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C. Stefanutti et al.: Liver Dysfunction supportive therapies
C. Stefanutti1, G. Novelli2, V. Morabito2,
S. Di Giacomo1, G. Labbadia1
Transplantationsmedizin
2010, 22. Jahrg., S. 325
Liver Dysfunction Supportive Therapies –
From Therapeutic Plasmapheresis to
Molecular Adsorbent Recirculating System
Background: Because of the scarcity of donor organs, liver support
strategies are being developed with the aim of either supporting patients
with borderline functional liver cell mass until an appropriate organ becomes available for transplantation. Up until ten years ago Therapeutic
Plasmapheresis (TPE) and Continuous Renal Replacement Therapy (CRRT) were the main treatment used. Currently, non-biological systems include Molecular Adsorbent Recirculating System (MARS) which is not
only used as “bridging therapy” but also until liver recovery without necessity of liver transplantation (LT).
Methods: This report focus on TPE in the form of Plasma-Exchange
(PE) that was introduced in our clinical activity since 1987, and MARS
utilized since 1999. The above systems were used as bridging therapy either to optimize the clinical status for LT or resolution without necessity
to LT with acceptable results.
Results: 1326 procedures of TPE on 101 patients with liver dysfunction
were carried out from 1987 to 1999. Liver function impairment was related to Acute on Chronic Hepatic Failure (AoCHF) (#76), Fulminant
Hepatitis (FH) (#23), Intractable Pruritus (IP) (#2).
Since 1999, 2866 treatments on 269 patients were performed with MARS
for ACLF [acute-on-chronic liver failure] (#140), FH (#46); Delayed
Function (#22), Primary No Function (#18), Acute Hepatic Failure
(AHF) after surgery (#25), and IP (#17). The most recent data relative to
treatment in our departments in the last 12 months (2009-2010) of patients with TPE (#5 patients) and with MARS (#10 patients) has been reported.
Conclusion: According to our clinical experience TPE can lower efficaciously bilirubin and hepatic enzymes. MARS detoxifies great volumes
of blood and eliminates pro-inflammatory molecules. TPE daily performed may be helpful in AoCHF patients until transplantation takes
place. MARS shows significant improvement above all in AoCHF and in
FH.
Key words: Bilirubin, therapeutic plasmapheresis, plasma exchange,
continuous renal replacement therapy, molecular adsorbent recirculating
system
Department of Clinical and Medical
Therapy; Plasmapheresis Unit, 2Department “Paride Stefanini”; General
Surgery and Organs Transplant;
“Sapienza” University of Rome; Italy
Supportive Therapien bei Leberfunktionsstörungen –
von therapeutischer Plasmapherese bis zu MARS
(Molecular Adsorbent Recirculating System)
Stefanutti C, Novelli G, Morabito V, Giacomo S, Labbadia G (2010) Liver
Dysfunction Supportive Therapies –
From Therapeutic Plasmapheresis to
Molecular Adsorbent Recirculating
System. Tx Med 22: 325-332
Hintergrund: Aufgrund des Mangels an Spenderorganen werden Strategien zur Unterstützung der Leber entwickelt, mit denen Patienten mit
grenzwertig funktioneller Leberzellmasse behandelt werden sollen, bis
ein geeignetes Organ zur Verfügung steht. Bis vor zehn Jahren waren die
Therapeutische Plasmapherese (TPE) und die Kontinuierliche Nierenersatztherapie (CRRT) die am meisten eingesetzten Behandlungen. Heute
1
Transplantationsmedizin
2010, 22. Jahrg., S. 326
C. Stefanutti et al.: Liver Dysfunction supportive therapies
gehört zu den nicht-biologischen Systemen das "Molecular Adsorbent
Recirculating System" (MARS), das nicht nur als "Überbrückung" verwendet wird, sondern auch bis zur Erholung der Leber ohne Notwendigkeit einer Transplantation (LT).
Methoden: Dieser Bericht konzentriert sich auf die TPE in Form von
Plasmaaustausch (PE), die 1987 in unsere klinische Praxis eingeführt
wurde, und auf das MARS-System, das seit 1999 verwendet wird. Die obigen Systeme wurden mit akzeptablen Ergebnissen als "Überbrückung"
eingesetzt, entweder um den klinischen Zustand des Patienten für die LT
zu verbessern oder bis zur Besserung der Leberfunktion ohne Transplantationsnotwendigkeit.
