Clinical Science (1992) 83, 191-198 (Printed in Great Britain)
191
Resting energy expenditure and the thermic effect of
adrenaline in patients with liver cirrhosis
Manfred J. MULLER, Olaf WILLMANN, Andrea FENK, Annette RIEGER, Oliver SELBERG,
Helmut CANZLER*, Alexander VON ZUR MUHLEN and Friedrich W. SCHMIDT
Medizinische Hochschule Hannover, Abteilung Gastroenterologie und Hepatologie,
Hannover, Federal Republic of Germany
(Received 4 September 1991/10 March 1992; accepted 31 March 1992)
1. Resting energy expenditure and the metabolic responses to adrenaline (infusion rate: 0.03 pg min- '
kg-' fat-free mass for l h ) were investigated in 25
patients with liver cirrhosis. The patient group was
heterogeneous and varied with respect to the aetiology of cirrhosis, the clinical condition (i.e. Child A or
B), the nutritional status and the degree of hyperinsulinaemia.
2. When compared with 10 healthy control subjects
the basal plasma adrenaline and noradrenaline concentrations were both increased in cirrhosis and
remained elevated during adrenaline infusion ( $. 39%
and
31%, respectively; P< 0.05). Concomitantly,
the peripheral plasma insulin concentration and the
molar C-peptide/insulin ratio were increased in liver
cirrhosis ( 96% and + 30%, respectively; P< 0.05).
Hyperinsulinaemia was more pronounced in patients
with ethanol-induced liver cirrhosis.
3. When expressed per kg fat-free mass, resting
energy expenditure was enhanced in liver cirrhosis
(+21%; P<0.05) and was more pronounced (i.e.
resting energy expenditures of +35% to +49%
above estimated values) in patients with ethanolinduced cirrhosis, at advanced stages of the disease
and in association with decreased body cell mass.
4. Infusion of adrenaline increased heart rate, O2
consumption and the plasma concentrations of glucose, lactate, free fatty acids, glycerol and 3hydroxybutyrate, and similar transient increases and
subsequent decreases in the respiratory quotient were
observed in both groups. However, the lipolytic, ketogenic and thermic responses were reduced in cirrhotic
patients. Reduced metabolic responses were more
pronounced in hyperinsulinaemic patients.
5. We conclude that resting energy expenditure is
variable but may be substantially increased in
patients with ethanol-induced cirrhosis. In contrast,
the thermic effect of adrenaline is reduced in cirrhotic
patients. Variations in resting energy expenditure are
strongly associated with variations in body cell mass,
+
+
which explains 65% of its variability. No parameter
of body composition is predictive for thermogenesis.
INTRODUCTION
Malnutrition is a characteristic feature of many
patients with liver cirrhosis and may be explained
by various factors. These include a poor dietary
intake, possible malabsorption of macro- and micronutrients, disturbances in the transport of energyyielding substrates and limited cellular substrate
utilization despite increased energy needs. Resting
energy expenditure (REE) is increased in some, but
not all, patients with liver cirrhosis, and hypermetabolism is more frequently observed in advanced
stages of cirrhosis and in malnourished patients
[l-31.
Twenty-four hour energy expenditure is the sum of
REE and diet- and work-induced thermogenesis (for
reviews, see [4, 51). Thermogenesis has been subdivided into an obligatory and a facultative component. Obligatory thermogenesis is directly related to
nutrient metabolism, whereas the facultative component is partly controlled by sympathetic nervous
system activity. Adrenaline-induced thermogenesis is
of particular interest, since it is increased in starvation, malnutrition, during transient hypoinsulinaemia and also in type 1 diabetes [6-10], and thus
it might contribute to the negative energy balance
and tissue catabolism in these clinical situations. In
contrast with data obtained during hypoinsulinaemia, hyperinsulinaemia per se and obesity reduced
the thermic response to adrenaline [111; for a
review, see [4]. Whether defective thermogenesis is
primary or secondary in obesity is not known.
However, diminished thermogenesis favours a positive energy balance in obesity. Considering these
findings, it is tempting to speculate that a possible
antagonism between adrenaline and insulin results
in different rates of thermogenesis [lo, 111.
Key words: adrenaline, body composition, energy expenditure, liver cirrhosis, malnutrition, thermogenesis.
Abbreviations: BIA, bioelectrical impedance analysis: FFM, fat-free mass; REE, resting energy expenditure; TBK, total-body potassium.
*Died 20 August, 1991.
