Changes of Intestinal Functions in Liver Cirrhosis

TLDR: This review summarizes major achievements regarding intestinal dysfunction in cirrhosis for future gastroenterology research and suggests that delayed small bowel transit in liver Cirrhosis may lead to SIBO, which could contribute to the symptoms of abdominal pain and diarrhea.

Abstract: Background: Understanding of the gut-liver axis is important for the up-to-date management of liver cirrhosis, and changes of intestinal functions form the core o

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Liver and Gut: Review
Inflamm Intest Dis 2016;1:24–40
DOI: 10.1159/000444436
Changes of Intestinal Functions in
Liver Cirrhosis
HiroshiFukui 
a
ReinerWiest 
b
a
 Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, Kashihara , Japan;
b
 Department of Gastroenterology, University Hospital of Visceral Surgery and Medicine, Bern , Switzerland
has been reported to be present in up to 59% of cirrhotic
patients and is associated with systemic endotoxemia. Clin-
ical and experimental studies suggest that delayed small
bowel transit in liver cirrhosis may lead to SIBO, which could
contribute to the symptoms of abdominal pain and diar-
rhea. In addition to autonomic neuropathy, metabolic de-
rangements and diabetic state, SIBO itself may delay intes-
tinal transit in cirrhotic patients. Several studies, both from
the West and the East, have shown that the gut microbiota
is altered in cirrhotic patients and particularly those with HE.
Further, a quantitative change in Bacteroides/Firmicutes ra-
tio, with a prevalence of potentially pathogenic bacteria
(e.g., Enterobacteriaceae ) and reduction in specific commen-
sals (e.g., Lachnospiraceae ), has been described. Structural
and functional changes in the intestinal mucosa that con-
tribute to increases in intestinal permeability for bacteria
and their products have been observed in patients with liv-
er cirrhosis, which is considered as an important pathoge-
netic factor for several complications. The mechanism of
intestinal barrier dysfunction in cirrhosis is multifactorial,
including alcohol, portal hypertension (vascular congestion
Key Words
Small intestinal dysmotility · Small intestinal bacterial
overgrowth · Intestinal hyperpermeability · Bacterial
translocation · Endotoxemia · Liver cirrhosis
Abstract
Background: Understanding of the gut-liver axis is impor-
tant for the up-to-date management of liver cirrhosis, and
changes of intestinal functions form the core of this interest-
ing research field. Summary: Most investigators noted small
intestinal dysmotility in their patients with liver cirrhosis.
Marked changes in the contraction pattern were observed
in early manometric studies. The orocecal transit time, par-
ticularly small intestinal transit, has generally been reported
to be prolonged, which has been demonstrated in multiple
investigations to be related to the severity of the liver dis-
ease (e.g., Child-Pugh class), the presence of small intestinal
bacterial overgrowth (SIBO) and hepatic encephalopathy
(HE) as well as a history of spontaneous bacterial peritonitis.
Bacteriologically proven SIBO in proximal jejunal aspiration
Received: January 17, 2016
Accepted: February 4, 2016
Published online: March 8, 2016
Hiroshi Fukui, MD, PhD
Department of Gastroenterology, Endocrinology and Metabolism
Nara Medical University, 840 Shijo-cho
Kashihara, Nara 634-8522 (Japan)
E-Mail hfukui
 @  naramed-u.ac.jp
Reiner Wiest, MD
Department of Gastroenterology, University Hospital of Visceral Surgery and Medicine
Freiburgstrasse, CH–3010 Bern (Switzerland)
E-Mail reiner.wiest
 @  insel.ch
© 2016 S. Karger AG, Basel
2296–9403/16/0011–0024$39.50/0
www.karger.com/iid
H. Fukui and R. Wiest contributed equally to this work.

