Re: liver disease staging/is fibrosis reversible?

[Guest guest]

Dear Stevie;

Regarding your question about whether or not liver fibrosis is reversible

(repairable), I'd like to comment that it can be reversed/repaired in animal

models, but research still needs to be done to extend this to human subjects.

One of the big factors causing liver fibrosis seems to be that the main vitamin

A-storing cells in the liver, hepatic stellate cells, lose all of their vitamin

A (retinol) during inflammation. This loss of vitamin A then triggers the

hepatic stellate cells to produce collagen. The key to fibrosis seems to be the

balance between collagen synthesis rate versus collagen degradation rate. If

collagen synthesis exceeds collagen degradation then liver fibrosis advances.

But if collagen synthesis can be blocked, while continued collagen degradation

is allowed to occur, then reversal of fibrosis can ensue.

In this paper they show that in experimental animal models of liver fibrosis, if

an inhibitor of collagen synthesis is wrapped in a vitamin-A coated liposome

(tricking the hepatic stellate cells into taking up the inhibitor), this blocks

collagen synthesis, essentially preventing (and reversing) liver fibrosis:

____________________________

Nat Biotechnol. 2008 Apr;26(4):431-42.

Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA

against a collagen-specific chaperone.

Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, Takimoto R, Takada K,

Miyanishi K, Matsunaga T, Takayama T, Niitsu Y.

Fourth Department of Internal Medicine, Sapporo Medical University, School of

Medicine, Sapporo, 060-8543, Japan.

There are currently no approved antifibrotic therapies for liver cirrhosis. We

used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA)

against gp46, the rat homolog of human heat shock protein 47, to hepatic

stellate cells. Our approach exploits the key roles of these cells in both

fibrogenesis as well as uptake and storage of vitamin A. Five treatments with

the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver

fibrosis and prolonged survival in rats with otherwise lethal

dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent

manner. Rescue was not related to off-target effects or associated with

recruitment of innate immunity. Receptor-specific siRNA delivery was similarly

effective in suppressing collagen secretion and treating fibrosis induced by

CCl(4) or bile duct ligation. The efficacy of the approach using both acute and

chronic models of liver fibrosis suggests its therapeutic potential for

reversing human liver cirrhosis. PMID: 18376398.

________________________

This is one of the many reasons why I am interested in vitamin A (retinol) and

its derivative (retinoic acid) in the progression of PSC.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

> From what I understand fibrosis is not repairable, does anyone know if that

is Fact??