Correspondence: Dr Manfred J. Miiller, Medizinische Hochschule Hannover, Abteilung Gastroenterologie und Hepatologie, Konstanty-Gutschow-Strasse8, D 3000 Hannover 61,
Federal Republic of Germany.
M. j. Miiller et al.
192
Table 1. Clinical data of control subjects and patients with liver cirrhosis. Data are means f SD. Abbreviations: AST, aspartate aminotransferase; ALT, alanine
aminotransferase; GLDH, glutamate dehydrogenase; AP, alkaline phosphatase; CHE, cholinesterase; PT, prothrombin time. Statistical significance between groups
(P<0.05): versus control subjects, (t); versus all cirrhotic patients (1).Statistical significance within the different groups of patients (P<O.O5): ethanol-induced cirrhosis
(*); versus post-necrotic cirrhosis (**).
GGT
activity
(units/l)
AP
activity
(units/l)
Bilirubin
concn.
(pmol/l)
CHE
(kU/I)
Albumin PT
(%)
concn.
(g/l)
Methionine
concn.
(Pol)
86.4
k23.6
313.8t
k223.2
22.7
k42.0
@.3t
k107.5
4.80
kl.30
2.02
k1.02
41.3
k2.9
36.8t
k8.2
98.0
k4.2
66.37
+I92
-
8.77
k8.9
13.9
k7.8
104.07
kl17.9
26.37$
k17.0
64.97$*
k50.4
54.7t*
k31.6
5.3
k8.l
7.5t
k4.8
15.07
k11.2
61.7t
k45.5
67.8t**
k43.8
205.9t$*-**
k182.7
191.37$
k77.3
354.9t*
k74.0
556.0t*-**
k293.0
98.9t
k92.8
96.3
k158.3
64.0
k55.7
1.79
kO.81
1.56
k0.83
2.87
k1.06
38.1
k6.2
34.07
k 11.9
38.1
k5.6
60.5t
61.3
44.27
39.9t
9.7t
k32.7 k 9 . 5
61.67*
k34.9
52.97
k44.4
129.97
k144.4
65.2t
k42.6
348.37
k279.2
262.0t
k81.6
45.6
k29.1
152.3t*
2.35
k0.98
1.51
k0.89
39.0
k32.3
Duration of
cirrhosis
(years)
AST
activity
(units/l)
ALT
activity
(units/l)
Control subjects
(n= lo)
-
Cirrhotic patients
5.0
k4.6
16.9
k20.6
51.27
k33.8
11.9
k3.8
46.6t
k37.4
41.5
k38.2
67.0t$**
k36.4
46.9t**
k17.9
(n =25)
Aetiology of disease
Ethanol-induced cirrhosis
(n= lo)
Post-necrotic cirrhosis
(n =8)
Primary biliary cirrhosis
(n=7)
Clinical state of patients
Child A (n = 15)
Child B (n = 10)
2.3
kO.8
5.3
k4.2
8.4
k5.7
5.7
5.4
4.0
k3.0
*
GLDH
activity
(units/l)
2.1
j-1.8
5.1
k4.2
We observed recently that glucose-induced
thermogenesis is increased in a subgroup of patients
with ethanol-induced liver cirrhosis [l2]. These
patients were also hypermetabolic, i.e. REE was also
increased [12]. Thus, increased REE plus increased
thermogenesis may both contribute to the negative
energy balance and malnutrition in patients with
liver cirrhosis. At present little is known about
adrenaline-induced thermogenesis in liver cirrhosis.
Since hyperinsulinaemia is a frequent finding in this
patient group [12] and insulin reduces the thermic
response to adrenaline (see above; [S, 10, ll]), it is
reasonable to assume a reduced response to adrenaline in liver cirrhosis.
To obtain further insight, we studied the resting
metabolic rate together with the metabolic responses to adrenaline in patients with liver cirrhosis.
Our patients were characterized according to the
aetiology of cirrhosis, the clinical condition and the
nutritional state, because all these factors may contribute to the metabolic picture seen in patients with
liver cirrhosis.