Ergebnisse: 1326 TPE-Anwendungen wurden an 101 Patienten mit Leberfunktionsstörungen im Zeitraum von 1987 bis 1999 durchgeführt. Die
Beeinträchtigung der Leberfunktion bezog sich auf "Acute on Chronic
Hepatic Failure" (AoCHF) (n=76), Fulminante Hepatitis (FH) (n=23)
und hartnäckigen Pruritus (IP) (n=2). Seit 1999 wurden 2866 Behandlungen an 269 Patienten mit MARS durchgeführt zur Behandlung von
ACLF [acute-on-chronic liver failure] (n=140), FH (N=46), verzögerter Transplantatfunktion (n=22), primärer Nichtfunktion (n=18), akutem
Leberversagen (AHF) nach der Operation (n=25) und IP (n=17). Die
neuesten Daten zu den in den vergangenen 12 Monaten (2009 bis 2010)
in unseren Abteilungen durchgeführten Behandlungen (TPE: n=5 Patienten und MARS: n=10 Patienten) wurden berichtet.
Schlussfolgerung: Nach unserer klinischen Erfahrung kann TPE Bilirubin und Leberenzyme effizient verringern. Das MARS-System entgiftet
große Mengen an Blut und entfernt entzündungsfördernde Moleküle. Eine täglich durchgeführte TPE könnte AoCHF-Patienten bis zur geplanten
Transplantation helfen. MARS zeigt hauptsächlich bei AoCHF und bei
FH eine signifikante Verbesserung.
Schlüsselwörter: Bilirubin, therapeutische Plasmapherese, Plasmaaustausch, kontinuierliche Nierenersatztherapie, Molecular Adsorbent Recirculating System
Introduction
AHF is the sudden destruction of hepatic cells in individuals with no history of
hepatic disease. The plasma ammonia
concentration increases and cannot be
metabolized to urea. Hepatic coma is
the following severe complication. On
the other hand, bile cannot be excreted,
the bilirubin concentration increases,
and jaundice and other symptoms related to liver failure occur. The therapeutic
intervention consists in nutritional management, CRRT or TPE and other extracorporeal techniques performed to support the patient until liver function is recovered or the patient is submitted to
LT (1-9), and AHF lead to hepatic failure and hepatic encephalopathy due to
severe liver dysfunction resulting from
marked, widespread hepatocyte necro-
sis. These two critical, life-threatening
diseases are still difficult to treat in
emergency medicine. TPE, CRRT, and
other extracorporeal procedures are performed for artificial liver support (ALS)
in critical care (10-16). ALS results in
significant improvement in the patient’s
systemic condition. Even the consciousness is maintained. The above
mentioned systems are also effective as
a bridging therapy to LT (17-20). In
these patients, CRRT is used because it
allows a slow, moderate blood purification process to reduce the patient’s burden. CRRT is indicated in patients with
severe acute pancreatitis (TPE is also
indicated), FH, postoperative liver failure, multiple organ failure, cardiovascular disease, and severe renal failure
(3,16,21,22). CRRT is provided mainly
in critical care and intensive care units.
More recently, MARS which has higher
detoxification level has been used successfully (23-25). Hyperbilirubinemia
is characterized by elevated plasma
bilirubin concentrations due to hemolytic anemia, alcoholic hepatitis, liver stones, etc. When the plasma bilirubin concentration becomes greater than
3.0 mg/dL, the patient exhibits jaundice. Plasma adsorption (PA) or PE are
performed to remove excessive bilirubin and bile acid from the blood (1,46,8,9,11). To eliminate protein-bound
toxic substances, PE was introduced. In
the case of FH or other hepatic failure,
the supply of coagulation factors is usually necessary; therefore, PE is a suitable method for the elimination of protein-bound toxins, for example, bilirubin. PE needs fresh frozen plasma or
another protein fraction from humans.
In the case of bilirubin, anion exchange
resin was also used to try to eliminate
this toxic substance from the patient’s
blood or plasma using a bilirubin adsorption column for plasma perfusion
(8,9,11). The therapeutic effects of the
above mentioned systems in a wide
range of hepatic failure patients are reported in literature although some studies show conflicting results. This survey was aimed to review retrospectively the clinical records of the patients
with severe liver function decompensation accepted at our Departments in the
years 2009-2010, and submitted to intensive treatment to remove toxins of
hepatic failure with non-biological systems such as TPE and MARS.
