Clinical Science and Molecular Medicine (1977) S, 155-163.
The association between fasting hyperbilirubinaemiaand
serum non-esteriiied fatty acids in man
R. E. COWAN,* R. P. H. THOMPSON, J. P. KAYE A N D G I L L I A N M. CLARK
Gastrointestinal Laboratory and Department of Clinical Chemistry,
St Thomas' Hospital, London
(Received 18 May 1976; accepted 28 March 1977)
S-Y
1. The concentrations of plasma total and
unconjugated bilirubin and of serum nonesterified fatty acids (NEFA) have been
measured in two healthy subjects during fasts
of up to 21 h.
2. Fasting was either continuous or interrupted by various procedures that altered the
concentrations of NEFA and total bilirubin.
3. When NEFA concentrations were increased by the administration of noradrenaline,
heparin or caffeine, bilirubin concentrations
also rose.
4. When NEFA concentrations were lowered
by insulin, bilirubin concentrations fell.
5. Meals of 3.138 kJ and more, taken during
the fasting period, lowered total bilirubin and
NEFA concentrationsin both subjects, whereas
the effects of smaller meals were less consistent.
6. These studies demonstrate a statistically
significant correlation between total bilirubin
and NEFA during uninterrupted fasting and an
association between these variables under other
experimental conditions. They suggest that the
control of bilirubin concentrations in the blood
is linked to lipid metabolism.
Key words: bilirubin, hyperbilirubinaemia,
fasting, non-esterified fatty acids.
Abbreviation: NEFA, non-esterifiedfatty acids.
*
Present address: Gastroenterology Unit. The
London Hospital, Whitechapel, London El 1BB.
Correspondence: Dr R. P. H. Thompson, St Thomas'
Hospital, London SEl 7EH.
Introduction
The concentration of unconjugated bilirubin in
the blood rises during fasting in normal individuals (Barrett, 1971a; Bloomer, Barrett,
Rodkey & Berlin, 1971), and also in patients
with a variety of liver diseases (Barrett, 1971a)
and experimental animals (Barrett, 1971b;
Gronwall & Mia, 1972). The mechanism of this
rise is not known, but in man there is a fall in the
clearance of 3H-labelled bilirubin from plasma
by the liver (Bloomer et ai., 1971), leading to the
suggestion that a substance interfering with
hepatic bilirubin clearance is either formed or
increases during fasting. Such a substance
could be non-esterified fatty acids (NEFA),
since their serum concentration rises during
fasting (Dole, 1956) owing to lipolysis of triglycerides stored in adipose tissue (Galton, 1975).
The liver takes up and metabolizes much of this
mobilized NEFA (Steinberg, 1964), so that
NEFA may interfere with the clearance of
bilirubin by the liver. We therefore attempted to
see if plasma bilirubin was related to serum
NEFA concentrations in healthy subjects
during fasting, various procedures being used
to alter these concentrations.
Methods
Subjects
The concentrations of plasma total and
unconjugated bilirubin and of serum NEFA
were measured serially in two of the authors
(R.T. and R.C.). Both subjects, who were
healthy and taking no drugs, fasted for about
21 h after an evening meal, until approximately
155
R. E. Cowan et al.
156
18.00 hours the following day. Blood samples
were taken at intervals during the last 8-10 h of
the fast for bilirubin, NEFA and, where
appropriate, glucose measurements. During
this time both subjects were ambulant.
Analytical methods
Bilirubin was estimated in triplicate by a
modification of the method of Michaelsson
(Thompson, 1969), the normal range being
34-14-5 pmolll, all measurements being made
within 3 days of collection, on specimens stored
in the dark at 4°C. Normal concentrations
remained unaltered under these conditions for
at least 5 days. The mean coefficient of variation
of measurements was 1.6%. Measurements on
reconstituted, freeze-dried, quality control serum
with known concentrations of bilirubin (Versato1 Hi and Versatol Lo, General Diagnostics,
U.S.A.) showed the method to be accurate
within 4% in the normal range, but high concentrations were underestimated by up to 8 %.
NEFA were estimated in duplicate by a semiautomated fluorimetric method (Carruthers &
Young, 1973), by using the extraction procedure
of Dole (1956). The mean coefficient of variation
was 4.6%. Blood for NEFA estimation was
collected into glass tubes, allowed to clot, and
then centrifuged at 1600 g (3000 rev./min) for 15
min at 4"C, the serum being stored at -20°C.