METH0DS
Patients and subjects
Twenty-five patients with biopsy-proven liver cirrhosis were compared with 10 healthy subjects, who
were recruited from a group of students. Their
physical, clinical and biochemical data are given in
Tables 1 and 2. Neither the control subjects nor the
patients had a family history of diabetes mellitus or
any previous evidence of non-insulin-dependent
k148.0
k3.2
33.4t
kI2.0
93.1
f 126.6
k8.0
k53.0
59.47
k24.9
82.67$****
k15.1
62.9
k49.4
159.5t*
k204.6
74.57
k 16.4
54.0tp
k16.8
54.8
k 17.9
152.4$*
k189.1
diabetes mellitus. All patients were hospitalized
because they were considered as potential candidates for liver transplantation, which did not mean
that they were all at advanced stages of their disease
(only patients considered as Child A or B were
included into the study protocol). The standard
protocol evaluations served the following goals:
establishment and confirmation of the diagnosis,
documentation of the severity of the disease, identification of specific indications and contraindications,
possible risks and complications, estimation of longterm prognosis, determination of optimal time for
surgery and development of a database. An intensive clinical and laboratory assessment was performed within a 2 week period. On examination, all
patients were in a stable clinical state and were on a
weight-maintaining diet containing 146 kJ (nonprotein calories: 70% carbohydrate, 30% fat) and 1g
of protein day-' kg-' body weight (at least 60g of
protein/day) for 1 week before the start of the study.
Standard medication included 100 mg of spironolactone, 300 mg of ranitidine, lactulose (3 x 20 ml)
and a supplement of vitamins (Multivitamin Lappe;
Bristol, Neu-Isenberg, Germany). The last medication was taken 24 h (spironolactone) and 12 h (ranitidine, lactulose, vitamins) before starting the protocols. Patients and subjects were all familiar with the
rationale of the investigational procedures and
volunteered for the study. The study protocol had
been reviewed and accepted by the Ethical Committee of the Medizinische Hochschule Hannover.
Subjects and patients were informed of the nature,
purpose and possible risks involved in the study
before they gave their informed written consent. All
clinical research has been conducted in accordance
Energy expenditure in liver cirrhosis
I93
Table 2 Nutritional state of control subjects and patients with liver cirrhosis. Data are meanskso. Abbreviations: BMI,
body mass index; TSF, triceps skinfold; BCM, body cell mass; MAC, mid-arm circumference. Fat mass, FFM and body cell mass were
determined by bioelectrical impedance measurements. Statistical significance between groups (P <0.05): versus control subjects (t);
versus all cirrhotic patients ($). Statistical significance within the different groups of patients (P<0.05): versus ethanol-induced
cirrhosis (*); versus post-necrotic cirrhosis (**).
Age
Control subjects
(n=IO)
(yean)
32.2
k9.8
Cirrhotic patients
(n = 25)
40.17
k10.9
Aetiology of disease
Ethanol-induced cirrhosis
(n=lO)
Post-necrotic cirrhosis
(n =8)
Primary biliary cirrhosis
(n=7)
Clinical state of patients
Child A (n = 15)
38.2
k2.3
36.6
+I32
46.31.
5 12.1
42.8t
k8.2
Child 8 (n = 10)
37.7
k15.1
Body wt.
(kg)
72.6
k7.9
65.5
k14.1
BMI
Fat mass
TSF
(kglm’)
(kg)
(mm)
23.0
k0.9
22.3
k4.5
15.3
10.3
f6.1
8.4
k4.3
57.3
k9.9
44.71.
7.3
k2.4
9.9
k4.8
8.4
k5.6
37.6t
9.0
47.91k13.3
39.87
k10.9
63.0
k14.8
70.7
k9.8
63.3
k17.3
21.4
70.7
k13.2
57.8t*
kIZ.0
24.0
k4.9
19.7t$,*
k4.2
23.1
k3.4
22.6
k6.2
k2.0
with the principles for human experimentation as
defined in the declaration of Helsinki.
The patient group differed with respect to the
aetiology of cirrhosis (10, ethanol-induced cirrhosis;
seven, primary biliary cirrhosis; eight, post-necrotic
cirrhosis), the clinical condition (15, Child A; 10,
Child B; i.e. Child-Pugh score based on the plasma
concentrations of bilirubin and albumin, the prothrombin time and the presence of ascites and
encephalopathy [13]), portosystemic shunting of
insulin (nine, increased; 16, normal; as reflected by
the molar C-peptide to insulin ratio) and the nutritional state (eight, body cell mass >30% of body
of body weight;
weight; 17, body cell mass ~ 3 0 %
see Tables 1 and 2). Unstable patients and patients
with late-stage liver disease (i.e. Child C) were
excluded from our study protocol for ethical reasons. On examination, the patients were in a stable
clinical state and had had no acute complications
during the last 3 weeks before admission to hospital.
Protocol
Measurements were performed after an overnight
fast. Patients and control subjects were asked to
stay in their beds in the morning (06.30 hours) and
after voiding they were transferred to the metabolic
ward. They rested in a semi-recumbent position in a
quiet room with a constant temperature of 21-24°C.
