Clinical Science and Molecular Medicine (1978) 54,451-455
SHORT COMMUNICATION
Effect of chenodeoxycholic acid on serum and biliary tipids
in patients with hyperlipoproteinaemia
B. ANGELIN, K. EINARSSON AND BARBRO LEIJD
Department of Medicine, Serafimerlasarettet, Karolinska Institutet, Stockholm, Sweden
(Received 25 August 1977; accepted 12 December 1977)
Summary
1. In order to study the effects of chenodeoxy­
cholic acid on serum and biliary lipids in hyper­
lipoproteinaemia, chenodeoxycholic acid was ad­
ministered to seven type Ila, eight type lib and
eight type IV patients in a daily dose of 750 mg
(1 -9 mmol) for 3 months.
2. The serum concentrations of cholesterol and
triglycerides were determined at 4-week intervals:
cholesterol remained unchanged whereas tri­
glycerides decreased 15-20%.
3. In 17 patients, biliary lipids were studied. The
proportion of chenodeoxycholic acid in the bile
increased to about 70%; lithocholic acid and
ursodeoxycholic acid increased significantly.
4. Bile saturation with cholesterol decreased and
correlated negatively with the proportion of
chenodeoxycholic acid in biliary bile acids but
positively with serum triglycerides.
5. It is concluded that chenodeoxycholic acid
treatment in hyperlipoproteinaemia is associated
with a parallel fall in serum triglycerides and biliary
cholesterol and thus may prove to be a useful
adjunct in hypolipidaemic treatment.
Key words: bile acid, bile cholesterol, cholic acid,
deoxycholic acid, lithocholic acid, lithogenicity,
serum cholesterol, serum triglycerides, ursode­
oxycholic acid.
Hofmann, Schoenfield & Thistle, 1972; Hofmann
& Paumgartner, 1975). During such therapy, a fall
in serum triglycerides has been observed whereas
serum cholesterol is unaffected (Bell, Lewis, Petrie
& Dowling, 1973; Hoffman, Hofmann & Thistle,
1974; Iser, Dowling, Mok & Bell, 1975). As
hypertriglyceridaemia per se appears to be linked
to an increased risk of gallstone development
(Einarsson, Hellström & Kallner, 1975) and as
triglyceride-lowering agents such as clofibrate
increase biliary cholesterol saturation (Pertsemlides, Panveliwalla & Ahrens, 1974) and gallstone
incidence (Coronary Drug Project, 1975; Cooper,
Geizerova & Oliver, 1975), chenodeoxycholic acid
may be useful in treatment of hypertri­
glyceridaemia. Previous studies have reported a
significant reduction (Miller & Nestel, 1974) as
well as no changes (Schlierf, Stiehl, Heuch, Lang,
Oster & Schellenberg, 1976) in serum triglycerides
in hypertriglyceridaemic patients treated with
chenodeoxycholic acid, whereas no information on
changes in biliary lipids in these patients is
presently available. We thus decided to study the
effect of chenodeoxycholic acid on serum and
biliary lipids in patients with hyper­
lipoproteinaemia.
Material and methods
We studied 23 outpatients with hyper­
lipoproteinaemia, all of whom gave their informed
consent to participate. (The investigation was
approved by the Ethical Committee of the
Karolinska Institutet.) Diagnostic criteria for lipoprotein patterning (Beaumont, Carlson, Cooper,
Fejfar, Fredrickson & Strasser, 1970) are given
elsewhere (Einarsson, Hellström & Kallner, 1974).
Introduction
Oral chenodeoxycholic acid may lower cholesterol
saturation of bile and induce gallstone dissolution
(Bell, Whitney & Dowling, 1972; Danzinger,
Correspondence: Dr Kurt Einarsson, Department of
Medicine, Serafimerlasarettet, S-l 12 83 Stockholm, Sweden.
451
452
B. Angelin, K. Einarsson and B. Leijd
Seven patients (four males and three females) had
type Ila, eight (two males and six females) type lib,
and eight (six males and two females) type IV
hyperlipoproteinaemia. An oral cholecystogram
was performed in all non-cholecystectomized sub­
jects. Gall-bladder disease was found in one type
Ila, five type lib and four type IV patients. Some of
the patients were continuously treated with
digitalis, diuretics and/or
/?-adrenoreceptorblocking agents; all medication was unchanged
before and during the studies. One type IV patient
had a mild diabetes, controlled by sulphonylurea.
After a control period of 3-4 weeks, the patients
were given 750 mg (1-9 mmol) of chenodeoxycholic acid (Chendol, AB Draco, Lund, Sweden)
daily in two divided doses (the approved ex­
perimental dose at the time) for 3 months. Body
weight, serum lipids and liver function tests were
determined before and at 4-week intervals during
treatment.
Seventeen of the patients were examined with
regard to biliary lipids under metabolic ward
conditions before and at the end of the treatment
period. After 4-7 days on a standardized diet of
natural type (see Einarsson et al., 1974), fasting
duodenal bile was obtained on 2 consecutive days
as described previously (Ahlberg, Angelin,
Einarsson, Hellström & Leijd, 1977).