Plasma glucose was measured in triplicate with
a glucose analyser (Beckman Instruments Inc.,
U.S.A.), blood being first collected into tubes
containing fluoride and oxalate, and the plasma
stored at 4°C.
during three of these fasts. The mean rates of
change, for each fast, of bilirubin and NEFA
were calculated in pmol h- 1-'.
Serum NEFA were increased by:
(1) A constant intravenous infusion of noradrenaline (Winthrop Laboratories), 18 pg
h-' kg-I body weight in 100 ml of NaCl
solution (155 mmol/l) given for 1 h.
(2) Two intravenous injections of heparin
(Evans Medical Ltd), 10 unitslkg body weight,
at an interval of 2-3 h.
(3) Caffeine (250 mg) ingested as black,
unsweetened, Nescafe coffee, 7.2 g in 500 ml of
hot water.
Serum NEFA were decreased by:
(1) A constant intraveous infusion of soluble
insulin (Weddel Pharmaceuticals), 0.04 unit
h-' kg-' body weight in 100 ml of NaCl
solution (155 mmol/l), given for 2 h. Plasma
glucose concentrations were measured during
and after the infusion.
(2) Meals containing 1-674,2.092,3-138,4.184
and 6.276 kJ (400,500,750,1000 and 1500 kcal.
respectively) were taken after approximately 16
h of fasting, which then continued. The carbohydrate, protein and fat contents of each meal
are shown in Table 1.
Results
The changes in plasma total bilirubin and serum
NEFA concentrations in these studies are
expressed as mean values from both subjects
together.
Fasting alone
Procedure
Total and unconjugated bilirubin concentrations were measured in both subjects during nine
uninterrupted fasts, and NEFA concentrations
During the uninterrupted fasts of up to 21 h
the mean rates of rise of plasma total bilirubin
and unconjugated bilirubin for the last 9 h in
both subjects were 0.63 pmol h-' 1-' and 0.60
TABLE
1. Carbohydrate, protein and fat contents of the meals of dif/erent energy value taken by the two subjects
Subject R.T.
1.674 kJ
2.092 kJ
3.138 kJ
4 1 8 4 kJ
6276 kJ
Subject R.C.
Protein
Carbohydrate
Fat
Protein
Carbohydrate
Fat
(9)
(g)
(g)
(g)
(g)
(9)
25
34
39
43
53
48
50
13
25
24
42
28
53
48
20
13
22
37
62
60
16
89
103
33
52
60
51
64
I5
103
157
Fasting hyperbilirubinaemiaand fatty acids
pmol h-I 1-I respectively (Fig. l), and serum
NEFA also rose steadily at a mean rate of 40
pmol h-' I-' (Fig. 2). The results obtained
during uninterrupted fasting were not all
collected at the times shown in Fig. 1 and Fig. 2,
some samples being collected before or after the
times shown, but the mean value of each
variable was calculated from these values for
each time-point shown.
Noradrenaline infusion
During the intravenous infusion of noradrenaline the mean rate of rise of NEFA in
both subjects was 735 pmol h-l l-l, but fell
sharply to pre-infusion values after the infusion.
The mean rate of rise of total bilirubin also
increased during the infusion, to 1.32 pmol
h-1 1-1, compared with 0-83pmol h-' 1-'
beforehand, and slowed to 0-31pmol h-' I-'
after the infusion until the end of the fast (Fig.
3).
Heparin injections
The two doses of heparin, given by intravenous injection to each subject during a single
fast, produced a mean rate of rise of NEFA of
155 pmol h- 1- and of total bilirubin of 0.95
Bmol h- 1- ' from the first dose until the end of
the fast, compared with mean rates of 67 pmol
h-l I-' and 0.45 pmol h-' 1-l respectively
before the first dose (Fig. 4). In subject R.C.
NEFA concentrations fell, after an initial rise,
during the 3 h between the two doses of heparin,
possibly because circulating heparin concentrations fell too low to stimulate lipolysis. Total
bilirubin concentrations also fell transiently but
not simultaneously. Although total bilirubin
concentrations started high in this study
higher values were reached than at any time
during these experiments (maximum 18.2 and
18.9pmol/l) at the end of the fast, at which time
NEFA were also at the highest values (1050
.umol/l) reached in both subjects.
Caffeine ingestion
After ingestion of caffeine, NEFA rose at a
mean rate of 129 pmol h-l I - l , and total
bilirubin at a mean rate of 0.78 pmol h- 1- for
the remainder of the fast, compared with mean
rates of 12 pmol h-' 1-I and 0-31pmol h-' I-'
respectively before caffeine.
Insulin infusion
During the intravenous infusion of soluble
I 6 r R.T.