A venous catheter (Venflon 2; Viggo, Helsingborg,
Sweden) was inserted into an antecubital vein for
hormone infusion, and a 19-gauge cannula (Butterfly; Abbot, Sligo, Republic of Ireland) was
inserted retrogradely into a wrist vein for blood
sampling. Both were kept patent by infusing mini-
k5.2
2l.Ot
-18.3
25.47
f6.9
I8.9t
k5.2
16.9
k10.7
22.8t
k9.2
18.2
k6.2
f5.0
7.6
k2.8
FFM
(kg)
k12.8
k13.5
52.0*
+10.0
46.31.
k10.4
BCM
MAC
(kd
(cm)
23.8
k3.9
18.57
k6.1
29.2
16.0t
k7.0
22.V
k4.4
I8.2t
k4.8
25.2t
k4.7
25.9
52.4
26.0
k4.3
20.1
k6.2
I6.Ot
27.3
k3.4
23.lt*
k3.1
k5.2
kI.0
25.7t
k3.8
mal amounts of 0.9% (w/v) NaCl (saline). The hand
was then placed into a heated box (60-70°C) to
achieve arterialization of venous blood. The subjects
were asked to remain motionless and awake and
were allowed 30 min to acclimatize to the environment. Measurements were started at 08.00 hours
using indirect calorimetry equipment as described
previously (Deltatrac Metabolic Monitor; Datex
Instruments, Finland; see [9, 10, 123). Briefly, a
clear-plastic ventilated hood was placed over the
subject’s head and room air was drawn through the
hood at a constant rate of 41 litres/min. The
subjects were asked to remain motionless and
awake during the test. Continuous measurements of
0, consumption (paramagnetic 0,-sensor) and CO,
production (infrared C0,-sensor) were integrated
over 5min intervals. Estimation of REE took at
least 60min and a steady pulse rate was taken to
indicate a resting state, which was usually reached
between 45 and 60 min. Calibrations were performed
immediately before and after the end of the test.
Variations due to the technique were calculated
from propane combustion measurements (n = 5) and
were found to be below 4%. Flow variation was
assessed separately using a Calibration Analyzer
RT-200 (Timeter Instrum. Corp., Oregon Pike,
Lancaster, U.S.A.) and showed a maximum deviation of 4.2% over a period of 27 h (readings taken
half-hourly; coefficient of variation << 1%). Daily
variances within individuals based on test-retest
measurements in 10 weight-stable patients on 3
different days within 2 weeks were below 10%.
Heart rate was determined directly from the electrocardiogram (Hellige Instruments, Gel, Germany).
The experimental protocol was started after a
M. J.Miiller et al.
194
baseline period of 60min and Adrenaline 0.03pg
fat-free mass (FFM) [Suprarenin;
min-' kgHoechst, Frankfurt, Germany] was infused for l h
using a peristaltic pump (Perfusa Secura; B. Braun
Melsungen AG, Melsungen, Germany). Adrenaline
was diluted with 50ml of saline, and 0.5ml of
ascorbic acid was added. Two blood samples for the
determination of catecholamines, glucose, lactate,
free fatty acids, glycerol, 3-hydroxybutyrate and
urea were obtained during the basal period (-15
and Omin) and after 30 and 60min of the infusion
period. Urine was collected overnight and during
the whole time period of the protocols and was
analysed for urea nitrogen.
Analyses of body composition by anthropometry
(see [3, 12]), bioelectric impedance analysis (BIA;
using a radiofrequency current of 800pA at 5OkHz
between a set of electrodes attached to the dorsum
of the hand and the foot; BIA 101; RJL Systems,
Detroit, MI, U.S.A.; see [3, 9, 10, 12, 141) and a
60 min determination of total-body potassium
(TBK; in a whole-body counter with a precision in
the order of 2%; [l5]) were performed on separate
days.
