Comparison of the Effectiveness in Administration of Lactulose,

Probiotics and a Combination of Lactulose and Probiotics against

Hepatic Encephalopathy in Patients with Liver Cirrhosis

Fauzi Yusuf

, Wahyuni

, Azzaki Abubakar

, Desi Maghfirah

Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine University of Syiah

Kuala/ Dr. Zainoel Abidin Centre Hospital, Banda Aceh, Indonesia

Keywords: Hepatic Encephalopathy, Lactulose, Probiotics, Cirrhosis

Abstract : Hepatic Encephalopathy (HE) is one of the most common complication of decompensated liver cirrhosis.

In chronic liver disease there will be a disruption of ammonia metabolism resulting in an increase of 5-10

times ammonia levels which will disrupt the physiology of the brain and brain metabolism. Treatment with

laktulosa and probiotics can provide benefits in improving hepatic encephalopathy. The research subjects

were divided into three groups: group A consisted of 17 people receiving 30-60ml/day lactulose, group B

received one capsule probiotic taken three times per day (each capsule containing 2 billion of Lactobacillus

acidophilus Rosell-52, 2 billion of Lactobacillus rhamnosus Rosell-11 2, 211 mg of Maltodextrin, 8mg of

Magnesium stearate and 1 mg of ascorbic acid) and group C received both lactulose and probiotics. In our

study, we found that there was an improvement in the degree of Hepatic Encephalopathy from severe HE to

mild HE in two people (40%) from group A and one person (50%) from group C with p> 0.05.

1 INTRODUCTION

Liver cirrhosis is an end-stage progressive hepatic

fibrosis characterized by distortion of hepatic

architecture and regenerative nodule formation

(Nurjannah S, 2009). The Indonesian Liver Research

Association known as Perhimpunan Peneliti Hati

Indonesia (PPHI) stated that the prevalence of

patients with liver cirrhosis is 3.5% of all patients

treated in internal medicine inpatient unit, or an

average of 47.4% of all liver disease patients treated

(PPHI-INA ASL., 2013).

Hepatic Encephalopathy (HE) is one of the

most common complication of decompensated liver

cirrhosis. It is a neuropsychiatric syndrome found in

patient with both acute and chronic liver failure. The

clinical features are mental disorders, neurological

disorders, presence of liver parenchymal

abnormalities and laboratory abnormalities.

HE is

caused by the failure of hepatocellular function,

decreased ability of the liver to detoxify ammonia

and other toxins along with a portosystemic shortcut

causing toxic materials to enter the systemic blood

and brain directly without previously being cleaned

in the liver (Zubir N, 2009).

Lactulose has laxative characteristics causing

a decrease in the synthesis and uptake of ammonia

by decreasing colon pH and also reducing glutamine

uptake. Lactulose is converted into monosaccharide

by normal flora and used as a food source so that the

growth of normal intestinal flora will suppress other

bacteria that produce urease. This process produces

lactic acid and also gives hydrogen ions to ammonia

so that the molecules change from ammonia (NH

)

and become ammonium ions (NH

). The presence

of this ionization attracts ammonia from the blood

towards the lumen (Nielsen B et al, 2004; Luo M et

al, 2011). Sharma et al (2011) and Watanabe et al

(1997) found that lactulose is effective in preventing

HE in patients with liver cirrhosis and upper

gastrointestinal bleeding.

Probiotics are defined as non-pathogenic

living microorganisms, which if consumed in a

certain amount will give beneficial effects for the

host. Ammonia is also produced by flora in the

intestine so that manipulation of intestinal flora is

one of the HE therapy strategies. Probiotics given to

HE patients can reduce total ammonia in the portal

blood by decreasing bacterial urease activity,

decrease absorption of ammonia by decreasing pH,

decrease intestinal permeability and increase

nutritional status of intestinal epithelium and reduce

inflammation caused by oxidative stress in

hepatocytes thus increasing hepatic clearance of

Yusuf, F., Wahyuni, ., Abubakar, A. and Maghﬁrah, D.

Comparison of the Effectiveness in Administration of Lactulose, Probiotics and a Combination of Lactulose and Probiotics against Hepatic Encephalopathy in Patients with Liver Cirrhosis.

DOI: 10.5220/0008791000680071

In Proceedings of the 2nd Syiah Kuala International Conference on Medicine and Health Sciences (SKIC-MHS 2018), pages 68-71

ISBN: 978-989-758-438-1

ammonia and toxins and reducing toxin uptake (Saji

S et al, 2011; Bousvaros A et al, 2005).

Several studies have shown that lactulose and

probiotics have good ability to prevent the

recurrence of hepatic encephalopathy and

significantly show improvement in psychometric

tests in patients with mild hepatic encephalopathy.

This is the underlying purpose to compare the

effectiveness between the administration of

lactulose, probiotics and the combination of

lactulose and probiotics to patients with liver

cirrhosis and hepatic encephalopathy.

