S. F. Solga
Johns Hopkins Hospital, Baltimore, USA
Summary
Hepatic encephalopathy (HE) is a common and dreaded complication of liver disease. The effects of HE can range from minimal to life threatening. Even ‘minimal HE’ causes major dysfunction in manyaspects of daily living.The exact pathogenesis of HE remains unknown. However, the products of gut flora metabolism are universallyrecognized as critical. Present treatments for HE include the cathartic agent lactulose and poorly absorbableantibiotics. While effective, these treatments incur numerous side-effects and cost.Probiotics are viable bacteria given orally to improve health. Probiotics have multiple mechanisms of action thatcould disrupt the pathogenesis of HE and may make them superior to conventional treatment.
ª 2003 Elsevier Science Ltd. All rights reserved.BACKGROUND/SIGNIFICANCE
Disease and pathogenesis Hepatic encephalopathy (HE) is a common and seriouscomplication of chronic liver disease. This complex neuropychiatric syndrome has been defined as ‘a disturbancein central nervous system function because of hepatic insufficiency’ (1). At least 50–70% of patients with cirrhosis will demonstrate abnormalities on pyschometric testing (2,3), and many will have significant functional impairment. Encephalopathy can occur in patients with both acute and chronic liver disease, and can be clinically overt or less apparent.
‘Minimal encephalopathy’ is a term that describes patients with chronic liver disease who have no clinical symptoms of brain dysfunction, but perform substantially worse on pyschometric tests compared to healthycontrols (4). An extensive body of research has consistently documented cognitive deficits in these patients, including impaired psychomotor speed, attention, and visual perception. Predictably, such impairments lead tomajor difficulties in safely performing routine activities
of life. Landmark work by Schomerus et al. (5) demonstratedthat 60% of cirrhotics with minimal HE were
unfit to drive, and an additional 25% were possibly
unfit to drive. In agreement with this finding, other
investigators have found impaired earning capacity,
particularly amongst blue-collar workers requiring psychomotor
skills in order to perform their jobs (6). Further,
extensive work using a 136 part ‘sickness impact
profile’ (a generic, non-disease-specific quality of life
questionnaire) found that minimal HE has major impact
on all aspects of a patient’s life (7).
Clinically apparent encephalopathy has been subdivided
into a semi-quantative grading scheme ranging
from mild (grade I) to severe (grade II–IV). According to
the West Haven Criteria (8), grade I encephalopathy indicates
a patient with ‘trivial lack of awareness, euphoria
or anxiety, shortened attention span, and impaired performance
of addition’. At times, clinicians may have
difficulty distinguishing these patients from patients
with minimal encephalopathy.
The pathogenesis of HE is unknown, but is almost
certainly multi-factorial. Gut-derived nitrogenous substances
are universally acknowledged to play a major
role. Specifically, ammonia is thought to be a critical
factor in the pathogenesis. While ammonia is produced
by many tissues, most results from the activity of urease
307
Received 3 September 2002
Accepted 11 November 2002
Correspondence to: Steven F. Solga MD, 600 North Wolfe Street, Blalock 4,
Division of Gastroenterology, Johns Hopkins Hospital, Baltimore, MD 21205,
USA. Phone: 410-502-7729; Fax: 410-955-2108;
E-mail: solga@jhmi.edu
Medical Hypotheses (2003) 61(2), 307–313
ª 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0306-9877(03)00192-0
producing gut flora and is released into the portal vein
after absorption by the intestinal epithelium. Ammonia
is converted into urea in the liver, carried to the kidneys,
and then excreted into the urine. Normally a very efficient
process, humans excrete over 20 pounds of urea a
year (9) and first pass hepatic clearance of ammonia is
around 80% (10). See Fig. 1.