Patients and Methods (TPE)
The records of all patients at our Department undergoing a total of 97 TPEs
between 2009 and 2010 were retrospectively reviewed. TPE was performed
more frequently before 1999, at which
time an aggressive LT policy was instituted. The indication for TPE was acute
and chronic hepatic failure, candidacy
for LT, and coagulopathy (prothrombin
time [PT] > 20 seconds). In the last 12
months # 5 patients (males: #4; females: #1) were submitted to TPE. Daily TPE was performed until the patient
recovered, died, or underwent LT. Age
at time of treatment was 53±18.4 years.
The primary etiology of liver failure
was acute decompensation of chronic
liver disease (Figure 1).
C. Stefanutti et al.: Liver Dysfunction supportive therapies
Fig. 1: Primary etiology of liver failure in patients treated with MARS
Treatment with TPE
The basic procedure consists of removal of blood, separation of blood
cells from plasma, and return of these
blood cells to the circulation, diluted
with fresh plasma or a substitute. Because of concerns over viral infection
and allergic reaction, fresh plasma is
not routinely used. The most common
substitute is saline solution with sterilized human albumin protein. During the
course of a single session, two to three
liters of plasma is removed and replaced. TPE requires insertion of a venous catheter, either in a limb or central
vein. Central veins allow higher flow
rates and are more convenient for repeat
procedures, but are more often the site
of complications, especially bacterial
infection. The patients underwent urgent treatment of TPE (a written informed consensus was obtained by the
patient or parents in case of loss of consciousness). 1-1.5 plasma volume x
procedure was processed (frequency:
daily). The vascular accesses utilized
were: central venous catheter (CVC) or
peripheral venous accesses. According
to our extracorporeal treatment protocol, heparin 5000 UI intravenous as a
bolus was administered at the beginning
of the procedure, while continuous anticoagulation during treatment is guaranteed by the use of Anticoagulant Citrate
Dextrose Solution A (ACD-A) ACD-A
can be used in a ratio of 1:25–50 to prevent severe hypocalcemia in AHF. Although the plasma is preferable as a replacement fluid due to moderate to severe coagulopathy in AHF, addition of
albumin is acceptable. In this sample
both plasma and albumin 5% as replacement fluids, were used. The centrifugal apheresis system used was
“Spectra” COBE, LRS System Turbo
Version 7.0 (COBE Laboratories, Inc.,
Lakewood, CO, USA).
Safety (TPE)
When blood is outside the body, it must
be treated to prevent it from clotting.
While most of the anticlotting agent is
removed from the blood during treatment, some is returned to the patient.
Side Effects
Immediate (related to extracorporeal
line, anticoagulation, and replacement
fluids):
vagus nerve syndrome, low or high
blood pressure; venous puncture hazards, air embolism; excessive bleeding,
allergy or thrombopenia induced by heparin, citrate poisoning with hypocalcemia symptomatology (headachecramps-swarming-tetanus rarely cardiac arythmia); chills-fever; nauseavomiting, diarrhea (albumin).
Delayed (impaired hemostasis):
hypocoagulative state 8-12 hours after
session; hypercoagulative state 24-72
hours by rebound effect (antithrombin 3
synthesis delayed) and increased thrombosis risk (promoting conditions: inflammation, confinement to bed). Preventive heparin treatment with normal
coagulation tests is needed.
Patients and Methods
(MARS)
From February 2009 to February 2010,
fourty-nine patients were treated with
MARS. In this paper 10 of these patients with acute decompensation of cirrhosis manifested by increasing jaun-
Transplantationsmedizin
2010, 22. Jahrg., S. 327
dice and encephalopathy grade I-II will
be considered. A written informed consensus was obtained by the patient or
parents in case of loss of consciousness.