Changes of Intestinal Functions in Liver
Cirrhosis
Inflamm Intest Dis 2016;1:24–40
DOI: 10.1159/000444436
25
and dysregulation), endotoxemia, SIBO, local inflammation
and, most likely, immunological factors and medications.
Key Messages: This review summarizes major achieve-
ments regarding intestinal dysfunction in cirrhosis for fu-
ture gastroenterology research. The question of whether
this intestinal barrier dysfunction is accompanied and/or
at least partly caused by structural and functional changes
in the epithelial tight junction proteins is as yet unsolved.
Development of new strategies to modulate gut-liver inter-
action is urgently needed.
© 2016 S. Karger AG, Basel
Introduction
The passage of viable bacteria from the intestinal lu-
men through the intestinal wall as well as to mesenteric
lymph nodes and other sites, defined as bacterial trans-
location (BT), generally explains the cause of bacterial in-
fections, which increase mortality 4-fold in patients with
liver cirrhosis [1] . The concept of BT was later broadened
to include microbial products and/or their fragments,
such as endotoxin and bacterial DNA [1] . Because the gut
barrier system of intestinal epithelial cells prevents the
translocation of large amounts of bacteria and bacterial
products, we should pay more attention to changes of in-
testinal functions for the management of liver cirrhosis.
Small bowel dysmotility, small intestinal bacterial over-
growth (SIBO) and intestinal hyperpermeability are
mutually related and finally lead to pathological increases
in BT.
This review discusses intestinal dysfunction from var-
ious viewpoints. In addition, structural and functional
changes to the gastrointestinal tract developing in liver
cirrhosis are discussed. Specific guidelines on the topic do
not exist, but the European Association has recently pub-
lished a consensus statement on the diagnosis and treat-
ment of bacterial infections in liver cirrhosis [2] . The final
remark of the key points and outlook was that a develop-
ment of new strategies to modulate gut-liver interaction
is urgently needed.
Small Intestinal Dysmotility
We will first introduce Western studies, since almost
all data concerning small intestinal dysmotility come
from the Western world. Table 1 summarizes studies
comparing gastrointestinal motility in patients with liver
cirrhosis versus healthy controls. The methods of study-
ing intestinal motility are roughly divided into manom-
etry and measurement of transit time. Since the first
manometric motility study by Chesta et al.
[3] , various
studies have shown small intestinal dysmotility in pa-
tients with liver cirrhosis
[4] . Chesta et al. [3] investigated
fasting proximal small intestinal motility in 16 cirrhotic
patients and 8 healthy controls. Changes in intraluminal
pressure were sensed by the external transducers con-
nected to the perfused catheter in the small intestine. The
authors analyzed the mean duration and characteristics
of the migrating motor complex and found that cyclic ac-
tivity – noted in all healthy controls – was absent in 2 cir-
rhotic patients showing a prolonged phase 2-like pattern.
The duration of the cycles was significantly longer in the
remaining 14 patients with cirrhosis compared with con-
trols. Additionally, marked changes in the contraction
pattern during phase 2, characterized by multiple clusters
of contractions separated by quiescent periods, were not-
ed in cirrhotic patients [3] . Madrid et al. [5] studied mo-
tility by means of perfused catheters and external trans-
ducers in 33 patients with liver cirrhosis and related the
changes in the migrating motor complex to Child-Pugh
classes. Absence of cycling activity was most frequently
observed in Child-Pugh class C patients. In these ad-
vanced cirrhotics, increased frequencies and amplitudes
of clustered contractions were noted compared to Child-
Pugh class A patients. The authors thought these findings
might be related to the delayed transit time observed in
liver cirrhosis [5] . Gunnarsdottir et al. [6] showed with
their antroduodenojejunal pressure recordings that long
clusters were more common in cirrhotics with portal hy-
pertension than in healthy subjects. Combined with their
results from bacterial cultures of jejunal aspirates, they
speculated that portal hypertension per se might be sig-
nificantly related to the small intestinal abnormalities
observed in patients with liver cirrhosis.
Van Thiel et al. [7] showed that the orocecal transit
time (OCTT) of a lactulose load was longer in cirrhotics
with hepatic encephalopathy (HE) and increased as a
function of HE grade. The OCTT as measured with a
scintigraphic technique was also shown to be prolonged
in end-stage cirrhotic patients awaiting liver transplanta-
tion
[8] . Kalaitzakis et al. [9] showed by radiologic proce-
dure that 38% of patients with cirrhosis had prolonged
small intestinal transit, and that prolonged small intesti-
nal transit was related to diarrhea and abdominal pain. A
recent study utilizing a wireless motility capsule (Smart-
Pill)
[10] also revealed that decompensated cirrhotics
have slower intestinal transit times than compensated
cirrhotics and healthy controls.