T
C'
1
14-
E
2
12-
.n
:
.-a 10E
2
G
Ol
8-
a
1
-
C
8
6-
I
a
A
L
-O
4-
0
2I
I
I
I
I
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1
1
I
08.00 10.00 12.00 14.00 16.00 18.00
Time (hour%)
Time (hours)
and mean (+m) unconjugated bilirubin
-0) concentrations during the final 8-9 h of nine uninterrupted fasts by two subjects (R.T. and
FIG.1. Changesin mean (fSD) plasma total bilirubin(.-.)
(@-
1
08;OO 10.00 12.00 14.00 16.00 18-00
*
R.C.).
R. E. Cowan et al.
158
I6rR . ~ .
f
-
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3.12-
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14-
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8-
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4-
0
8
2-
I
u
08-00 10.00 12.00 14.00 16.00 18.00
00.00 10.00 12.00 14.00 16.00 18.00
Time (hours)
Time (hours)
FIG.2. Changes in mean (+_sD)
plasma total bilirubin (0-0)
and mean (+SD) serum non-esterified
fatty acid (NEFA; - - - 0 ) concentrations during the final 8-9 h of uninterrupted fasting by two
subjects.
0
.-----I
0
a
2-
18
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Fasting hyperbilirubinaemia and fatty acids
159
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w
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Heparin
I
Heparin
I
08.00 10.00 12.00 14.00 16.00 18.00
Time (hours)
Time (hours)
FIG.4. Changes in plasma total bilirubin(.-.)
and serum non-esterified fatty acid (NEFA; - - - 0 )
concentrations produced by two intravenous injections of heparin (10 unitslkg) to two fasting subjects. The shaded area represents the changing mean plasma total bilirubin (+SD) during nine uninterrupted fasts by both subjects.
insulin NEFA concentrations fell at a mean rate
of 63 pmol h-' I-' and total bilirubin at a mean
rate of 0.87 pmol h-' I-' (Fig. 5). After the
infusion there was a prompt rise in NEFA and
later in bilirubin concentrations. Since both
subjects experienced symptoms of hypoglycaemia during the infusion, with mid-infusion
blood glucose values of 3.4 mmol/l and less,
release of endogenous noradrenaline might have
caused the rises in NEFA and bilirubin when
the insulin was stopped.
Meals of different calorific value
In both subjects meals of 3,138, 4.184 and
6.276 kJ were followed by falls in blood NEFA
and total bilirubin, although the falls in NEFA
were not always sustained for the remainder of
the fast. After the meal of 6-276kJ, for instance,
the mean rate of fall of NEFA in both subjects
was 56 pmol h-' I-' and of total bilirubin 0.61
pmol h-' I-' until the end of the study (Fig. 6).
A meal of 1.674 kJ in R.T. did not prevent the
rise in NEFA continuing at 67 pmol h- 1- ',
and total bilirubin at 0-59 pmol h-' 1-' after
the meal, although after 1.674 kJ in R.C. there
was a fall in both rates to 76 pmol h-I 1-I and
0.71 pmol h-' I-' respectively (Fig. 6). In this
subject, however, a meal of 2.092 kJ was
followed by a continued rise in both variables.
Statistical analysis
Each of the three variables was related to
time by least-squares regression, in all studies
when the subjects fasted alone, the results from
both subjects-being combined..
These regression equations are (values k SE) :
Total bilirubin = 3-68 ( 50.24) f0.52 ( +0*06)t
(n = 97, r = 0.67, P < 0.01)
Unconjugated bilirubin = 3.73 (50.30) +0.31
(k0.09)t (n = 50, r = 0.43, P <0.01)
NEFA = -2.19 (+0.42)+0.48 (&O*ll)t(n =
32, r = 0.64, P < 0.01)
where t = time (h). Regression analyses were
also performed for total bilirubin with NEFA,
separately for each subject, in all studies when
fasting was uninterrupted. The correlation
coefficients ( r ) for these regression equations
R. E. Cowan et al.
160
--
14-
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c
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B
W
0 12-
-E3.
-
a
10II.
W
z
z
x
R.C.
\
1210
14-
8-
x
8-
N
N
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0
6-
L
0
I
I
i
6-
I
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n
L
0
I-
'x.0.
Sol. insulin
08.00 10.00 12.00 14.00 16.00 18.00
08.00 10.00 12.00 14.00 16.00 18.00
Time (hours)
Time (hours)
FIG.5. Changes in plasma total bilirubin (0-0)
and serum non-esterified fatty acid (NEFA; 0 - - - 0 )
concentrations produced by intravenous infusion of soluble insulin (0.04 unit h-' kg-') for 2 h during
fasting in both subjects. The shaded area represents the changing mean plasma total bilirubin (fSD)
during nine uninterrupted fasts by both subjects.
are 0.63 for subject R.T. (n = 16, P<O.Ol) and
0.61 for subject R.C. (n = 16, P<0.05).