'
Laboratory analyses
Plasma glucose concentration was determined by
using a Beckman I1 glucose analyser (Beckman
Instruments, Fullerton, CA, U.S.A.). Methods for
measurements of hormones (measured by r i a . in
the case of insulin and C-peptide and by h.p.l.c./
radioenzymic techniques in the case of catecholamines) and substrates [by standard spectrophotometric (glucose, lactate, glycerol, 3-hydroxybutyrate)
or colorimetric (free fatty acids) techniques] have
been described previously [9-12, 161.
women [lS]. A close correlation was found between
BIA- and TBK-derived FFM (r = 0.84, P <O.OOOl),
but BIA data exceeded TBK data at low body
weights. It should be mentioned that the assumptions of 68.1 or 64.2mmol of K+/kg lean body mass
has not been validated in patients with liver cirrhosis. Alterations in intracellular osmolarity (e.g. by
spironolactone treatment) are unlikely to explain the
observed differences (i.e. BIA- versus TBK-derived
FFM), because both methods would be affected in
the same direction if the intracellular osmolarity
was reduced. With respect to the possible effect of
ascites, BIA data were also measured in five patients
before and after paracentesis of about 4 litres of
ascites. The mean deviations were 7.5 LO.4 Ohm
(resistance) and 0.8 kO.1 Ohm (reactance), resulting
in corresponding changes in body composition
analyses of 0.4 kg FFM/litre of ascites, +0.2 kg
body cell mass/litre of ascites and + 0.4 kg fat mass/
litre of ascites. Estimation of the amount of ascites
in our patient group by ultrasound examination
revealed a maximum of 3 litres in some, but not all,
of our patients. We concluded that the maximum
error introduced by the presence of ascites in our
group was too small to affect the significance of our
data. Malnutrition was defined as a reduced body
cell mass of less than 30% of body weight.
Since the fractional hepatic extraction of insulin
by the cirrhotic liver may be reduced, our data have
to be corrected for the degree of portosystemic
shunting of insulin. C-peptide is secreted together
with insulin, but is not significantly extracted by the
liver, whereas insulin undergoes extensive hepatic
degradation. The molar C-peptide/insulin ratio measured in the peripheral blood is a rough indicator of
the 'net' portosystemic shunting of insulin (i.e. decreased hepatic extraction plus portosystemic shunting) under steady-state conditions.
+
Statistical analyses
Data analyses
REE was calculated according to previously
reported procedures [17, 181. Analyses of body
composition were performed by different methods.
Limitations of the individual techniques in patients
with liver cirrhosis have been discussed recently
[19]. The value of BIA has been described in
normal-weight and obese subjects as well as in
malnourished patients [20]. Body cell mass was
calculated as: lean body mass x 0.673 x log phase
angle [20]. BIA data may be affected by the
presence of ascites. However, minor amounts of
ascites do not significantly affect BIA data (see
[ll]). To test the impact of ascites on BIA data,
TBK was determined in another group of 20
patients and lean body mass was then calculated
assuming 68.1mmol of K+/kg lean body mass in
men and 64.2mmol of K+/kg lean body mass in
All data are shown as meanskSD. Statistical
analyses were performed using the SPSS/PC +
system. Statistical significance was tested by using
the t-test for differences between control subjects
and patients. Analyses of variance were applied to
control subjects and subgroups of patients with liver
cirrhosis, i.e. classification according to Child score
(see Table 5 ) and aetiology (see Table 4), and was
followed by Scheffe's procedure for multiple comparisons. In addition, multiple linear regression
analyses were performed. REE or adrenalineinduced thermogenesis were the dependent variables, and body cell mass, fat mass, ideal body
weight, basal plasma catecholamine concentrations,
the increase in plasma adrenaline concentration in
response to adrenaline infusion, basal plasma insulin
and C-peptide levels, the molar insulin/(=-peptide
ratio and the Child score were the predictor variables. Stepwise regression analyses were performed
I95
Energy expenditure in liver cirrhosis
Table 3. Plasma adrenaline, noradrenaline and dopamine concentrations before and during adrenaline infusion in
control subjects and patients with liver cirrhosis. Data are rneanr fSD. Statistical significance between groups (P <0.05): versus
control subjects (t); versus all cirrhotic patients ($). Statistical significance within groups (P<O.O5): versus ethanol-induced cirrhosis
(*); versus post-necrotic cirrhosis (**).
Adrenaline concn.
(nrnol/l)
Control subjects
(n=lO)
Cirrhotic patients
(n=Z)
Aetiology of disease
Ethanol-induced cirrhosis
(n=lO)
Post-necrotic cirrhosis
(n=8)
Primary biliary cirrhosis
(n=7)
Clinical state of patients
Child A (n= 15)
Child B (n = lo)
Noradrenaline concn.
(nrnol/l)
Doparnine concn.
(nrnol/l)
0 rnin
60 min
0 rnin
60 rnin
0 rnin
60 rnin
0.79
f0.23
I.lOt
f0.37
2.23
f0.70
2.93t
f0.91
2.39
f0.9 I
4.38t
f 1.99
2.77
f0.95
5.54t
f 2.98
0.42
f0.07
0.45
f0.06
0.47
f0.06
0.52
f0.16
1.13t
-10.29
1.21t
f 0.43
0.93
f0.40
2.89
f 1.25
3.07
f0.70
4.591.