Three patients affected by cirrhosis
HBV-related; three patients by cirrhosis
HCV-related, two patients by cirrhosis
alcohol-related; one patient by primary
biliary cirrhosis and one patient by cirrhosis HCV- and alcohol-related. These
patients (8 male and 2 female) were
treated with MARS® (Gambro Stockholm, Sweden) in association with
equipment for dialysis machine Hospal
Integra® (Gambro, Zaventem, Belgium). The mean age of these patients
was 49.3 ± 5.9 years. The mean number
of MARS procedures was 6.5 (range 48). Each procedure lasted approximately 8 hours. The patients were evaluated
from their enrolment with a survival
follow up at three months. Vascular access was obtained by insertion of a double lumen dialysis catheter (Arrow International, Reading, PA, USA) into the
right internal jugular vein in two patients and into subclavian vein in eight
patients. For anticoagulation, a bolus of
2.500 units of unfractionated heparin
was injected into the extracorporeal
system during the priming, followed by
flushing saline solution every 60 minutes. Two patients presented transitory
hypotension (80/40 mmHg) that was
positively corrected through administering saline solution and cortisone.
Three patients with transitory hypoglycaemia were treated with glucose solution (33%). The thrombocytopenia was
controlled through administration of
platelets before the start of treatment
when the patients showed levels under
50.000 mm3 (two patients). During the
sessions, fresh frozen plasma was administered to all patients. Survival data
were obtained from hospital medical
records as well as clinic notes. Patients
were examined before and immediately
after MARS. Neurologic status was determined by clinical assessment using a
standard hepatic encephalopathy scale
and was correlated with the concentration of blood ammonia.
Treatment with MARS
MARS® (Gambro Stockholm, Sweden)
is a blood purification technique which
can remove all known substances that
accumulate in the blood during liver
failure and cause hepatic dysfunction
Transplantationsmedizin
2010, 22. Jahrg., S. 328
and neurological abnormalities, aggravate injury to the liver and other organs
and inhibit hepatic regeneration. After
the introduction of MARS in 1999 our
clinical experience has forced us to focus on four aspects concerning this
technique: safety, coagulopathy, pump
volume flow rate and albumin function.
Since 1999, 2866 procedures on 269
patients were performed with MARS.
From 2004 we started working closely
with a group of engineers from “La
Sapienza” University of Rome. Our aim
was to optimize MARS treatment by
clinically applying what had already
been demonstrated in in-vitro studies
through the application of a mathematical model (26). By applying this model,
improved clearance of different substances (35%) was observed.
Safety (MARS)
The treatment with MARS can be considered biologically compatible, comprehensive and highly secure. At 2.688
treatments performed, we found 1.81%
complications more likely related to the
former clinical conditions of patients
before treatment. We have observed: severe hypotension (1.7% of sessions had
a clinical record of blood pressure of
60/40 mmHg not modifiable by medical
therapy or by the interruption of procedure), and bleeding from CVC with
change in ranking (4.1%) and infections
of CVC catheter, substituted every 15
days (29%) from 1999 to 2002, and
since 2003 with replacement of CVC
after 10 days (21.7%) at new site.
Laboratory Methods
Clinical laboratory measurements were
performed in a certified central university hospital laboratory. The pattern of
coagulopathy was assessed by determination of PT (adjusted to International
Normalized Ratio [INR]) and the partial
thromboplastin time. Measurements of
individual clotting factors were taken
before and immediately after exchange
and included fibrinogen, factor II, factor V, factor VII, and factor IX. Standard biochemistry panels were taken 1
hour after TPE or MARS and included
measurements of sodium, potassium,
chloride, bicarbonate, and liver function
tests (bilirubin, aspartate transaminase,
AST and alanine transaminase, ALT).
C. Stefanutti et al.: Liver Dysfunction supportive therapies
Laboratory parameters were determined by usual enzymatic and chemical
methods. The blood cell count was determined with a Beckman Coulter ACT
Diff. (Beckman Coulter, S.p.A, Milan,
Italy-EU). Model for End-Stage Liver
Disease (MELD) score was evaluated
according the following formula: 3.8 x
log (e) (bilirubin mg/dL) + 11.2 x log
(e) (INR) + 9.6 log (e) (creatinine
mg/dL). Creatinine clearance rate
(Glomerular Filtration Rate: GFR) was
estimated using Cockcroft-Gault formula (27).
bly, Venice, Italy, October 1983, and the
41st World Medical Assembly, Hong
Kong, September 1989.