Similar analyses have not been performed on
the individual experiments (e.g. insulin, heparin
etc.) as the number of observations from each
was necessarily small, and also the changes in
total bilirubin and NEFA concentrations were
often out of phase with each other, probably
due to their different rates of hepatic uptake.
Discussion
These studies in two healthy subjects confirm
that there is a steady rise in the concentration of
total bilirubin in plasma during fasting and
that this is mostly in unconjugated bilirubin.
They also codinn that NEFA concentrations
in the blood rise during fasting. The subjects
could not rest throughout these studies so that
their mild exercise may have affected the results.
The studies were confined to two of the authors
as we did not wish to submit other volunteers to
repeated unpleasant periods of starvation.
The absolute changes in total bilirubin
concentrations were small, the values usually
remaining within the normal range, but the
changes were reproducible, and outside the
limits of error of the method. It is interesting
that since one-twenty-fourth of the bilirubin
synthesized during 24 h is excreted by the liver
in each hour, a reduction of only 20% in this
excretion should raise blood concentrations of
bilirubin at an initial rate of 0.70pmol h- 1- l , a
rate similar to that which occurred during fasting
in these studies.
The mechanism of fasting hyperbilirubinaemia has remained obscure since it was first
described by Gilbert & Herscher (1906). It is
unlikely to result from an increased production
of bilirubin (Bloomer et al., 1971), but in
healthy subjects there is a decrease in the
clearance of bilirubin by the liver from plasma
during fasting (Bloomer ef al., 1971), and the
raised concentrations of NEFA could be
responsible for this.
When noradrenaline increased the mean rate
of rise of NEFA by approximately tenfold
during the infusion, the mean rate of rise of
total bilirubin simultaneously almost doubled.
Noradrenaline increases NEFA concentrations
in the blood by stimulating the activation of
triglyceride lipase, which is responsible for the
initial breakdown of stored triglycerides to
fatty acids (Galton, 1975). Similarly, intravenous injections of heparin produced an
increase in NEFA at threefold and total
bilirubin at twice the mean rates during fasting,
total bilirubin then reaching higher absolute
Fasting hyperbilirubinaemia and fatty acids
16
161
r(ol
R.T.
I4t
4
I
,
I,
08.00 10.00 12.00 14.00 16.00 18.00
I
I
I,
I
I
00.00 10.00 12.00 14.00 16.00 18.00
Time (hours)
Time (hours)
I
I
I
FIG.6. Changes in plasma total bilirubin ( 0 4 ) and serum non-esterified fatty acid (NEFA;
0 - - 0 )concentrationsproduced by meals (at arrows) of 6.276 kJ (a and b) or 1.674 kJ (c and d) value
taken by both subjects during fasting. The shaded area represents the changing mean plasma total
blirubin ( +SD) during nine uninterrupted fasts by both subects.
-
values in both subjects than during any of the
other studies. Heparin raises NEFA concentrations in the blood by liberating clearing factor
(lipoprotein) lipase into the circulation, where
it releases NEFA from lipoprotein triglycerides
(Korn, 1955). Caffeine, which also has an
NEFA-mobilizing effect in man (Bellet, Kershbaum & Finck, 1968), produced a tenfold
increase in the mean rate of rise of NEFA and a
25-fold increase in the mean rate of rise of
total bilirubin. Caffeine has this effect on NEFA
concentrations either by increasing secretion of
catecholamines, secondary to central nervous
system stimulation, or by preventing the
breakdown of cyclic AMP, which participates
in the activation of triglyceride lipase (Oberman,
Harell, Herzberg, Hoerer, Jaskolka & Laurian,
1975).
Conversely, during intravenous infusion of
insulin a fall in NEFA concentrations was
accompanied by a fall in total bilirubin. The
anti-lipolytic effects of insulin are well known
162
R. E. Cowan et al.
(Dole, 1956; Mahler, Stafford, Tarrant &
Ashmore, 1964; Schonhofer, Skidmore &
Krishna, 1972) and this effect on bilirubin is
particularly interesting since, apart from the
ingestion of meals, this was the only procedure
which reversed the rise of bilirubin during fasting.