Total bile acids (Fausa & Skälhegg, 1974),
cholesterol (Hanel & Dam, 1955) and phospholipids (Bartlett, 1959) were determined as described
(Ahlberg et al., 1977). The cholesterol content was
expressed as a molar percentage of total biliary
lipids: 100 x cholesterol (mol)/[cholesterol + bile
acids + phospholipids (mol)]. Saturation of bile
with cholesterol was calculated in terms of lithogenic indices (Thomas & Hofmann, 1973), by
using both the solubility limits of Admirand &
Small (1968) and of Hegardt & Dam (1971), and
Holzbach, March, Olszewski & Holan (1973).
Bile acid composition was determined as
described previously (Ahlberg et al., 1977) with the
exception that the methyl trimethylsilyl ethers were
analysed by gas-liquid chromatography on a 1%
Hi-Eff 8BP column.
Significance of differences were evaluated with
the paired /-tests and of linear regressions by
estimating the correlation coefficient, r (Snedecor
& Cochran, 1974). Mean values are given ±SEM.
Results
Body weights remained constant in all cases during
treatment with chenodeoxycholic acid. Seven
patients developed mild transient diarrhoea and for
four of them the dose had to be reduced for some
days. Serum aspartate aminotransferase (EC
2.6.1.1) and alanine aminotransferase (EC 2.6.1.2)
rose significantly after 4 weeks of therapy but in all
cases returned to normal after treatment ended.
Serum cholesterol concentrations remained un­
changed in all types of hyperlipoproteinaemia
during treatment with chenodeoxycholic acid
(Table 1). Serum triglycerides fell in type lib and in
type IV hyperlipoproteinaemia. In all patients
taken together, the triglycerides were reduced 1 5 20% during the treatment period.
The proportion of chenodeoxycholic acid in bile
increased in all subjects, from 28-8 ± 1-5 to 72.4 +
3-6% (P < 0-001), and the proportions of cholic
acid and deoxycholic acid decreased reciprocally,
from 41-2 ± 2-6 to 11-5 ± 1-6% (P < 0-001) and
from 29-6 ± 3-6 to 11-2 ± 2-5% (J> < 0-001)
respectively. Ursodeoxycholic acid was present in
trace or small amounts in only three patients before
treatment, and was increased by treatment with
chenodeoxycholic acid, from 0-2 + 0-2 to 3-2 +
0-7% {P < 0-001). Similarly, lithocholic acid was
present in small amounts in four patients before
treatment and also showed a rise during
medication, from 0-2 ± 0-2 to 1-7 ± 0-4% (P <
0-005). No patients with type Ila hyper­
lipoproteinaemia displayed an increase in litho­
cholic acid.
The mean biliary cholesterol saturation and the
lithogenic indices decreased in all patients but one
type lib (Table 1). A lithogenic index (Hegardt &
Dam, 1971; Holzbach et al., 1973) of >1·0
indicates supersaturated bile. Before treatment, all
patients except one type Ila and one type lib had
an index >l-0. During treatment, three type lib
and five type IV patients still had an index > 1 -0.
The cholesterol concentration (% of total biliary
lipids) and cholesterol saturation correlated
negatively with the proportion of chenodeoxycholic
acid in biliary bile acids (r = - 0 - 6 5 , P < 0-001,
and r = -0-67, P < 0-001 respectively; n = 34)
but positively with serum triglycerides (r = +0-47,
P < 0-01, and r = +0-48, P < 0-01 respectively; n
= 34). The change in lithogenic index correlated
weakly but significantly with the change in serum
triglycerides (r = +0-51, P < 0-05; n = 17).
Detailed results have been deposited as Clinical
Science and Molecular Medicine Table no. 77/26
with the Librarian, the Royal Society of Medicine
(1 Wimpole Street, London WIM 8AE), who
will issue copies on request.
453
Chenodeoxycholic acid in hyperlipoproteinaemia
TABLE 1. Serum lipids and biliary lipid composition in hyperlipoproteinaemic patients before and during
treatment with chenodeoxycholic acid (750 mglday; 1 ·9 mmol/day)
Figures in parentheses indicate numbers of subjects. Significantly different from pretreatment values (Student's
Significantly different from pretreatment valnes (Student's paired /-test): *P<005; **P < 0-02; ***P < 0-01;
paired (-test): *P < 0-05; **P < 002; ·**/> < 0-01; ****P < 0-005; *****/> < 0001.
