barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
154 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 155
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
Figure: evolution of the number of proliferating hepatic progenitors (MiB1+/CK7+ cells) and mature
hepatocytes (MiB1+/CK18+ cells), expressed as % changes in the liver biopsy repeated at day 7 in both
G-CSF treated and non treated patients with cirrhosis and ASH [6]
Taken together, G-CSF administration in patients with cirrhosis is well tolerated, is associated with signs
of BM derived cell mobilization, and stimulates the proliferation of hepatic progenitors on the short term in
decompensated alcoholics. However, no improvement in liver function was evident over a 4-week period.
Harb (2009)
Li (2010)
Monocrotaline +
radiation in rats
Radiation injury in
mice
No G-CSF
5 x 10 6 unsorted BM
Cells
G-CSF +
10 5 CD34+ cells
Tail vein
Tail vein
Improved liver repair
via SEC of BM origin
Improved liver repair
Abbreviation: SEC: sinusoidal endothelial cell; NOD-SCID: non obese diabetic severe combined
immunodeficiency
IS G-CSF FOLLOWED BY BM STEM CELL TRANSPLANTATION ASSOCIATED WITH LIVER
REGENERATION
Experimental studies
Transplantation of bone marrow derived cells (either hematopoietic, mesenchymal, or endothelial progenitors)
may contribute to liver repair in acute liver injury models [7] [8] [9] [10]. Due to great variability between
studies (design, type of liver injury, use of G-CSF, protocols for cellular isolation and characterization, etc..)
and real life situations (fibrosis, repeated episodes of liver injury, bone marrow exhaustion, etc..), results
should be interpreted with caution.
Table 1: Selected list of experimental studies of bone marrow derived cells transplantation
Author (yr)
Terai (2003)
Kuo (2008)
Piscaglia (2007)
Model
CCl 4
in mice
CCl 4
in NOD-SCID
mice
Radiation injury in
rats
Transplantation
protocol
No G-CSF
10 5 unsorted BM
Cells
No G-CSF
1.4 x 10 6 MSC/kg
G-CSF +
5 x 10 7 unsorted BM
Cells
Route
Tail vein
Intravenous
Tail vein
Outcome
Evidence of
transdifferentiation
25% repopulation of
damaged liver
Stimulation of
endogenous
hepatocyte
proliferation
Endogenous oval cell
stimulation
Improved liver repair
Clinical studies
Clinical studies with autologous BM derived stem cells have reported some benefits in terms of biological and
clinical parameters (serum bilirubin, albumin, coagulopathy, ascites), but the vast majority are uncontrolled
and only few recent trials have included a control group [11] [12-14]. To optimize the potential benefit of
BM-derived pluripotent cells, unsorted mononuclear cells (including both hematopoietic and mesenchymal
stem cells) are used. Table 3 summarizes the results issued from 3 RCT[15-17]. In a Chinese study of
decompensated hepatitis B patients[17] (mean MELD score of 30; mean number of BM cells 3.4 x 10e8),
a significant improvement in MELD score was observed during several weeks after treatment, while
autologous BM transplant in decompensated alcoholics (mean MELD score of 19; mean number of BM
cells/kg: 10e8) was not associated with any benefits in terms of liver function over 3 months of follow-up[16].
Thus, autologous BM stem cell therapy seems relatively well tolerated without severe side effects, and is
associated with either a modest and transient improvement in liver function or with no benefit as compared
to standard of care alone.
Table 2: Selected list of uncontrolled clinical studies of autologous BM- derived cells transplantation
in chronic liver disease
Author (yr) Pts (n) Clinical setting Protocol Route Outcome
Terai (2006) 9
Gordon (2006) 5
Mohamadnejad
(2007)
4
Pai (2008) 9
Viral compensated
cirrhosis
Cirrhosis
(4 = alcoholic)
Decompensated
cirrhosis (mixed
etiology)
Abstinent alcoholic
cirrhosis
No G-CSF
BMA+
78 x 10 9
MNC
G-CSF+
No BMA
10 6 -10 8
CD34+ cells
No G-CSF
BMA+
3 x 10 6
CD34+ cells
G-CSF +
No BMA
2 x 10 8
MNC
Peripheral
vein
PV = 3
HA = 2
HA
HA
Improved Child-Pugh
score at 6 months
Modest improvement
in biological
parameters
Major side effect
Improvement in
Child-Pugh score at 3
months