0.47
f0.07
0.44
fO.05
0.42
0.58
f 0.55
5.lO-f
+2.17
3.24$**
f 1.06
6.60t*
f 3.85
5.69t
f2.36
3.88t$*
1.28
I.03t
3.10-f
fO.85
2.67
f0.96
4.37
f 1.83
4.397
f2.3 I
5.82t
f 3.34
5.127
f2.44
0.45
f0.07
0.44
fO.05
f0.29
1.21t
$0.46
2.82
between REE or adrenaline-induced thermogenesis
and the various predictor variables.
RESULTS
Basal plasma adrenaline and noradrenaline levels
were increased in most patients with liver cirrhosis
and remained elevated in some, but not all, patients
during adrenaline infusion (Table 3). There were no
differences in the calculated metabolic clearance rate
of adrenaline between the two groups (cirrhosis
116& 68 versus control 135i-59 ml/min). The basal
plasma insulin level was increased in cirrhotic
patients, cirrhosis 27 f15 versus control 15f8 punits/ml; P <0.05), whereas mean plasma C-peptide
concentrations were similar in both groups (cirrhosis 1.6+ 1.1 versus control 1.3f0.8ng/l; not significant). Thus, the mean molar C-peptide/insulin ratio
was slightly reduced in cirrhotic patients (cirrhosis
10.1 f3.8 versus control 13.1 f4.3; not significant).
Hyperinsulinaemia associated with liver cirrhosis
was variable and most pronounced in patients with
ethanol-induced liver cirrhosis (42 rt 27 p-units/ml;
P <0.05 versus both other aetiologies). Normal
values were found in patients with primary biliary
cirrhosis (15 f 11p-units/ml; for
comparison
22 f14p-units/ml in post-necrotic cirrhosis; not significant versus control subjects). Hyperinsulinaemia
was independent of the clinical and nutritional state
of the patients and the degree of portosystemic
shunting (as reflected by the molar C-peptide/insulin
ratio).
Liver cirrhosis increased REE when expressed per
kg FFM (basal: cirrhosis 115i- 37.0 versus control
+2.15
*
f0.06
f0.24
0.50
f0.06
0.48
f0.00
0.55
f0.20
0.48
f0.08
95.6f10.5J min-' kg-' FFM. This was more
pronounced in patients with ethanol-induced liver
cirrhosis (Table 4). Patients with reduced body cell
mass (<30% of body weight; data not shown) and
patients who were classified as Child B (Table 5 )
showed more frequently increased REE.
Infusion of adrenaline increased energy expenditure (cirrhosis 125f39.4 versus control 108f10.5J
min-l kg-' FFM; P<O.O5 for both, Tables 4 and
5 ) and heart rate (Fig. 1) in patients with liver
cirrhosis as well as in control subjects. However, the
effect on REE was less pronounced in the patient
group if expressed per kg body weight (cirrhosis
+6.50 f2.77 versus control +9.91 i- 3.57 J min- '
kg- body weight, P <0.05). Adrenaline transiently
increased, but then decreased, the respiratory quotient and this effect was similar in both groups
(Fig. 1).
Liver cirrhosis did not affect the basal plasma
concentrations of glucose, lactate, free fatty acids
and glycerol, but plasma 3-hydroxybutyrate levels
were significantly reduced in the patient group (Fig.
2). Infusion of adrenaline increased the plasma
concentration of all substrates in both groups, but
the responses of glucose and 3-hydroxybutyrate
were reduced in patients with liver cirrhosis (Fig. 2).
This was most pronounced in patients with ethanolinduced liver cirrhosis and in patients who were at
advanced stages of liver disease (i.e. in patients
considered as Child B. Although the mean values
suggested a similar lipolytic (i.e. increase in plasma
glycerol concentration) response to adrenaline in
control subjects and in cirrhotic patients (Fig. 2),
patients with ethanol-induced cirrhosis showed a
M. J. Muller et al.
I%
Table 4. Adrenalineinduced changes in REE and heart rate in control subjects and patients with liver cirrhosis of different aetiologies. Data are
means +so. Statistical significance: t P <0.05 versus control; 3P <0.05 versus both other aetiologies.