Further understanding of urease and ammonia is important
to the pathophysiology of HE and potential
treatments. Urease-producing bacteria exist in abundance
in the gut of ‘ureolytic’ animals (11). Ureolytic
animals, including humans, excrete nitrogenous waste
primarily via urea in the urine. Urease is a bacterial
enzyme that catalyzes the hydrolysis of urea to carbamate
and ammonia (12). Bacteria from many different
genera produce urease, and its expression can be nitrogen
regulated, urea inducible, or constitutive (13). Urease-
producing bacteria are frequently gram negative
Enterobacterceae. The potential therapeutic consequences
of blocking urease activity were established
decades ago by demonstrations that injection of antiurease
antibodies reduced ammonia production and
improved encephalopathy (14). Such ‘immunization’
against urease, however, caused many side effects and
was ultimately abandoned (15).
Ammonia is a weak base with a pKa of 9.25 (16).
Therefore, decreases in lumenal pH increases the ratio of
ionized to unionized ammonia, and decreases passive
non-inonic diffusion. As a result, less ammonia is absorbed
into the portal blood and more is excreted in
feces (17). Further, lower lumenal pH itself reduces the
degradation of nitrogenous compounds (proteins and
amino acids) and production of ammonia (18).
The physiologic balance of ammonia production and
clearance is disrupted on multiple levels in patients with
cirrhosis, resulting in HE. An extensive body of evidence
reports that cirrhotics harbor more gut urease-active
bacteria than controls (19), and that this leads directly to
increased intestinal hydrolysis of urea and absorption of
nitrogenous products (20). Altered small intestinal
dysmotility frequently accompanies cirrhosis (21) and
likely exacerbates this problem. Further, increased portal
ammonia results in markedly increased systemic ammonia
because of: (1) impaired hepatic processing of ammonia
and (2) the shunting of portal blood away the
liver. Finally, ammonia crosses the blood–brain barrier
more readily patients with HE (22), where it acts on
impaired astroctyes and results in a cascade of pathopysiologic
neurochemical events (23). See Fig. 2.
Other gut-derived toxins may also play a role in the
pathogenesis of HE (24). For example, intestinal flora
may produce benzodiazepine-like substances (25) or
mercaptans (26) which can be additive or synergistic to
the effects of ammonia. The importance of gut-derived
products for HE is further supported by the efficacy of
complete surgical exclusion (e.g., total colectomy) in the
treatment of refractory HE (27).
Standard treatment options
Presently, lactulose and poorly absorbable antibiotics
are the mainstay of treatment for HE. Lactulose is a nonabsorbable,
synthetic disaccharide that has multiple effects
on gut flora and, therefore, several potential
mechanisms of action. Its most obvious effect is as a
laxative; however, laxatives alone (e.g., water enemas)
(28) are ineffective for HE. Additional putative mechanisms
for the efficacy of lactulose may include:
1. Decreasing ammonia production by decreasing urease
activity and increasing assimilation of nitrogenous
products by bacteria;
2. Acidifying the colon contents resulting in a decrease
in ammonia absorption into the gut; and
3. Decreasing toxic C4–C6 short chain fatty acid production
by enhancing the production of non-toxic
acetate (29).
Finally, lactulose may function as a prebiotic in the
treatment of hepatic encephalopathy (30). A ‘prebiotic’ is
defined as ‘a non-digestible food ingredient that
Fig. 1 Normal physiology. (A) Urease producing gut flora cleave urea in an enzymatic process resulting in net ammonia production. (B) Portal
blood is then processed in the liver where most of it is cleared, allowing for normal brain function, (C).
308 Solga
Medical Hypotheses (2003) 61(2), 307–313 ª 2003 Elsevier Science Ltd. All rights reserved.
beneficially affects the host by selectively stimulating
the growth and/or activity of one or a limited number of
bacteria in the colon, and thus improves host health’
(31). Specifically, lactulose significantly increases concentrations
of bifidobacteria and lactobacilli, and may
have therapeutic effect through the mechanisms of
these flora (32,33).
Non-absorbable antibiotics, principally neomycin and
metronidazole, are also effective, presumably by killing
gram negative and anaerobic urease producing bacteria.