2 PATIENTS AND METHODS

2.1 Research Methods

Clinical trials with paired categorical analytic

studies was carried out in the internal medicine

inpatient unit at Dr. Zainoel Abidin Hospital in

Banda Aceh. The study samples were taken from

patients who were diagnosed with decompensated

cirrhosis with hepatic encephalopathy and fulfilled

the inclusion and exclusion criterias (diarrhea, using

alcohol ≥ 20 g/day, decreased level of consciousness

caused by other conditions than HE, having

spontaneous bacterial peritonitis for the past 6

weeks, and taking antibiotics such as Neomycin,

Metronidazole and Rifaximin).

The diagnosis of decompensated liver

cirrhosis is based on medical history, physical

examination, laboratory findings and abdominal

ultrasonography. The research subjects were taken

by consecutive sampling, then all research subjects

were carried out simple randomization with a

random table system and subjects were allocated

into three groups: A, B, and C. Group A was given

lactulose 30-60 ml per day until the patients secreted

soft defecation 2-3 times per day. Group B was

given one capsule probiotics three times per day

(each capsule containing 2 billion of Lactobacillus

acidophilus Rosell-52, 2 billion of Lactobacillus

rhamnosus Rosell-11, 211 mg of Maltodextrin, 8 mg

of Magnesium stearate and 1 mg of ascorbic acid).

And group C received both lactulose and probiotics.

The therapy is carried out for two weeks.

Ammonia examination using an ammonia test

kit was done by taking capillary blood from the

patient's fingertip as much as 20 µl, dropping it in

the reagent then inserting it into the device, the

results were read in µg/dl after 3 minutes.

Ethical clearance was obtained from the

Ethics Committee of the Faculty of Medicine, Syiah

Kuala University.

2.2 Operational Definition

Liver cirrhosis is diagnosed based on medical

history, physical examination, laboratory findings

and upper abdominal ultrasonography. Hepatic

encephalopathy is a disorder of cognitive function in

patients with liver disease that cannot be identified

only with complete medical history and neurological

examination including family member interviews.

To diagnose hepatic encephalopathy, we need to

find some abnormalities from neuropsychometric or

neurophysiological tests using NCT A/B and West

Haven criteria. In this study, HE degrees were

measured using West Haven criteria. Ammonia is a

major factor in the pathogenesis of hepatic

encephalopathy. Increased ammonia levels can be

due to high protein intake, constipation,

gastrointestinal bleeding, infection, azotemia,

hypokalemia. Normal level of blood ammonia is 0-

150 µg/dl.

2.3 Statistical Analysis

Statistical analysis was carried out by

computerization, with a significance level of p

<0.05. Normal data distribution was analysed by

repeated anova test and continued with Bonferroni

post-hoc analysis to find out which groups have

significant result.

3 RESULTS

The research subjects were divided into three

groups: 17 people in lactulose group, 17 people in

probiotic group and 17 people in lactulose +

probiotic group. During the research two people

from the lactulose + probiotic group resigned. The

number of subjects that followed the research until

the end were 49. The lactulose group received

standard cirrhosis therapy plus lactulose 30-60

ml/day, the probiotic group received standard

cirrhosis therapy plus probiotics 1 capsule 3 times

per day (each capsule containing 2 billion of

Lactobacillus acidophilus Rosell-52, 2 billion of

Lactobacillus rhamnosus Rosell-11, 211 mg of

Maltodextrin, 8 mg of Magnesium stearate and 1 mg

ascorbic acid), while the third group received both

lactulose and probiotics. The study was conducted

for two weeks and the parameters assessed were

Comparison of the Effectiveness in Administration of Lactulose, Probiotics and a Combination of Lactulose and Probiotics against Hepatic

Encephalopathy in Patients with Liver Cirrhosis

ammonia level in the blood and the degree of hepatic

encephalopathy. Before the study begins, all subjects

were examined for hepatitis B and C markers,

endoscopy examination, albumin level, bilirubin

level and liver function. We found that all the basic

characteristics in the subjects were the same in the

three groups.

Table 1. Basic Characteristics of The Subjects.

Variable

Groups

Lactulose

(n=17)

Probiotics

(n=17)

Lactulose

+Probiotic

(n=15)

Age (years) 53,11±12,81 56,41±12,97 57,86±17,42 p

>0,05

Gender

Male

Female

10(29,4%)

7(46,7%)

12(35,3%)

5(33,3%)

12(35,3%)

3(20,0%)

Liver cirrhosis

Etiology

HBV

HCV

Non B dan C

7(25,0%)

1(25,0%)

9(52,9%)

12(42,9%)

1(25,0%)

4(23,5%)

9(32,1%)

2(50,0%)

4(23,5%)

>0,05

HE degree (%)

Mild

Severe

12(30,8%)

5(50,0%)

14(35,9%)

3(30,0%)

13(33,3%)