Basal
Stimulated
Increase
Basal
Stimulated
Increase
Basal
Stimulated
Increase
Increase in
heart rate
(beatslmin)
Control subjects
(n= 10)
5.42
f0.76
6.13
f 0.76
0.72
f0.25
74.6
f5.71
84.5
f5.71
9.91
f 3.57
95.6
f 10.5
108.0
f 10.5
12.6
f4.8
7.7
54.1
Aetiology of patients
Ethanol-induced cirrhosis
(n= lo)
Post-necrotic cirrhosis
(n = 8)
Primary cirrhosis biliary
(n=7)
4.87
k0.7 I
5.08
k0.59
4.24t
fl.55
5.33
kO.80
5.37
k0.7 I
4.70t
f0.59
0.46
k0.21
0.347
f0.21
0.46
f0.13
80. I
k 16.0
72.7
k 13.4
69.6
f 12.2
87. I
k 17.0
77.9
k 14.7
76.8
f 12.8
6.93t
f2.86
5.I7f
f 2.86
7.22
f2.35
142.373
k41.7
100.1
f8.3
99.4
f 13.7
154.5t$
k43.8
108.3
f23.5
104.4
f 15.0
12.0
4.5
7.13
f 3.9
9.9
-3.3
10.7
f4.7
7.9
k6.5
8.6
f4.4
REE (kJ/min)
REE Umin-lkg-1
body wt.)
REE Omin-Ikg-IFFM)
*
+
Table 5. Adrenalineinduced changes in REE and heart rate in control subjects and patients with liver cirrhosis of different clinical states. Data are
meansf SD. Statistical significance: tP<0.05 versus control; SP<0.05 versus Child B.
REE (kJ/min)
Control subjects
(n=lO)
Clinical state of patients
Child A
(n= 15)
Child B
(n= 10)
REE umin-'kg-1
REE (1 min - I kg -1 FFM)
body wt.)
Basal
Stimulated
Increase
Basal
Stimulated
Increase
Basal
Stimulated
Increase
Increase in
heart rate
(beatslmin)
5.41
f0.76
6.13
f0.76
0.72
f0.25
74.6
f5.71
84.5
f5.71
9.91
f 3.57
95.6
f 10.5
108.0
f10.5
12.6
f4.79
7.7
f4.1
4.66t
5.12t
kO.80
5.251.
k0.67
0.46t
f0.21
0.38t
+0.13
67.4
73.83
6.34t
f3.02
6.591.
k2.43
106.1
k35.8
I30.0t
k35.7
115.9
f37.8
140.2
k39.1
9.79
f4.62
9.95
f4.28
9.6
f 5.5
8.7
f4.9
f0.71
4.87
k0.63
k10.0 f11.0
85.9
k 12.8
reduced response ( P c 0.05 versus other aetiologies
and control subjects), whereas patients with primary
biliary cirrhosis and post-necrotic cirrhosis had elevated basal and stimulated plasma glycerol concentrations (P<O.O5, data not shown). There were no
differences between the mean values obtained in the
subgroup of patients who were in a poor nutritional
state and those who had a high molar C-peptide/
insulin ratio (data not shown).
Linear regression analysis indicated that 99% of
the variance in REE could be explained by the covariates tested (see the Methods section; rz =0.99,
P<O.OOOl). Body cell mass accounted for 65.1% of
the variance (P<O.OOOl). In contrast, only 66% of
the variance in adrenaline-induced thermogenesis
could be accounted for by the co-variates tested and
no significant association was found between
thermogenesis and any parameter of body composition or plasma hormone concentration.
DISCUSSION
The essential finding of the present study is that
REE is increased and that hypermetabolism is evident in certain subgroups of patients with liver
cirrhosis (e.g. patients with ethanol-induced liver
cirrhosis, patients at more advanced stages of the
disease and patients in a poor nutritional state). In
contrast, the thermic and metabolic responses to
92.5
& 14.4
adrenaline infusion are reduced in liver cirrhosis.
These data provide evidence that resting metabolic
rate and stimulated thermogenesis are regulated
independently, and that both factors contribute differently to daily energy expenditure in patients with
liver cirrhosis.
Since
glucose-induced
thermogenesis
was
increased by about 50% in a subgroup of hypermetabolic patients with ethanol-induced liver cirrhosis [12], our study supports the concept that
thermogenesis by itself is regulated by different
factors. To obtain further insight, it is worthwhile
remembering that the thermic effect of food has
been divided into two components: first, an obligatory component that relates to digestion, absorption
and processing of nutrients, and second a facultative
component that is due to energy expended in excess
of the obligatory demands [21]. Obligatory thermogenesis results from insulin-induced substrate metabolism [22], whereas facultative thermogenesis has
been mainly attributed to sympathetic nervous
system activity [23]. The metabolic basis of the
latter component has been explained by the sum of
energy-wasting processes (e.g. substrate cycling; see
[4, 5)). Our previous finding of an increase in
glucose-induced thermogenesis in association with
reduced rates of insulin-induced glucose disposal in
patients with ethanol-induced liver cirrhosis indicates that substrate cycling associated with glucose
I97
Energy expenditure in liver cirrhosis
I
Adrenaline
I
...
