Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.38048.506134.EE (Published 29 April 2004) Cite this as: BMJ 2004;328:1046
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We would like to applaud Bodil Als-Nielson et al. on their excellent
systematic review of randomised trials using lactulose/lactilol for
hepatic encephalopathy (HE), (1) which in our opinion has been warranted
for some time. We agree that non-absorbable disaccharides have been
introduced into clinical practice without any convincing evidence base,
but question the authors’ conclusion that there is ‘insufficient evidence’
to determine whether non-absorbable disaccharides are of benefit to
patients with HE. Surely, this comprehensive review clearly demonstrates
that lactulose is ‘ineffective’ for treatment of HE rather than there
being ‘insufficient evidence’. Furthermore, the results of this study have
several important implications:
(a) What should comprise standard medical therapy for HE? Lactulose should
no longer be included, but strict attention should be paid to treating the
precipitating factors, with correction of dehydration, electrolyte and
acid-base imbalance, (2) constipation and infection. (3)
(b) A plea for placebo controlled trials: There should be no restriction
on the conduct of placebo controlled studies on ethical grounds.
(c) We need to go back to the drawing board to revisit the interorgan
metabolism of ammonia and reference the recent studies which demonstrate
the important roles of the small intestine, muscle and kidneys in
regulating the blood levels of ammonia. (4)
Reference List
1. Als-Nielsen B, Gluud L, Gluud C. Non-absorbable disaccharides for
hepatic encephalopathy: systematic review of randomised trials. British
Medical Journal 2004; 328:1046-1050.
2. Jalan R, Kapoor D. Reversal of diuretic-induced hepatic
encephalopathy with infusion of albumin but not colloid. Clinical Science
2004; 106(5):467-474.
3. Shawcross D, Davies N, Williams R, Jalan R. Systemic inflammatory
response exacerbates the neuropsychological effects of induced
hyperammonemia in cirrhosis. Journal of Hepatology 2004; 40(2):247-254.
4. Olde Damink S, Jalan R, Deutz N, Redhead D, Dejong C, Hynd P et
al. The kidney plays a major role in the hyperammonemia seen after a
simulated or actual upper gastrointestinal bleeding in patients with
cirrhosis. Hepatology 2003; 37:1277-1285.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
I read with interest this systemic review conducted by a Cochrane
hepato-Biliary Group of researchers [1] who found the equivocal use of non
-absorbable disaccharides [NADs]and antibiotics in the treatment of
hepatic encephalopathy [HE], which may have acute or chronic
neuropsychiatric manifestations including mild delirium to deep coma and
other associated symptoms such as restlessness, hyperactivity and
sometimes agitation and aggressive spells. Hepatic encephalopathy is
attributed to excessive blood level of ammonia normally produced by gut
bacteria, which is not handled by deteriorating hepatic functions due to
chronic cirrhosis of liver or other hepatic-biliary diseases including
malignancies. Since long time, neomycin and other related antibiotics are
used as standard treatments of HE, which are reported to bring about
considerable improvements in patients with HE, by reducing the production
and absorption of ammonia. Clinical evidence very fairly suggested this
observation over long years of medical practice. As these antibiotics were
coupled with some adverse events mainly including development of
resistence and other severe effects, the alternative drugs were developed.
As a result, NADs that is lactulose and lactitol were used for the
treatment of patients with HE. These medications also clinically proved
their efficacy in hepatic encephalopathy and were found to have no major
adverse effects. When the use of antibiotics were compared with NADs in
patients with acute HE, equivocal differences were revealed but both drug
regimens were found to have good improvement in hepatic encephalopathy.
Moreover, in other trials, may be short or not fulfilling quality
standards, these medications when compared with placebo revealed good
results in patients with HE, ofcourse over placebo.
Now comes data from Cochrane Hepato-Biliary Group of researchers who
provided surprising results, which may undermine the effective, clinical
use of these medications in patients with hepatic encephalopathy. The
clinical experience and clinical evidence of effective use of NADs and
antibiotics over many years around the world is pushed aside just by one
systemic review. Now what are the alternative options for the treatment of
patients with acute or chronic hepatic encephalopathy. Liver
transplantation is one, which can alleviate the sufferings of patients
with HE but is it available to all patients who develop HE globally, as it
is very expansive and unaccessible to all with HE and also associated with
other medical misadventures. Therefore, the use of antibiotics and NADs
should continue until and unless there are more effective drugs with
excellent clinical profile to serve this treatment purpose.
Reference:
Bodil Als-Nielsen, Lise L Gluud, and Christian Gluud
Non-absorbable disaccharides for hepatic encephalopathy: systematic review
of randomised trials
BMJ 2004; 328: 1046-0
Competing interests:
None declared
Competing interests: No competing interests
Hepatic Encephalopathy: An immunologic response to chronic endotoxemia?
