying to limit the liver's work-load, so we get the familiar portal hypertension.  Shunts open up between the portal and hepatic vein branches, so some blood goes back to the heart completely bypassing the liver.

We need to remove the cause of the hepatocyte damage i.e. remove the HCV. Now we have drugs to do this, so we can attain SVR. The liver cell death stops, proinflammatory cytokine production stops and the HSC's revert back to their quiescent state.  Some suggest the HSC's play an active part in liver regeneration.  As stem cells, they can become hepatocytes, bile duct or blood vessel cells etc.  Then there are the anti-inflammatory cytokines. These promote resorption of the collagen, and obviously would be a great drug to give cirrhotics. There are a host of compounds( ACE inhibitors, TNF-alpha inhibitors etc)- steroids are obvious but would be ill-advised!  There is ongoing research to see whether the K.cells and HSC's play a part in this.

That's it folks. A good cell that does bad things to our liver, then tries to heal it. Cheers.

* You may wonder why I'm interested in this stuff. When you've had the disease for 45 years (18 years as non-A, non-B hepatitis), initially with no hope of a cure, you do a lot of research to see what the virus is doing to your body.