...
...
...
'OL-lb
d
I0 ZO 3;
Time (min)
40
i0 6i
...
...
Time (min)
Fig. 1. Increases in 0, consumption, respiratory quotient (RQ) and
heart rate in response to adrenaline infusion in 10 control subjects
( 0 )and 25 patients with liver cirrhosis (0).Data are presented as
means with bars indicating SD.
Fig. 2. Plasma concentrations of glucose, lactate, glycerol, free fatty
acids (FFA) and 3-hydroxybutyrate (3-OHB) 0, 30 and 60min after
adrenaline infusion for 60min in 10 control subjects (left) and 25
patients with liver cirrhosis (right). Statistical significance: *P <0.05
compared with control subjects.
disposal may be increased in this patient group
[12]. The present findings show that adrenalineinduced thermogenesis is reduced in liver cirrhosis.
These data are not contradictory, since both stimuli
(glucose/insulin versus adrenaline) affect different
metabolic and/or haemodynamic events. Infusion of
adrenaline results in (i) increased mobilization of
endogenous fuels (i.e. acute glycogen breakdown in
muscle and liver, mobilization of lipids in adipose
tissue and muscle), (ii) increases in the fluxes
through the tricarboxylic acid cycle and gluconeogenesis, and (iii) increased work by the heart.
Glucose/insulin stimulates energy expenditure by
enhancing glucose storage as glycogen or as lipids
but also increases muscle blood flow [24]. About
80% of the thermic effect of glucose/insulin is
explained by muscle metabolism [25], whereas only
50% of the thermic effect of adrenaline results from
skeletal muscle [26]. Thus, different haemodynamic
and metabolic events as well as different organs
contribute to increased thermogenesis in response to
various stimuli.
One could speculate that reduced adrenaline-
induced thermogenesis simply results from depleted
substrate stores in patients with liver cirrhosis. An
alternative explanation is that cirrhotic patients are
frequently hyperinsulinaemic (for a review, see [27]).
Since hyperinsulinaemia antagonizes the action of
adrenaline [lo, 111, insulin may further reduce
adrenaline-induced thermogenesis in liver cirrhosis.
A reduction in adrenaline-induced thermogenesis
would contribute to a more positive energy balance
in patients with liver cirrhosis. Hyperinsulinaemic
patients also have a reduced lipolytic response to
adrenaline and frequently show an increased fat
mass. Since these patients have a reduced body cell
mass, their body weight is frequently normal or only
slightly reduced. It is evident that the nutritional
state is heterogeneous in patients with liver cirrhosis
and that some of our patients might be considered
as normal weight but obese (i.e. they have an
increased fat mass). In a separate study performed
on 123 patients with liver cirrhosis, 70% had some
sign of protein-calorie malnutrition [28]. Only about
11% of the patients were underweight owing to
significant losses in body cell mass and body fat,
M. J. Miiller et al.
198
whereas 30% of the population had an increased fat
mass [28].
It should be mentioned that our data do not
answer the question of whether changes in energy
expenditure are causative of, or secondary to,
changes in body composition. However, it is interesting to note that hypermetabolic patients (i.e.
patients with a high resting metabolic rate) frequently have a reduced body cell mass [2, 3, 121.
Since most patients with ethanol-induced liver
cirrhosis are hypermetabolic and also hyperinsulinaemic, these two factors together may result in loss
of body cell mass and an increase in body fat.
However, to understand the various forms of malnutrition associated with liver cirrhosis, other
factors have to be considered. In addition to energy
expenditure, a variable energy intake and/or longterm protein restriction also contribute to malnutrition in liver cirrhosis. It has been shown before that
long-term protein restriction contributes to the discordance between FFM and body fat, since malnourished patients given a low-protein, high-energy
diet may gain fat while losing some FFM [29].
In conclusion energy expenditure is variable and
frequently increased, but
adrenaline-induced
thermogenesis is reduced, in patients with liver
cirrhosis. These changes may contribute to the
different forms of malnutrition in patients with liver
cirrhosis.
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