The need for a hepatic failure model for better understanding is
greater than meta-analyses of clinical trials
Dear Sir,
We read with great interest Bodil Als-Nielson et al. article on the
failed meta analysis of RCTs using lactulose / lactilol for hepatic
encephalopathy (HE) (1). Deficiencies in study design or quality can cause
meta-analysis to fail. If meta-analyses demonstrate a protective effect
from an intervention of more than 40%, it has a 60% probability of
correctly predicting results of the same magnitude of the largest trial
(2). A hepatic failure model illustrating the neurological complications
could prove more useful to the clinician.
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome
characterized by neuronal inhibition and damage probably by chronic
accumulation of endotoxins. The production of tumour necrosis factor-a
(TNF-a) is of the earliest events in hepatocyte injury, which trigger
cytokine production, damage hepatocytes and Kupffer cells release
transforming growth factor b which initiate fibrogenesis as the healing
response. Studies have shown that higher plasma levels of endotoxin and
TNF-a to be significantly associated with more blunted motor activities in
Sprague-Dawley rats with fulminant hepatic failure induced by
intraperitoneal thioacetamide (3). Serum levels of TNF-a correlate
strongly with the severity of encephalopathy in patients with chronic
liver failure (4). In the cirrhotic liver, impaired clearance of endotoxin
together with increased secretion of TNF-a by extrahepatic macrophages may
play an important role in the progression of hepatic and renal
disturbances (5).
Normal hepatocytes are resistant to TNF-a induced apoptosis, but
hepatocytes from rats with alcoholic liver disease die quickly after in-
vitro exposure to minute amounts of TNF-a (6). Recombinant granulocyte-
colony stimulating factor (rG-CSF) (7) and chylomicron pre-treatment (8)
have shown promising results in reversing histologically evident liver
injury and protecting against endotoxin-induced lethality in laboratory
animals, respectively. Endotoxemia without sepsis has been shown to be a
constant finding in cirrhosis and increasing levels of TNF-a are
associated with hepatic failure, encephalopathy, and death (9).
There is mounting evidence of the role of TNF-a and endotoxin-
inducible cytokines in the pathogenesis of hepatic encephalopathy. New
therapeutic agents that preferentially block TNF-initiated cell death
signalling merits evaluation as treatment in this serious and potentially
fatal disease.
References:
1.Bodil Als-Nielsen, Lise L Gluud, and Christian Gluud Non-absorbable
disaccharides for hepatic encephalopathy: systematic review of randomised
trials BMJ 2004; 328: 1046-0.
2.Villar J, Carroli G, Belizan JM. Predictive ability of meta-analyses of
randomised controlled trials. Lancet. 1995 Mar 25;345(8952): 772-6.
3.Chu CJ, Chen CT, Wang SS, Lee FY, Chang FY, Lin HC, Wu SL, Lu RH, Chan
CC, Huang HC, Lee SD. Hepatic encephalopathy in rats with thioacetamide-
induced fulminant hepatic failure: role of endotoxin and tumor necrosis
factor-alpha. Zhonghua Yi Xue Za Zhi (Taipei). 2001 Jun;64(6):321-30.
4.Chu CJ, Lee FY, Wang SS, Chang FY, Lin HC, Wu SL, Chan CC, Tsai YT, Lee
SD. Establishment of an animal model of hepatic encephalopathy. Zhonghua
Yi Xue Za Zhi (Taipei). 2000 Apr;63(4):263-9.
5.Odeh M, Sabo E, Srugo I, Oliven A. Serum levels of tumor necrosis factor
-alpha correlate with severity of hepatic encephalopathy due to chronic
liver failure. Liver Int. 2004 Apr;24(2):110-6.
6.Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, et al. GSH transport in
mitochondria: defence against TNF-induced oxidative stress and alcohol-
induced defect. Am J Physiol 1997;273:G7-G17.
7.Theocharis SE, Papadimitriou LJ, Retsou ZP, Margeli AP, Ninos SS,
Papadimitriou JD. Granulocyte-colony stimulating factor administration
ameliorates liver regeneration in animal model of fulminant hepatic
failure and encephalopathy. Dig Dis Sci. 2003 Sep;48(9):1797-803.
8.Harris HW, Grunfeld C, Feingold KR, Read TE, Kane JP, Jones AL, Eichbaum
EB, Bland GF, Rapp JH. Chylomicrons alter the fate of endotoxin,
decreasing tumor necrosis factor release and preventing death. J Clin
Invest. 1993 Mar;91(3):1028-34.
9.Bigatello LM, Broitman SA, Fattori L, Di Paoli M, Pontello M, Bevilacqua
G, Nespoli A. Endotoxemia, encephalopathy, and mortality in cirrhotic
patients. Am J Gastroenterol. 1987 Jan;82(1):11-5.
.
Competing interests:
None declared
Competing interests: No competing interests