Received: 27 July 2023 | Accepted: 4 September 2023
DOI: 10.1097/HC9.0000000000000295
REVIEW
Lactulose in cirrhosis: Current understanding of efficacy,
Downloaded from by BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60EtgtdlLYrLzSPu+hUapVK5dvms8 on 10/13/2023
mechanism, and practical considerations
Patricia P. Bloom | Elliot B. Tapper
Department of Internal Medicine, Division of
Gastroenterology and Hepatology, University Abstract
of Michigan, Ann Arbor, Michigan, USA
HE is a complication of cirrhosis characterized by neuropsychiatric and
Correspondence motor dysfunction, and results in decreased quality of life and increased
Patricia P. Bloom, Division of Gastroenterology
and Hepatology, Department of Medicine,
mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966,
1500 E. Medical Center Drive, Ann Arbor, MI though many questions about its use remain unanswered. Lactulose
48104
Email: reverses minimal HE, prevents overt HE, improves quality of life, increases
the rate of recovery from overt HE, and improves survival rates. Lactulose’s
clinical effect appears to be derived from its impact on intestinal microbes,
likely a result of its enteric acidifying effect, positive pressure on beneficial
taxa, and improvement of gut barrier function. There are several practical
considerations with lactulose including (1) a need to avoid excessive bowel
movements and subsequent dehydration, (2) treatment titration protocols
need further investigation, (3) baseline or treatment-induced gastrointestinal
side effects limit adherence in some cases, and (4) the utility of monitoring
stool consistency or pH remains unknown. Further research is needed to
optimize our use of this effective treatment for HE.
INTRODUCTION in healthy adults, so lactulose makes its impact within the
intestinal lumen.[5] Lactulose’s clinical effect appears to
HE is a complication of cirrhosis characterized by be derived from its impact on intestinal microbes, likely a
neuropsychiatric and motor dysfunction. Manifestations result of its pH-lowering effect, positive pressure on
can range from subtle (minimal HE) to severe (overt HE) beneficial taxa, and improvement of gut barrier function.
and even coma. HE is associated with considerable
patient and caregiver burden, decreased quality of life,
and poor survival.[1–3] Lactulose has been used to treat CLINICAL EFFICACY OF
HE since 1966, yet our understanding of how to best L A C T U L O S E T O TR E A T H E P A T I C H E
use lactulose in clinical treatment plans and its
mechanism remains relatively unclear. Lactulose is an effective treatment for HE (Figure 1). A
Lactulose is a synthetic disaccharide composed of 1 Cochrane review including 38 randomized controlled
molecule of galactose and 1 molecule of fructose.[4] Only trials of nonabsorbable disaccharides found a beneficial
0.3% of lactulose is absorbed by the gastrointestinal tract effect on HE (RR = 0.58, 95% CI: 0.5–0.69).[6] Lactulose
Abbreviations: PEG, polyethylene glycol; SCFA, short-chain fatty acid.
-------------------------------------------------------------------------------------------------------
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Hepatology Communications. 2023;7:e0295. www.hepcommjournal.com | 1
, 2
| HEPATOLOGY COMMUNICATIONS
also reduced mortality to 8.5% in patients with cirrhosis Lactulose for minimal HE
and overt HE versus 14% among those with overt HE
not taking lactulose.[6] A network meta-analysis of 25 Lactulose therapy is associated with consistent
trials found that when comparing lactulose, rifaximin, improvements in health-related quality of life. This has
probiotics, and L-ornithine L-aspartate (an ammonia- been observed using validated indices such as the
lowering agent) for the treatment of minimal HE, Sickness Impact Profile,[21,22] Euro-QOL,[23] and the
lactulose was the only agent able to meet all 3 Modified Chinese Quality of Life Questionnaire.[24] The
Downloaded from by BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60EtgtdlLYrLzSPu+hUapVK5dvms8 on 10/13/2023
endpoints: reverse minimal HE, prevent overt HE, and impact is particularly clear for subscales involved in
improve quality of life.[7] Although many patients social activities, home management, emotional behav-
experience breakthrough overt HE episodes while on ior, and sleep functioning.[21,22] In a randomized trial of
lactulose,[8] lactulose withdrawal markedly increases crystalline lactulose for patients enrolled on the basis of
the risk of breakthrough in patients on rifaximin.[9] high activity impairment, 28 days of lactulose did not
significantly improve health-related quality of life meas-
ured using the Short Form-8 but did improve activity
Lactulose for overt HE impairment, sleep quality, and cognitive function meas-
ured using the Animal Naming Test.[25]
Lactulose is the first-line therapy for overt HE.[10] Despite
this recommendation, high-quality data are relatively
limited. Specifically, there are no controlled multicenter THERAPEUTIC MECHANISM OF
trials demonstrating lactulose efficacy for overt HE LACTULOSE
treatment or primary prevention. In the original controlled
studies of lactulose compared with sorbitol, it was Lactulose metabolism in the gut
effective at inducing resolution of altered mental status
and particularly after cross-over to lactulose after Lactulose is a synthetic disaccharide composed of one
