6.3.1 Introduction
AH often precipitates decompensation in patients with alcoholic cirrhosis and this
may lead to associated organ failure. It has also been suggested that histological
necrosis and an acute inflammatory infiltrate contributes to the worsening of portal
hypertension in these patients (132). Our previous study on the effects of anti-TNF
therapy and those o f others(147) suggest that the inflammatory mediators of AH,
especially pro-inflammatory cytokines such as TNFa, are especially important, and
modulation of these factors may result in an amelioration o f portal pressure. This
implies that portal hypertension in the setting o f acute AH may possibly be more
labile and amenable to therapeutic interventions compared to that in alcoholic
cirrhosis without evidence of hepatic inflammation. Moreover, an increased risk of
variceal bleeding due to AH would have potentially more serious consequences with
respect to outcome due to the associated decompensation. Albumin dialysis using the
Molecular Adsorbents Recirculating System (MARS; Teraklin AG, Rostock,
Germany) has been used mainly in the treatment of liver failure (148), and our group
had previously shown its potential benefit in patients with severe acute AH. (149)
in four patients with acute-on-chronic liver failure (ACLF) after the first session of
MARS, which increased before the second session but again underwent reduction,
albeit less steep, after the second session (150). A noteworthy point is the fact that all
four patients had evidence o f hepatic inflammation (AH-3, non-alcoholic
steatohepatitis-1). The aim of this study, was thus to evaluate the acute effects of
albumin dialysis, using MARS, on portal haemodynamics in patients with severe
acute AH. Patients treated with haemofiltration alone were investigated using the
same protocol to establish whether changes observed were specific to albumin
dialysis or just an effect of extracorporeal therapy.
6.3.2 Methods
6.3.2.1 Patient selection
Inclusion criteria: (i) Patients were included with severe AH, which was defined by
a history o f alcohol abuse, clinical and laboratory stigmata o f acute AH and
supported by histological evidence, (ii) Acute-on-Chronic Liver Failure (ACLF),
defined as acute deterioration in liver function over 2-4 weeks due to a defined
precipitant leading to severe, progressive clinical deterioration despite supportive
care (over 72 hours) with (a) increasing jaundice (bilirubin>85pmol/L), and (b)
either hyperbilirubinaemia>300pM and/or encephalopathy (>grade 2) (151) and/or
renal failure, (iii) Clinically significant portal hypertension: (HVPG >12mmHg).
Exclusion criteria: Patients were excluded if they were <18 or >75 years old,
adequate consent could not be obtained, were already enrolled in another study
protocol, had uncontrolled variceal bleeding or uncontrolled infection over the past
48 hours, had known hepatic/extrahepatic malignancy, were pregnant, had co
6.3.2.2 Study design
Eleven patients were finally included and received a 6-hour session of extracorporeal
therapy. Eight patients received MARS treatment in conjunction with
haemofiltration. Three others did not consent to MARS but agreed to haemodynamic
assessment and haemofiltration, and received a 6-hour session o f veno-venous
haemofiltration alone. HVPG changes at 6 and 24 hours were the primary end
points.
6.3.2.3 Monitoring: The patients were evaluated clinically and biochemically and
The Child Pugh score (87) and discriminant function (89) were calculated. The
severity of encephalopathy was assessed using the West Haven criteria (151). Mean
arterial pressure, electrocardiogram, heart rate and temperature, were monitored
continuously during treatment. The patients were actively warmed to a core
temperature o f 37°C if temperature dropped during treatment. Intravascular volume
was maintained using crystalloids, colloids or red cells as appropriate to maintain
central venous pressure between 8 and 10cm H2O. Blood glucose was maintained
between 5-7mmol/L with infusion of 50% dextrose.
6.3.2.4 Extracorporeal therapy: The MARS system consists of a blood circuit, an
albumin circuit, and a renal circuit, in our studies using continuous veno-venous
haemofiltration (Hospal BSM 22c, Hospal, Lyon, France). Blood is dialysed across
an albumin-impermeable high-flux dialysis membrane (MARS Flux; Teraklin AG).
The albumin circuit contains 600 ml of 20% human albumin, which passes through
the dialysate compartment of the blood dialyser. It subsequently undergoes
haemofiltration and passage through activated charcoal and anion exchange resin
columns to remove acquired toxins. Heparin was used as required (if patient’s INR
were run at 150 ml/min, with 1 L/hour fluid exchange, maintaining equal fluid
balance. Each MARS session was continued for 6-8 hours duration.
6.3.2.5 Haemofiltration: Continuous veno-venous haemofiltration (Hospal BSM 22c)
was performed with similar rates of blood flow (150 ml/min) and fluid exchange (1
L/hour) as that used for MARS.
6.3.2.6 Haemodynamic measurements: Haemodynamic studies were performed at
the time of trans-jugular liver biopsy prior to the extracorporeal session, and this
followed an overnight fast and a 1-hour period during which the patient had been
resting supine. The methodology applied for measurement of HVPG and systemic
haemodynamics was as described previously (chapter 2, section 2.1.2.1-2.1.2.3).
Patients were sedated for the procedure using midazolam (median dose o f 3 [range
2-5] mg; Phoenix Pharma Ltd., Gloucester, UK).
6.3.3 Results
Eleven patients with severe alcoholic hepatitis (median DF >68) were studied who
had been assigned to treatment with MARS (n=8) or standard medical therapy (n=3),
which included haemofiltration, as part of a larger trial on assessment of the efficacy
of MARS [Teraklin AG, Rostock, Germany]. Patients in the 2 groups were
comparable with respect to liver disease severity (discriminant function and MELD
score) but patients in the treatment arm had a significant reduction in bilirubin within
24 hours (p<0.001) and a trend towards a lower serum creatinine. O f interest, there
were no significant differences in CRP, white blood cell count or liver function in
between the groups after MARS treatment. None o f the patients received any
immuno-modulatory treatments as all had contra-indications (sepsis, recent GI bleed
and/or renal failure).
after 6 hours (the end o f a treatment session), and remained at this level by 24 hours.
The reduction in HVPG was greater than 20% reduction from baseline levels in 7/8
patients receiving MARS, both at 6 and 24 hours, as shown in Figure 6.5.