Further treatments can include dietary protein restriction
(34), ornithine salts (35), and benzoate (36), although
the latter are rarely used in practice.
While these treatments are effective, they impose side
effects, toxicities, and cost. Lactulose has an unpleasant
taste and causes flatulence and diarrhea. Due to unpredictable
dose–responses, the diarrhea can be severe and
result in hypertonic dehydration with hypernatremia
with subsequent hyperosmolarity and altered mental
status (37). Neomycin causes auditory loss, renal failure,
diarrhea, and staphylococcal superinfection. Metronidazole
neurotoxicity can be severe in cirrhotics (38).
Antibiotics alter flora and result in bacterial resistance.
Even dietary recommendations come with disadvantages;
compliance is low, and an overly negative protein
balance lead to loss of muscle mass and susceptibility to
infections (39).
As a result of these concerns, clinicians and patients
at times under-appreciate and under-treat HE, and often
overlook minimal HE. Clearly, safe, well-tolerated, inexpensive
alternatives are needed.
Rationale for probiotics
Probiotics may have multiple beneficial effects in the
treatment of minimal HE. In principle, probiotics may
exhibit efficacy in the treatment of hepatic encephalopathy
by:
1. Decreasing total ammonia in the portal blood by:
(a) decreasing bacterial urease activity,
(b) decreasing ammonia absorption by decreasing pH,
(c) decreasing intestinal permeability,
(d) improving nutritional status of gut epithelium.
2. Decreasing inflammation and oxidative stress in the
hepatocyte leading to increased hepatic clearance of
ammonia and other toxins.
3. Decreasing uptake of other toxins.
These processes may be additive or synergistic in treating
minimal HE.
First, by altering gut flora composition, selected viable,
non-pathogenic bacteria can directly decrease ammonia
production and absorption. This can be
accomplished by changes in gut metabolism and pH, gut
permeability, and the nutritional status of gut epithelium.
As noted above, urease is a critical enzyme of
bacterial lumenal metabolism that results in ammonia
production and increased pH. Increased ammonia generation
and higher pH accelerate ammonia absorption
into the portal blood; decreased pH result in decreased
ammonia absorption. Probiotics may alter this process
by competitive inhibition with urease-producing bacteria
and increasing lumenal bacteria concentration. Experimental
evidence (presented below) have proven
these mechanisms in humans. The exact mechanism by
which probiotics have been shown to decrease fecal
urease activity and pH are uncertain, but probiotics have
been demonstrated to result in reduced concentrations
of many bacteria (40), particulary gram negatives that
produce urease. Further, probiotics improve human intestinal
permeability in experimental models (41).
In addition, some have proposed that probiotics may
Fig. 2 Pathophysiology in cirrhosis. Intestinal dysmotility (A) exacerbates overgrowth of ureaseþ bacterial (B) and increased absorption
of nitrogenous products (C) into the portal blood. Shunting (D) and impaired hepatic processing (E) result in increased systemic exposure
to an impaired blood–brain barrier (F) and astrocyte dysfunction (G) results.
Probiotics can treat hepatic encephalopathy 309
ª 2003 Elsevier Science Ltd. All rights reserved. Medical Hypotheses (2003) 61(2), 307–313
enhance intestinal epithelial viability by providing essential
nutritional support (e.g., medium chain fatty acids)
that inhibits apoptosis of lumenal epithelial cells
(42). Thus, there are numerous possible mechanisms by
which probiotics could decrease the absorption of ammonia
into the portal blood.
Second, an extensive body of research has demonstrated
that gut-derived inflammatory signaling adversely
effects the hepatocyte itself, and that therapy
directed against gut flora (e.g., probiotics) can limit or
reverse this damage. These observations were first made
in rodent studies that identified a pathogenic role for
intestinal bacteria in alcohol-induced liver disease.