sorbitol-induced worsened cognitive function.[11,12] Com- molecule of galactose and one molecule of fructose.[4]
pared with a glucose control, lactulose also increased the Only 0.3% of lactulose is absorbed by the gastrointestinal
rate of mental status recovery in overt HE.[13] In a tract in healthy adults, so lactulose makes its impact within
randomized trial, lactulose delivered by means of enema the intestinal lumen.[5] Lactulose is metabolized by
compared with tap water enemas was stopped early for bacterial enzymes into carbon dioxide and short-chain
efficacy.[14] Frequent lactulose doses until improving fatty acids (SCFAs).[4] Lactulose increases fecal nitrogen
mental status has been associated with improved excretion in rats with gut bacteria, but not in germ-free rats,
hospital length of stay in nonrandomized trials.[15,16] supporting the role of bacteria in lactulose metabolism.[26]
When combined with or when followed by large-volume
polyethylene glycol (PEG) colonic purges, the time to
mental status normalization is shortened.[17,18] Lactulose Lactulose absorption is minimal
is also highly effective for the secondary prevention of
overt HE episodes.[19] Breakthrough overt HE during In 2021, it was shown in multiple experiments involving
lactulose therapy is most often related to nonadherence healthy controls and patients with diarrhea-type irritable
(ie, consuming no or insufficient lactulose), but bowel syndrome that <0.4% of lactulose is absorbed using
closely followed by dehydration from excessive bowel radiolabeled ingestions.[5] The majority of that absorption
movements.[20] occurs in the small bowel, based on the finding that most
urinary lactulose is collected within 8 hours of consumption.
There was no effect of age, sex, or the presence of irritable
bowel syndrome on lactulose absorption. Another study
performed a multisugar test (designed to evaluate intestinal
permeability) in patients with compensated cirrhosis and
controls.[27] While they did not report the absorption of
lactulose alone, there was no difference in the absorbed
ratio of lactulose/rhamnose between patients with cirrhosis
and controls. Likely very little lactulose is absorbed by the
intestine, unmetabolized, in patients with cirrhosis.
Location of lactulose metabolism
F I G U R E 1 Clinical benefits of lactulose. Lactulose has multiple The geography of lactulose fermentation is challenging
clinical benefits for patients with cirrhosis and HE. to ascertain, because it is technically difficult to access
DOI: 10.1097/HC9.0000000000000295
REVIEW
Lactulose in cirrhosis: Current understanding of efficacy,
Downloaded from by BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60EtgtdlLYrLzSPu+hUapVK5dvms8 on 10/13/2023
mechanism, and practical considerations
Patricia P. Bloom | Elliot B. Tapper
Department of Internal Medicine, Division of
Gastroenterology and Hepatology, University Abstract
of Michigan, Ann Arbor, Michigan, USA
HE is a complication of cirrhosis characterized by neuropsychiatric and
Correspondence motor dysfunction, and results in decreased quality of life and increased
Patricia P. Bloom, Division of Gastroenterology
and Hepatology, Department of Medicine,
mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966,
1500 E. Medical Center Drive, Ann Arbor, MI though many questions about its use remain unanswered. Lactulose
48104
Email: reverses minimal HE, prevents overt HE, improves quality of life, increases
the rate of recovery from overt HE, and improves survival rates. Lactulose’s
clinical effect appears to be derived from its impact on intestinal microbes,
likely a result of its enteric acidifying effect, positive pressure on beneficial
taxa, and improvement of gut barrier function. There are several practical
considerations with lactulose including (1) a need to avoid excessive bowel
movements and subsequent dehydration, (2) treatment titration protocols
need further investigation, (3) baseline or treatment-induced gastrointestinal
side effects limit adherence in some cases, and (4) the utility of monitoring
stool consistency or pH remains unknown. Further research is needed to
optimize our use of this effective treatment for HE.
INTRODUCTION in healthy adults, so lactulose makes its impact within the
intestinal lumen.[5] Lactulose’s clinical effect appears to
HE is a complication of cirrhosis characterized by be derived from its impact on intestinal microbes, likely a
neuropsychiatric and motor dysfunction. Manifestations result of its pH-lowering effect, positive pressure on
can range from subtle (minimal HE) to severe (overt HE) beneficial taxa, and improvement of gut barrier function.
and even coma. HE is associated with considerable
patient and caregiver burden, decreased quality of life,
and poor survival.[1–3] Lactulose has been used to treat CLINICAL EFFICACY OF
HE since 1966, yet our understanding of how to best L A C T U L O S E T O TR E A T H E P A T I C H E
use lactulose in clinical treatment plans and its
mechanism remains relatively unclear. Lactulose is an effective treatment for HE (Figure 1). A
Lactulose is a synthetic disaccharide composed of 1 Cochrane review including 38 randomized controlled
molecule of galactose and 1 molecule of fructose.[4] Only trials of nonabsorbable disaccharides found a beneficial
0.3% of lactulose is absorbed by the gastrointestinal tract effect on HE (RR = 0.58, 95% CI: 0.5–0.69).[6] Lactulose
Abbreviations: PEG, polyethylene glycol; SCFA, short-chain fatty acid.