Ethics
Results
Informed consent was obtained from all
patients or their families, according to
the recommendations of the declaration
of Helsinki guiding physicians in biomedical research involving human subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June
1964, amended by the 29th World Medical Assembly, Tokyo, Japan, October
1975, the 35th World Medical Assem-
The data refers to therapeutic management over the last 5 patients with AHF
undergoing treatment through TPE (tables 1, 2) and of the last 10 cases treated with MARS (tables 3, 4, 5) over a
period of 12 months, between 2009 and
2010. Patients treated with TPE were
two males and 3 females between 58
and 72 years of age (table 1). Those given treatment with MARS were 10 pa-
Statistical Analysis
Statistical analysis was performed according to parametric tests, depending
on parameters under evaluation. All results are expressed as means ± SD.
Within group differences were tested
for statistical significance using Student’s t test for paired data.
Tab. 1: Demographic and biochemical characteristics of # 5 patients with AHF submitted to TPE (12 months: 2009-2010)
Patients
1
2
3
4
5
Gender
F
F
M
M
F
Age (years)
46
46
46
72
58
ALT *
185
318
226
68
235
AST
50
134
248
93
84
Total Bilirubin ** 13.4
34.5
44
16
15.6
Ammonia ***
82
192
151
85
122
ALT before
140± 59
314± 46
103.5± 7.5 59.5± 9.5
42± 1
ALT after
83.5± 17.5 141± 27
61.5± 1.5
48± 17
24± 12
AST before
254± 51
362.5± 21.5 150± 60
61.5± 1.5
112.5± 18.5
AST after
163± 42
163± 9
83± 25
51± 10
72.5± 9.5
Total Bilirubin
before
27± 1
32± 1
32± 5
27.6± 1.7
19.6±3.5
Total Bilirubin
after
13.5± 0.5
14.5± 1.5
19.5± 7.5
17.5± 1.5
9± 2
Ammonia
82
192
151
85
122
Ammonia I
session
138
121
151
60
53
Ammonia II
session
114
107
158
90
80
Baseline
Treatment (TPE)
*: UI/L; **: mg/dL; ***: mcg/dL
C. Stefanutti et al.: Liver Dysfunction supportive therapies
mg/dL
Transplantationsmedizin
2010, 22. Jahrg., S. 329
X±SD
Total bilirubin
before
27.4±9.7
Total Bilirubin
after
14.5 ±14.4 ^
Nitrogen
before
100±106
Nitrogen
after
80.9±118.1
Creatinine
before
0.95±0.61
Creatinine
after
0.76±0.71
GFR * ml/min
Tab. 2: Total bilirubin and renal function
in # 5 patients with AHF submitted to
TPE
96.4±31
^: P=0.001
*: evaluated according Cockcroft-Gault's formula
Tab. 3: Demographic and biochemical characteristics of # 5 patients (whole sample # 10) with AHF submitted to MARS (12
months: 2009-2010)
Patient
1
2
3
4
5
Age (years)
45
41
47
59
49
Gender
F
M
M
M
M
Liver disease
Alcohol-related
Cirrhosis
HBV-related
Cirrhosis
HBV-related
Cirrhosis
HCV-Alcohol
related Cirrhosis
Alcohol-related
Cirrhosis
# treatments
7
5
6
7
7
MELD
pre
32
32
28
30
33
MELD
post
22
29
18
17
23
A
A
A
D
A
Outcome (3 months)
AST
pre
113
122
144
62
254
AST
post
101
102
97
157
70
ALT
pre
230
112
124
225
229
ALT
post
201
153
99
89
111
Tot Bilirubin
pre
19
32
16
24
19
Tot Bilirubin
post
9
18
9
7.9
9.1
Ammonia
pre
287
129
118
117
123
Ammonia
post
76
53
64
130
61
Albumin
pre
3
2.7
2.5
2
2.9
Albumin
post
3.4
3
2.4
2
3.3
INR
pre
3.1
3.1
2.6
2.3
2.9
INR
post
1.9
2.8
1.3
1.3
2.1
Urea
pre
25
62
37
65
49
Urea
post
11
12
14
26
15
Creatinine
pre
1.2
0.7
0.7
1.2
1.4
Creatinine
post
0.9
1
0.6
0.7
0.5
MELD: Model for End-Stage Liver Disease score; Outcome: Alive (A), Deceased (D); INR: International Normalized Ratio; AST: Aspartate transaminase; ALT: alanine transaminase
tients of an average age of 49.3 ± 5.9
(table 5). In the group of patients who
underwent TPE, liver and renal functions were taken into consideration. In
table 1, values are reported of ALT, of
AST, total bilirubin and ammonia to the
baseline and in treatment with TPE. The
values of the above mentioned variables
improved after treatment as expected.