Patients
Pretreatment
Treatment
4 weeks
8 weeks
Serum cholesterol (mmol/1)
Type Ha (7)
9-4 + 0-2
Type lib (8)
9-3 + 0-7
Type IV (8)
7-1 ±0-3
Total
(23) 8-6 + 0-3
9-6 + 0-4
9-1 +0-8
7-6 + 0-4
8-8 ±0-4
9-4 + 0-4
8-9 ±0-9
7-3 ±0-4
8-5 + 0-4
9-3
9-4
7.5
8-4
Serum triglycerides (mmol/1)
Type Ha (7)
1-7 + 0-1
Type lib (8)
3-6 + 0-4
Type IV (8)
4-7+0-5
Total
(23)
3-3 + 0-3
1-4 ±0-2
2-4 + 0-2**
3-9 + 0-5
2-6 ± 0-3****
1-5 + 0-2
2-6 ± 0-6**
4-0 + 0-5*
2-7 + 0-3*****
1-4 + 0-1
2-9 + 0-4*****
4-1 +0-7
2-8 + 0-4****
Biliary cholesterol (% of total biliary lipids)
Type Ha (4)
9-1 ± 1-3
Type lib (5)
9-0+1-0
Type IV (8) 11-3 + 0-7
Total
(17)
9-6 + 0-8
12 weeks
+0-3
+ 0-6
+ 0-5
+ 0-5
5-7 + 0-5*
7-2 + 0-9
7-6 + 0-7****
7-0 + 0-5***»
Biliary bile acids (% of total biliary lipids)
Type Ha (4) 66-9 ± 1-5
Type lib (5) 69-8 ±2-9
Type IV (8) 65-4 + 2-3
Total
(17) 67-0 + 1-4
72-9+ 1-2**
73-7 + 0-8
69-5 + 1-8
71-5 + 1-0***
Biliary phospholipids (% of total biliary lipids)
Type Ha (4) 24-0 ±0-4
Type lib (5) 21-2 ±2-1
Type IV (8) 23-3 ±2-3
Total
(17) 23-4 ± 1-2
21-4 ±0-7*
19-1 + 1-1
22-9+ 1-3
21-5 ±0-8
Lithogenic index (Admirand & Small, 1968)
Typella (4) 0-91 + 0-1
Type lib (5) 0-91 ±0-1
Type IV (8) 1-15 ± 0 1
Total
(17) 1-02 ±0-1
0-58 ±0-1*
0-74±0-l
0-77 + 0-1****
0-71 + 0-1*****
Lithogenic index (Hegardt& Dam, 1971;Holzbache(a/., 1973)
Typella (4) 1-25 + 0-1
Typellb (5) 1-34 + 0-1
Type IV (8) 1-63 ±0-1
Total
(17) 1-46 ±0-1
0-87 + 0-1*
1-20 + 0-2
1-10 ±0-1***
1-07+ 0-1*****
Discussion
Bile acid formation in man is regulated by a
negative feedback control triggered by the amount
of bile acids reaching the liver via the portal vein
(Hofmann, 1976). Expansion of the chenodeoxy­
cholic acid pool is associated with a reduced pool
size and formation of both cholic acid and
deoxycholic acid (Danzinger, Hofmann, Thistle &
Schoenfield, 1973; Kallner, 1975). In the present
study, after 3 months of treatment chenodeoxy­
cholic acid constituted about 70% of the biliary bile
acids. The small increases of ursodeoxycholic acid
and lithocholic acid are well known from studies in
normolipidaemic patients (e.g. Bremmelgaard &
Pedersen, 1976; Thistle, Hofmann, Yu & Ott,
1977; Danzinger et al, 1973; Coyne, Bonorris,
Chung, Goldstein, Lahana & Schoenfield, 1975;
Stiehl, Raedsch & Kommerell, 1975).
B. Angelin, K. Einarsson andB. Leijd
454
At the dose administered, chenodeoxycholic acid
reduced bile cholesterol saturation in all patients
except one. However, half of the patients still had
an oversaturated bile. The saturation index
correlated with the percentage of chenodeoxycholic
acid in duodenal bile, and above 80% chenodeoxy­
cholic acid only one patient had saturated bile. The
dose of chenodeoxycholic acid, about 10 mg/kg,
may have been too low, as Iser et al. (1975) now
recommend 14-15 mg/kg for non-obese subjects.
Administration of chenodeoxycholic acid was
followed by a 15-20% decrease in serum triglycerides. Miller & Nestel (1974) have shown
decreases of triglyceride concentration to parallel
reduction of the very-low-density lipoprotein frac­
tion. They suggested that chenodeoxycholic acid
inhibits triglyceride production. We have found (B.
Angelin, K. Einarsson, K. Hellström & B. Leijd,
unpublished work) that chenodeoxycholic acid
decreases triglyceride synthesis by 20-30% in
hyperlipidaemia.
The parallel decrease in serum triglyceride
concentrations and bile cholesterol and the
inhibition of bile acid synthesis by chenodeoxy­
cholic acid (Kallner, 1975) suggests an integrated
regulation of these variables (cf. Hellström,
Angelin, Einarsson, Kallner & Leijd, 1977). We
have shown that type IV hyperlipoproteinaemia is
associated with an increased occurrence of gall­
bladder disease (Einarsson et al., 1975) and an
elevated biliary cholesterol saturation (J. Ahlberg,
B. Angelin, K. Einarsson, K. Hellström & B. Leijd,
unpublished work). The lowering of biliary
cholesterol that accompanies the decrease of
triglyceride during treatment with chenodeoxy­
cholic acid may thus make this compound a useful
adjunct in hypolipidaemic therapy.
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