-------------------------------------------------------------------------------------------------------
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Hepatology Communications. 2023;7:e0295. www.hepcommjournal.com | 1
, 2
| HEPATOLOGY COMMUNICATIONS
also reduced mortality to 8.5% in patients with cirrhosis Lactulose for minimal HE
and overt HE versus 14% among those with overt HE
not taking lactulose.[6] A network meta-analysis of 25 Lactulose therapy is associated with consistent
trials found that when comparing lactulose, rifaximin, improvements in health-related quality of life. This has
probiotics, and L-ornithine L-aspartate (an ammonia- been observed using validated indices such as the
lowering agent) for the treatment of minimal HE, Sickness Impact Profile,[21,22] Euro-QOL,[23] and the
lactulose was the only agent able to meet all 3 Modified Chinese Quality of Life Questionnaire.[24] The
Downloaded from by BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60EtgtdlLYrLzSPu+hUapVK5dvms8 on 10/13/2023
endpoints: reverse minimal HE, prevent overt HE, and impact is particularly clear for subscales involved in
improve quality of life.[7] Although many patients social activities, home management, emotional behav-
experience breakthrough overt HE episodes while on ior, and sleep functioning.[21,22] In a randomized trial of
lactulose,[8] lactulose withdrawal markedly increases crystalline lactulose for patients enrolled on the basis of
the risk of breakthrough in patients on rifaximin.[9] high activity impairment, 28 days of lactulose did not
significantly improve health-related quality of life meas-
ured using the Short Form-8 but did improve activity
Lactulose for overt HE impairment, sleep quality, and cognitive function meas-
ured using the Animal Naming Test.[25]
Lactulose is the first-line therapy for overt HE.[10] Despite
this recommendation, high-quality data are relatively
limited. Specifically, there are no controlled multicenter THERAPEUTIC MECHANISM OF
trials demonstrating lactulose efficacy for overt HE LACTULOSE
treatment or primary prevention. In the original controlled
studies of lactulose compared with sorbitol, it was Lactulose metabolism in the gut
effective at inducing resolution of altered mental status
and particularly after cross-over to lactulose after Lactulose is a synthetic disaccharide composed of one
sorbitol-induced worsened cognitive function.[11,12] Com- molecule of galactose and one molecule of fructose.[4]
pared with a glucose control, lactulose also increased the Only 0.3% of lactulose is absorbed by the gastrointestinal
rate of mental status recovery in overt HE.[13] In a tract in healthy adults, so lactulose makes its impact within
randomized trial, lactulose delivered by means of enema the intestinal lumen.[5] Lactulose is metabolized by
compared with tap water enemas was stopped early for bacterial enzymes into carbon dioxide and short-chain
efficacy.[14] Frequent lactulose doses until improving fatty acids (SCFAs).[4] Lactulose increases fecal nitrogen
mental status has been associated with improved excretion in rats with gut bacteria, but not in germ-free rats,
hospital length of stay in nonrandomized trials.[15,16] supporting the role of bacteria in lactulose metabolism.[26]
When combined with or when followed by large-volume
polyethylene glycol (PEG) colonic purges, the time to
mental status normalization is shortened.[17,18] Lactulose Lactulose absorption is minimal
is also highly effective for the secondary prevention of
overt HE episodes.[19] Breakthrough overt HE during In 2021, it was shown in multiple experiments involving
lactulose therapy is most often related to nonadherence healthy controls and patients with diarrhea-type irritable
(ie, consuming no or insufficient lactulose), but bowel syndrome that <0.4% of lactulose is absorbed using
closely followed by dehydration from excessive bowel radiolabeled ingestions.[5] The majority of that absorption
movements.[20] occurs in the small bowel, based on the finding that most
urinary lactulose is collected within 8 hours of consumption.
There was no effect of age, sex, or the presence of irritable
bowel syndrome on lactulose absorption. Another study
performed a multisugar test (designed to evaluate intestinal
permeability) in patients with compensated cirrhosis and
controls.[27] While they did not report the absorption of
lactulose alone, there was no difference in the absorbed
ratio of lactulose/rhamnose between patients with cirrhosis
and controls. Likely very little lactulose is absorbed by the
intestine, unmetabolized, in patients with cirrhosis.
Location of lactulose metabolism
F I G U R E 1 Clinical benefits of lactulose. Lactulose has multiple The geography of lactulose fermentation is challenging
clinical benefits for patients with cirrhosis and HE. to ascertain, because it is technically difficult to access