When ethanol-fed rats are given neomycin (to partially
decontaminate the gut) polymyxin (43) (to bind lipopolysacchride
(LPS) and reduce its translocation from the
intestinal lumen into the mesenteric blood) or lactobacillus
(44) (to modify intestinal flora), they are protected
from alcohol-induced liver damage. This protective effect
is the result of reduced hepatic exposure to intestinal
products, such as LPS, that promote the release of the
pro-inflammatory cytokine, tumor necrosis factor alpha
(TNFa), from hepatic macrophages.
Similar mechanisms are now acknowledged to be
important for the pathogenesis of both alcohol-related
and non-alcohol related fatty liver disease (45,46), and a
growing body of evidence suggests that the same
mechanism may also contribute to liver damage caused
by other hepatotoxins. Accordingly, there may be a
common mechanism (namely, LPS-induced hepatotoxicity)
that explains how diverse insults lead to liver
damage (47). Such damage, in turn, disrupts normal
hepatocyte function and leads to mitochrondial oxidative
stress. Ultimately, the hepatocyte is impaired, and
the clearance of toxins (including ammonia) is reduced.
Treatment with probiotics may be ideal because they
may protect against inflammation and hepatocyte damage
from intestinal flora due to numerous mechanisms.
As noted above, this has already been demonstrated in
rodent models of alcohol liver disease. Recent work on a
murine model of non-alcoholic fatty liver disease also
supports this concept. These investigators found
improvement in numerous molecular markers of
inflammation (i.e., NfK-B and TNFa) in the livers of mice
that were fed oral probiotics (48).
Third, probiotics might inhibit the uptake of toxins
other than ammonia that have not yet been identified.
This notion is supported by research in patients with end
stage renal disease on hemodialysis. These patients often
have altered mental status due in part to gut-derived
toxins, such as phenol and indican, that not cleared by
dialysis. Trials of lactic acid probiotics in humans with
end stage renal disease to alter the gut flora and consequently
reduce such toxins have demonstrated efficacy
(49,50). As noted above, some of the efficacy lactulose
may indeed derive from its action as a ‘prebiotic’ encouraging
the growth of the same lactic acid bacteria
used in probiotics. Probiotics are inexpensive, safe, and
have no known negative long-term effects. This hypothesis
is especially timely given that the expanding list
of positive effects of probiotics are delineated by various
laboratories (51,52). Further, probiotics are a natural
therapy and, as such, are widely accepted by the public.
Indeed, they are sometimes considered part of complementary
or alternative medicine (CAM). Studies consistently
demonstrate extensive use of CAM by patients,
including those with liver disease (53).
PRELIMINARY DATA
The study of hepatic encephalopathy has been greatly
hindered by the lack of properly designed therapeutic
trials (54). According to a recent consensus statement,
criticisms that apply, to some degree, to all trials include
‘the large spectrum of clinical conditions summarized
under the [term hepatic encephalopathy], the definition
of study endpoints, the treatment of control groups, and
the methods used to quantify therapeutic effects (55)’.
Unfortunately, no useful animal models exist to study
minimal hepatic encephalopathy. Accordingly, preliminary
data must nevertheless come from relevant
human trials and consideration of the relevant mechanisms
of action.
All four published studies on the effect of probiotics
on hepatic encephalopathy have demonstrated efficacy
(56–59). These trials employed high doses of non-
Summary of putative mechanisms
Alter flora,
+ N4þ production
+ Intra-luminal pH,
+ N4þ absorption
Alter short chain
fatty acid production
+ Intestinal
permeability
+ Inflammatory
signaling, mitochondrialoxidative
stress in
hepatocyte
+ Absorption of
other toxins
Lactulose
p p p
Antibiotics
p
Probiotics
p p p p p p
310 Solga
Medical Hypotheses (2003) 61(2), 307–313 ª 2003 Elsevier Science Ltd. All rights reserved.
urease-producing bacteria, either Lactobacillus acidophilus
or Enterococcus faecium SF68. Because these studies
did not employ highly concentrated, viable bacteria, they
required frequent dosing and/or ingestion of a large
quantity of fluid (up to a liter). Further, the mechanisms
of action of these probiotic strains in liver disease or
hepatic encephalopathy are uncertain, and have not
been thoroughly studied with this interest in mind. Finally,
these studies were small, lacked a placebo controlled
design and firm, well-established endpoints.