Reduction of food intake to 1.674 kJ/day
usually elevates bilirubin in normal subjects, and
especially in patients with Gilbert’s syndrome
(Owens & Sherlock, 1973; Davidson, RojasBueno, Thompson & Williams, 1975). In the
present studies the total bilirubin and NEFA
concentrations consistentlyfell when fasting was
interrupted by meals of 3.138 kJ and more. In
subject R.T., however, the smallest (1.674 kJ)
meal was followed by a continued rise in
bilirubin and NEFA, whereas in subject R.C.
both values fell steadily. In R.C., however, a
small (2.092 kJ) meal did not prevent continued
increases in both variables. These differencesare
probably due to the different amounts of carbohydrate, fat and protein in the meals (Table 1).
Gollan, Hatt & Billing (1975a) and Gollan,
Bateman & Billing (1975b) have shown in
patients with Gilbert’s syndrome and in Gunn
rats that a high carbohydrate, low-lipid diet
increased total bilirubin, which fell when the
lipid content was increased without changing
the calorific value, but NEFA were not measured in these studies.
Thus manipulations of serum concentrations
of NEFA were frequently accompanied by
corresponding changes in plasma total bilirubin. Since bilirubin concentrations will be
slower to respond to changes in the rate of
hepatic uptake, the plasma bilirubin will not
change in parallel with the rapid changes of
serum NEFA. Thus bilirubin may be highest
when NEFA are falling.
NEFA might interfere with bilirubin at any
stage of its metabolism, from its passage in the
blood to conjugation by the hepatic cell (Odi&re, 1975). NEFA bind reversibly to plasma
albumin (Goodman, 1958) and might compete
with bilirubin for the binding sites (Starinsky &
Shafrir, 1970), although the concentrations of
NEFA required for the competitive displacement of bilirubin in uitro are too high to be
achieved in life (Thiessen, Jacobsen & Brodersen, 1972). Moreover, since unconjugated
bilirubin separates from albumin immediately
before its hepatic uptake (Bloomer, Berk,
Vergalla & Berlin, 1973), competitive displacement of bilirubin from albumin should reduce,
rather than increase, plasma concentrations.
Alternatively, NEFA might interfere with
receptors on the hepatic cell membrane that
probably interact with the albumin molecule to
separate bilirubin (Bloomer et al., 1973), and
thereby diminish hepatic bilirubin uptake.
Levi, Gatmaitan & Arias (1969) showed that
unconjugated bilirubin also binds to the
organic anion-binding Y-protein (ligandin) and
Z-protein, in the liver cell cytoplasm, with
preferential binding to Y-protein but overflow
to Z-protein. Long-chain fatty acids bind
preferentially to Z-protein (Ockner, Manning, Poppenhausen & Ho, 1972) and only a
little to Y-protein (Foliot, Housset, Ploussard,
Petite & Infante, 1973). There may therefore
be competition with bilirubin for these
binding proteins when blood concentrations
and hepatic uptake of NEFA are increased
during fasting.
Finally, NEFA may decrease hepatic bilirubin clearance by interfering with its enzymatic
conjugation. Inhibition of hepatic UDPglucuronyl transferase (EC 2.4.1.17) activity by
NEFA has been demonstrated in uitro (Bevan &
Holton, 1972), but the importance of such
inhibition in uiuo is uncertain. The activity of
hepatic UDP-glucuronyl transferase falls in
starved rats (Owens & Sherlock, 1973), but
Gunn rats, in which there is no detectable
activity of the enzyme, show further increases
in their raised bilirubin when they are starved
(Bloomer et al., 1971). However, patients with
Gilbert’s syndrome and reduced hepatic UDPglucuronyl transferase activity show a greater
absolute rise in total bilirubin during calorie
restriction than do normal subjects (Felsher &
Carpio, 1975).
Thus there are several ways in which NEFA
might contribute to the unconjugated hyperbilirubinaemia of fasting. These studies demonstrate a significant correlation between fasting
values of total and unconjugated bilirubin and
NEFA. Moreover, since hepatic uptake of
NEFA is proportional to their serum concentrations (Steinberg, 1964), changes in hepatic
uptake of NEFA produced in these studies
might similarly affect the hepatic uptake of
bilirubin. We therefore suggest that the control
of bilirubin concentrations in blood may be
linked to lipid metabolism.
Fasting hyperbilirubinaemia and fatty acids
Acknowledgments
R.E.C. was a Medical Research Council
Clinical Research Fellow when performing this
work. The authors are grateful to Miss C. Iles
for dietetic assistance and to Mr D. J. Shannon
for the statistical analyses using the computer
facilities at the Department of Community
Medicine, St Thomas’ Hospital.
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