2(20,0%)

>0,05

Endoscopy (%)

PHG

VE/PHG

12(42,9%)

3(50,0%)

2(13,3%)

6(21,4%)

3(50,0%)

8(53,3%)

10(35,7%)

5(33,3%)

>0,05

Albumin (g/dl) 2,50±0,43 2,55±0,61 2,46±0,43 p

>0,05

Bilirubin

(mg/dl)

6,15±8,23 3,21±2,39 4,16±6,18 p

>0,05

SGOT (U/1) 146,35±97,99 133,94±87,71 113,33±68,4

>0,05

SGPT (U/1) 92,94±66,21 94,82±73,87 91,80±63,77 p

>0,05

Ammonia

(ug/dl)

198,29±21,44 197,35±22,20 188,53±26,0

>0,05

HBV = Hepatitis B Virus, HCV = Hepatitis C Virus, HE = Hepatic Encephalopathy, VE

= Varices Esophagus, PHG = Portal Hypertension Gastropathy, SGOT = Serum

Glutamic Oxaloacetic Transaminase, SGPT = Serum Glutamic Piruvic Transaminase

There was a decrease in ammonia level in

average in all three groups around 194.97 ± 16.05

ug/dl. The reduction in ammonia level in each group

was statistically significant. But the difference

between the ammonia levels in the three groups is

8.59 ug/dl which is not statistically significant (p>

0.05).



Table 2. Ammonia level in three groups before and after two

weeks of therapy

Groups

Ammonia levels

before therapy

(ug/dl)

Ammonia levels

after two weeks

of therapy (ug/dl)

Lactulose

Probiotic

Lactulose+

Probiotic

198,29±21,44

197,35±22,20

188,53±26,04

136,11±19,99

143,76±29,73

129,93±22,4

p< 0,05

p < 0,05

There was an improvement in the degree of

hepatic encephalopathy from severe HE to mild HE

in two people from goup A (40%) and one person

from group C (50%). The improvement in HE

degree was not statistically significant (p> 0.05).



Figure 1. The change in the Hepatic Encephalopathy degree

before and after two weeks of therapy in the three groups.

4 DISCUSSION

Based on this study, there was a significant

reduction in ammonia level in the blood after two

weeks of therapy in the three groups. Lactulose can

reduce ammonia levels in the blood and improve the

results of psychometric tests thus affect the quality

of life of patients with liver cirrhosis who

experienced HE. The results of this study are

consistent with the study of Nie et al in 2003, who

conducted a study of lactulose administration for 8

to 28 weeks in patients with liver cirrhosis who had

hepatic encephalopathy. There was reduction in

ammonia levels in the blood, improved

psychometric tests and prevention of recurrent

encephalopathy (Nie YQ et al, 2003).

In 2011, Saji S et al. conducted a study by

administering probiotics to 21 patients with liver

cirrhosis who had been diagnosed with hepatic

encephalopathy for at least 6 months. The results

showed that ammonia levels decreased from 140.29

± 7.28 to 122.38 ± 10.69 and there was a significant

decrease in the second and third days compared to

the first day.

Probiotics can reduce blood ammonia

levels by increasing the concentration of non-urease

SKIC-MHS 2018 - The 2nd Syiah Kuala International Conference on Medicine and Health Sciences

bacteria and acting as a beneficial agent for the

balance of intestinal flora (Pawar RR et al, 2012).

In 2000, Dhiman et al. conducted a study by

administering lactulose for 3 months in subclinical

patients with hepatic encephalopathy. After that,

they performed NCT examination, FCT, block

design and picture assembly. And later, they found

some improvements in psychometric tests and

minimal hepatic encephalopathy.

In 2014, Shavakhi et al. administered probiotics

and lactulose to liver cirrhosis patients with mild

hepatic encephalopathy for 2 weeks and 8 weeks

follow-up. They found that lactulose and probiotics

were effective for minimal improvement of hepatic

encephalopathy. In comparison, probiotics are

superior to lactulose in improving hepatic

encephalopathy.

This study had several limitations. Firstly, the

number of samples was relatively small thus there

can be a bias in processing. Secondly, the

examination of hepatic encephalopathy only used

West Haven criteria, so we cannot assess the

changes in the degree of mild hepatic

encephalopathy to non-hepatic encephalopathy

which can be confirmed by a more accurate

examination such as Critical Flicker Frequency

(CFF). Thirdly, the limited time for the research

made us unable to observe the long term side effect

of lactulose and probiotics administration.

5 CONCLUSIONS

Administering lactulose, probiotics and a

combination of both probiotics and lactulose have

the same effectiveness in reducing ammonia levels

in the blood, as well as decreasing HE degree from

severe to mild degree.

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Comparison of the Effectiveness in Administration of Lactulose, Probiotics and a Combination of Lactulose and Probiotics against Hepatic

Encephalopathy in Patients with Liver Cirrhosis