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Inflamm Intest Dis 2016;1:24–40
DOI: 10.1159/000444436
26
Table 1. Studies comparing gastrointestinal motility in patients with liver cirrhosis versus healthy controls
Authors Country Cirrhotics, n Healthy
controls, n
Methods applied Main results
Chesta et al. [3],
1993
Chile (W) 16 8 Manometry Marked changes in the
contraction pattern during
phase 2 in cirrhosis
Gupta et al. [4],
2010
India (E) 102 (26 with cirrhosis
with SIBO, 76 with
cirrhosis without
SIBO)
– OCTT with the
lactulose breath test
OCTT was significantly
prolonged in cirrhotics with
SIBO compared with those
without SIBO
Madrid et al. [5],
1997
Chile (W) 33 (Child-Pugh A 8,
B 12, C 13)
– Manometry Clustered contractions and the
frequency and amplitude
of contractions were increased
from Child-Pugh class A to
class C
Gunnarsdottir et al.
[6], 2003
Sweden (W) 24 (12 with portal
hypertension,
12 without portal
hypertension)
32 Manometry with
antroduodenojejunal
pressure recordings
Long clusters were more
common in cirrhotics with
portal hypertension than
in healthy subjects
Van Thiel et al. [7],
1994
USA (W) 30 (10 without HE,
10 with subclinical
HE, 10 with grade 1
HE)
– OCTT by the lactulose
load
OCTT was longer in cirrhotics
with HE and increased
as a function of the hepatic
encephalopathy grade
Galati et al. [8],
1997
USA (W) 10 (advanced cirrhosis
undergoing evaluation
for orthotopic liver
transplantation)
10 OCTT with a
scintigraphic
technique
OCTT was longer in end-stage
cirrhotic patients awaiting liver
transplantation
Kalaitzakis et al. [9],
2009
Denmark (W) 42 Child-Pugh A (24),
B (15), C (3)
83 Small bowel transit
with the radiologic
procedure
38% of cirrhotics had
prolonged small bowel transit,
and that prolonged small bowel
transit was related to diarrhea
and abdominal pain
Chander Roland
et al. [10], 2013
USA (W) 20 (10 compensated,
10 decompensated)
(Historical
healthy
controls)
A wireless motility
capsule (SmartPill)
Decompensated cirrhotics had
slower intestinal transit times
as compared with compensated
cirrhotics and healthy controls
Sadik et al. [11],
2003
Sweden (W) 16 (10 male, 6 female) 83 Gastrointestinal transit
with a newly developed
radiological procedure
Small bowel residence time was
significantly longer in male
patients with alcoholic cirrhosis
as compared to male patients
with other causes of portal
hypertension
Chen et al. [12],
2000
Taiwan (E) 23 with HBV-related
liver cirrhosis, 26 with
chronic hepatitis B,
45 asymptomatic HBV
carriers
45 OCTT with the
hydrogen breath test
OCTT was delayed in patients
with HBV-related liver
cirrhosis but not in those with
chronic hepatitis B or in
asymptomatic HBV carriers
Chen et al. [13],
2002
Taiwan (E) 40 with HCC, 20 with
liver cirrhosis
40 OCTT with the
hydrogen breath test
HCC patients mostly with viral
liver cirrhosis showed delayed
gastrointestinal transit like
patients with viral cirrhosis

Changes of Intestinal Functions in Liver
Cirrhosis
Inflamm Intest Dis 2016;1:24–40
DOI: 10.1159/000444436
27
Authors Country Cirrhotics, n Healthy
controls, n
Methods applied Main results
Chang et al. [14],
1998
Taiwan (E) 40 (20 with a history
of SBP, 20 without a
history of SBP)
– Manometry with a
3-channel solid-state
manometric catheter
Small intestinal motility
dysfunction was more severe in
cirrhotic patients with a history
of SBP
Nagasako et al. [15],
2009
Brazil (W) 32 patients with
nonalcoholic cirrhosis
(Child-Pugh A, B)
8 OCTT with the
lactulose hydrogen
breath test
OCTT values were significantly
higher in Child-Pugh class B
patients than in controls
Madsen et al. [27],
2000
Denmark (W) 8 (postsinusoidal
hepatic pressure
gradient ≥13 mm Hg)
8 Small intestinal transit,
colonic transit
rates with the gamma
camera technique
No difference in small intestinal
mean transit time of liquid and
solid markers between patients
and controls; the patients had a
faster colonic transit
Chacko [28], 1997 India (E) 10 (decompensated
nonalcoholic male
cirrhotics)
10 (male
controls)
Total and segmental
colonic transit time
with a radiopaque
marker method
Total and left colonic transit
times were shorter in cirrhotics
as compared to healthy controls
Karlsen et al. [29],
2012
Denmark (W) 15 (with portal
hypertension; Child-
Pugh A 8, B 6, C 1)
18 Small intestinal
motility with a
magnet-based motility
tracking system; total
gastrointestinal transit
time by radiopaque
markers and
abdominal radiographs
Cirrhotics with portal
hypertension displayed a
faster-than-normal transit
through the proximal small
intestine
Sato et al. [18],
2012
Japan (E) 30 (Child-Pugh A 14,
B 11, C 5)
17 Electrogastrography
and
13
C octanoic acid
breath test
Half-time of gastric emptying
was significantly increased in
cirrhotics with PHG; the EGG
frequency increased at baseline
in all cirrhotics with PHG,
particularly in those with severe
PHG (more than in those with
mild PHG)
Gumurdulu et al.
[19], 2003
Turkey (E ) 24 (Child-Pugh A 8,
B 8, C 8)
25 Gastric scintigraphy Prolonged gastric emptying
half-time in cirrhotic
Child-Pugh class B/C patients
and/or autonomic dysfunction
(being significantly improved
with cisapride)
Ishizu et al. [21],
2002
Japan (E ) 25 18 Gastric scintigraphy Prolonged gastric emptying
half-time
Verne et al. [24],
2004
USA (W) 20 (Child-Pugh A 5,
B 8, C 7)
10 (HCV
without
cirrhosis)
Gastric scintigraphy Mean percentage of gastral
retention after 100 min was
significantly higher in cirrhotics
Charneau et al. [25],
1995
France (W) 18 (GAVE 8,
no GAVE 10)
8 Ultrasound Antral area half-time was
increased and the antral area
postprandially was reduced in
cirrhotics with GAVE as
compared to other groups
Table 1 (continued)