In particular, the average variation of
the total bilirubin results as being statistically significant. (P=0.001). Also in
table 1 there is reference to the ammonia that demonstrates a not linear devel-
opment and which is different in every
patient. In table 2 values have been reported before and after TPE, of nitrogen, creatinine and GFR. In tables 3 and
4 data is reported in reference to liver
and renal functions and the correction
of coagulopathy (INR) and the MELD
Transplantationsmedizin
2010, 22. Jahrg., S. 330
C. Stefanutti et al.: Liver Dysfunction supportive therapies
Tab. 4: Demographic and biochemical characteristics of # 5 patients (whole sample # 10) with AHF submitted to MARS (12
months: 2009-2010)
Patient
6
7
8
9
10
Age (years)
48
47
47
50
60
Gender
M
F
M
M
M
Liver disease
Primary Biliary
Cirrhosis
HCV-related
Cirrhosis
HCV-related
Cirrhosis
HCV-related
Cirrhosis
HBV-related
Cirrhosis
# treatments
4
6
7
8
8
MELD
pre
32
32
34
29
27
MELD
post
32
21
28
20
20
D
D
D
A
A
AST
pre
266
216
117
108
210
AST
post
256
92
68
104
201
ALT
pre
129
78
94
222
185
ALT
post
121
104
170
287
305
Tot Bilirubin
pre
32.6
16.4
24
44
31
Tot Bilirubin
post
28.4
11
7.2
19
12
Ammonia
pre
132
121
128
120
232
Ammonia
post
84
134
138
73
111
Albumin
pre
2.4
2.1
2.7
2.5
3.1
Albumin
post
2.5
2.3
2.9
3.1
3.4
INR
pre
3.1
2.3
3.3
2.1
2
INR
post
2.8
1.2
2.2
1.2
1.4
Urea
pre
55
87
64
52
39
Urea
post
48
74
38
24
15
Creatinine
pre
0.7
1.9
1.3
0.9
0.6
Creatinine
post
1.1
1.4
1.8
0.6
0.6
Outcome (3 months)
MELD: Model for End-Stage Liver Disease score; Outcome: Alive (A), Deceased (D); INR: International Normalized Ratio; AST: Aspartate transaminase; ALT: alanine transaminase
X ± SD
Age (years)
P
49.3 ± 5.9
# treatments
6.5 ± 1.2
MELD
before
30.9 ± 2.2
MELD
after
23 ± 2.2
AST
before
161.2 ± 70
AST
after
124.8 ± 61.1
ALT
before
163 ±61.3
ALT
after
164 ± 78
Tot Bilirubin
before
25.8 ± 9
Tot Bilirubin
after
13.06 ± 7
Ammonia
before
151 ± 59
Ammonia
after
91.6 ± 31.5
Albumin
before
2.54 ± 0.3
Albumin
after
3 ± 0.4
INR
before
2.2 ± 0.4
INR
after
2 ± 0.6
Urea
before
53.5 ± 17.5
Urea
after
28 ± 2.2
Creatinine
before
1 ± 0.4
Creatinine
after
0.9 ± 0.4
Tab. 5: Demographic and biochemical
characteristics (X ± SD) of # 10 patients
with AHF submitted to MARS (12
months: 2009-2010)
0.001
ns
ns
0.001
ns
ns
ns
0.001
ns
MELD: Model for End-Stage Liver Disease score;
Outcome: Alive (A), Deceased (D); INR: International Normalized Ratio; AST: Aspartate transaminase; ALT: alanine transaminase; ns: not significant
C. Stefanutti et al.: Liver Dysfunction supportive therapies
score in patients who underwent treatment with MARS. In tables 3 and 4, the
pathology that determined AHF in each
patient and not only the necessity of
treatment with MARS has been reported. Also reported in these tables is the
clinical outcome of survival at 3
months. In the follow up at 3 months 6
patients were alive (A), while 4 patients were deceased (D). Finally, in
table 5, the mean ± standard deviation
of the variables given before and after
treatment with MARS, with the exception of the clinical outcome, have been
reported. The MELD score, the total
bilirubin and the urea, demonstrate a
variation which is statistically significant after treatment (all variables:
P=0.001).