Nevertheless, their success demonstrates a certain ‘proof
of principle’ that warrants further attention.
One possible probiotic compound that might be ideally
suited to HE is the highly concentrated combination
probiotic, VSL#3.This product contains 5 1011 cfu/g of
viable, lyophilized bifidobacteria (Bifidobacterium longum,
Bifidobacterium infantis, and Bifidobacterium
breve), lactobacilli (L. acidophilus, Lactobacillus casei,
Lactobacillus delbrueckii subsp. Lactobacillus bulgaricus,
and Lactobacillus plantarium) and a mixture of Streptococcus
thermophilus strains. Viability has been proven by
stool collection (60). Potential advantage for its application
to HE include:
1. VSL#3 has been shown to reduce stool urease activity
in humans.
2. VSL#3 has been shown to reduce stool pH in humans.
3. VSL#3 alters production of short chain fatty acids in
humans.
4. VSL#3 improves intestinal permeability and decrease
inflammatory signals in murine and human colonic
cell culture models.
First, VSL#3 has been proven to reduce stool urease activity.
In a clinical trial (61), 10 patients with irritable
bowel syndrome or functional diarrhea were given
VSL#3, and urease activity was measured at study entry,
20 days after VSL#3 administration, and 10 days after
discontinuation. The investigators found a greater than
50% reduction during VSL#3 administration, and a
subsequent return toward baseline levels upon discontinuation.
Second, VSL#3 is proven to reduce stool pH (60). Stool
specimens were studied in 20 patients with ulcerative
colitis who were intolerant of or allergic to 5-aminosalicylic
acid in order to determine the impact on fecal composition
by VSl#3. Stool composition of component
bacteria all increased significantly. Of particular interest is
that the stool pH dropped significantly (p < 0:005) and
remained stable throughout the treatment. Since uptake
of nitrogenous compounds is favored by a higher pH and
diminished by a lower pH, this effect could have a major
impact on ammonia generation in patients with cirrhosis.
Further, VSL#3 may reduce short chain fatty acids,
including butyrate in particular. In vitro culture of
human ileostomy effluent inoculated with VSL#3 demonstrated
a decrease in short chain fatty acids and butyrate
compared to control (62). VSL#3 also improves
intestinal permeability and decreases inflammatory signaling
in murine colitis models (the interleukin-10
knockout mouse) and human colonic cell cultures (T84
monolayers) (63). Oral VSL#3 for four weeks lead to decreases
in mucosal secretion of the pro-inflammatory
cytokines TNFa and interferon c and increased resistance
to samonella invasion.
Finally, as noted previously, an attribute shared by all
probiotics is their intrinsic safety and tolerability.
CONCLUSIONS
Hepatic encephalopathy is a serious and common complication
of liver disease. While the exact pathogenesis
remains uncertain, nitrogenous products of gut flora
metabolism certainly play a critical role. Present treatment
strategies, including lactulose and poorly absorbable
antibiotics, may not be optimal therapy for all
patients with liver disease due to side-effects and cost.
Compliance with therapy, particularly for minimal HE, is
often low.
Probiotics have multiple mechanisms of action that
may make them superior to conventional therapy. Since
probiotics are a safe, natural, well-tolerated therapy appropriate
for long-term use, probiotic therapy for HE
may be ideal. Amongst presently available probiotic
products, VSL#3 may be best suited for this purpose.
This hypothesis should be tested in rigorously designed
clinical trials.
ACKNOWLEDGEMENT
The author would like to acknowledge Anna Mae Diehl, MD, for
advice and support.
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