Fukui/Wiest
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DOI: 10.1159/000444436
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Sadik et al. [11] found that the small bowel residence
time was significantly longer in male patients with alco-
holic cirrhosis as compared to male patients with other
causes of portal hypertension, while that in female pa-
tients was not different from that in healthy subjects.
These findings suggest that the etiology of the liver dis-
ease and gender may influence transit in patients with
portal hypertension [11] .
Studies from Asia reported data on nonalcoholic cir-
rhosis. Using a noninvasive hydrogen breath test, Chen et
al. [12] from Taiwan reported that the OCTT was delayed
in patients with hepatitis B virus (HBV)-related liver cir-
rhosis but not in those with chronic hepatitis B or in as-
ymptomatic HBV carriers. They further reported that he-
patocellular carcinoma patients mostly with viral liver cir-
rhosis showed delayed gastrointestinal transit like patients
with viral cirrhosis
[13] . Chang et al. [14] showed that
small intestinal motility dysfunction was more severe in
cirrhotic patients with a history of spontaneous bacterial
peritonitis (SBP). There is another study from Latin Amer-
ica
[15] that reports delayed OCTT in Brazilian patients
with nonalcoholic cirrhosis of Child-Pugh class B. The po-
tential primary role of prolonged small intestinal transit as
for BT in patients with cirrhosis can be extrapolated from
a pilot trial in the UK showing that it precedes the appear-
ance of bacterial DNA in serum and ascites
[16] .
However, in liver cirrhosis not only the small intestine
is affected by dysmotility but also the stomach. This de-
serves mentioning here, since gastric motility is physio-
logically closely linked to small and large intestinal motil-
ity. A significantly prolonged gastric emptying time has
been reported in cirrhotic patients as compared to healthy
controls in multiple independent trials from the East [17–
21] and West [9, 22–25] . Delayed gastric emptying with
enhanced gastric accommodation and prolonged small
intestinal transit time appear to correlate with gastro-
intestinal symptoms (early satiety, postprandial fullness,
nausea, etc.) as well as with postprandial hyperglycemia,
hyperinsulinemia and hypoghrelinemia
[9, 26] . These al-
terations may be mediated at least in part by autonomic
dysfunction
[24] .
Although most studies have reported prolonged gas-
tric and small intestinal transit times (as stated above),
there still remain contradictory results. By means of a
gamma camera, Madsen et al.
[27] observed no difference
in small intestinal mean transit time of liquid and solid
markers between patients with well-characterized portal
hypertension and healthy controls, although the patients
Authors Country Cirrhotics, n Healthy
controls, n
Methods applied Main results
Miyajima et al. [20],
2001
Japan (E ) Child-Pugh A 7,
B/C 22
20 Electrogastrography Gastric dysmotility, particularly
postprandially (not basal) in
Child-Pugh class B/C patients
Kalaitzakis et al. [9],
2009
Denmark (W) 42 (Child-Pugh A 24,
B 15, C 3)
10 Radiopaque markers 24% of cirrhotic patients had
delayed half gastric emptying
time (correlated with
postprandial fullness and levels
of glucose, insulin and ghrelin)
Isobe et al. [17],
1994
Japan ( E ) 20 10 Gastric scintigraphy Prolonged gastric emptying
half-time correlated with
gastrointestinal symptom score
Balan et al. [22],
1996
UK (W) 57 (Child-Pugh A 47,
B 10)
16 Gastric scintigraphy No difference in gastric
emptying time
Pimpo et al. [23],
1996
Italy (W) 10 12 Ultrasound Delayed gastric emptying in
cirrhotics, which was
ameliorated with cisapride
Four studies [4, 5, 7, 14] subdivided cirrhotic patients based on SIBO, Child-Pugh classes, HE and history of SBP and compared them.
E = East; W = West; HCC = hepatocellular carcinoma; PHG = portal hypertensive gastropathy; GAVE = gastric antral vascular ectasia.
Table 1 (continued)