Discussion
Without spontaneous recovery of liver
function, the standard treatment of AHF
is supportive care as a bridge to LT.
Plasmapheresis is indicated in severe
hepatic disease, metabolic disease, collagen disease, autoimmune disease,
neurological disease (12,13,28). Centrifugation and membrane separation
techniques are used for plasma separation. There are four main types of membrane plasmapheresis: plasma exchange
(PE), double filtration plasmapheresis
(DFPP), plasma adsorption (PA), and
immunoadsorption (IA). ASFA has categorized the use of TPE in Acute Liver
Failure as a Category III (Strenght of
evidence II-3) indication: “suggestion
of benefit for which existing evidence is
insufficient, either to establish the efficacy of therapeutic apheresis or to clarify the risk/benefit (or sometimes the
cost/benefit) ratio.” (29). In AHF, TPE
removes albumin bound and large molecular weight toxins – aromatic amino
acids, ammonia, endotoxin, indols,
mercaptans, phenols –, and other factors. The increase in plasma of these
toxic substances may be responsible for
hepatic coma, hyperkinetic syndrome,
decreased systemic vascular resistance,
and cerebral blood flow. TPE restores
hemostasis by supplying the coagulation factors and removing activated
clotting factors, tissue plasminogen activator, fibrin, and fibrinogen degradation products. It was also reported improved cerebral blood flow, mean arterial pressure, cerebral perfusion pressure and cerebral metabolic rate, in-
creased hepatic blood flow, after TPE.
Laboratory parameters such as
cholinesterase activity, or galactose
elimination capacity were improved by
TPE. In some patients, the liver may regenerate during TPE and in other patients TPE can be viewed as bridging
therapy to LT (17-19). The molecular
adsorbent recirculating system (MARS)
represents a cell-free, extracorporeal,
liver assistance method for the selective
removal of albumin-bound substances
(23-25). Moreover, it enables the removal of excess water and water-soluble substances via an inbuilt dialysis
step. According to our previous clinical
experience and even in the last case series TPE can lower bilirubin and hepatic enzymes, meanwhile improving coagulopathy in AHF. TPE performed daily may be helpful until transplantation
takes place or self-regeneration occurs.
A limitation in our interpretation of the
available data is that we have a poor
knowledge about the clinical outcome
as our therapeutic plasmapheresis unit
usually is requested to treat patients
from other departments that have a major role in the clinical management of
patients and consecutive clinical evolution. On the contrary the department of
general surgery and organs transplant
has a complete awareness of what is the
life expectancy and the survival rate of
patients submitted to MARS. Moreover
their clinical management of the patients is not limited to the extracorporeal treatment but also finalized to the LT.
MARS has a role in the treatment of liver failure where the primary goal is to
provide blood purification. Notwithstanding the response to TPE or MARS
should be evaluated daily. In fact, the
improvement determined by the removal of bilirubin and hepatic enzymes
and other toxic substances does not necessarily reflect a favourable change in
the patient’s clinical condition which
can be highly critical and irreversible.
To conclude, liver dysfunction supportive therapies are essential techniques
when the clinical target is to make any
effort to control severe, overwhelming
and above all life-threatening liver failure, and valuable bridging therapies
supporting the decision making process
leading to the LT (28,30-32). The data
reported in the present survey which
refers to the use of TPE and MARS in
our departments over the last 12 months
confirms our data which is already
available and reported in literature. In
Transplantationsmedizin
2010, 22. Jahrg., S. 331
our opinion, these are superimposable
to findings reported by other authors.
The tendency in our hospital is for progressive increase in the use of MARS in
grave hepatic insufficiency in patients
who are awaiting or not awaiting LT,
without undermining the therapeutic
importance of TPE which is widely
used in the same pathology.
Conflict of Interest and Financial
Disclosure
The authors certify that they have no affiliation with or financial involvement
in any organization or entity with a direct financial interest in the subject matter or materials discussed in this manuscript.
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Claudia Stefanutti, M.D., Ph.D.
Professor of Internal Medicine
Department of Clinical and Medical
Therapy
Plasmapheresis Unit
University of Rome “La Sapienza”
“Umberto I” Hospital
155, Viale del Policlinico
I-00161 Rome
Italy
[email protected]