Review for 10.1186/1471-230X-13-13 (2013)

Reviewer's report
Title:Erythromycin versus neomycin in the treatment of hepatic encephalopathy
in cirrhosis: a randomized double-blind study
Version: 2Date:23 October 2012
Reviewer: Felix Gundling
Reviewer's report:
Review: major revisions necessary!
'Erythromycin versus neomycin in the treatment of hepatic encephalopathy in
cirrhosis: a randomized double-blind study' by Fernando G Romeiro, Fabio S
Yamashiro, Madileine F Américo, Luciana A Corá, Giovanni F Silva, José
Ricardo A Miranda and Carlos A Caramori
Romeiro and coworkers analyse the effect of the antibiotic erythromycin versus
neomycin in the treatment of hepatic encephalopathy in patients with cirrhosis.
Erythromycin represents an antibiotic with low complication rate while prokinetic
activity is a common side effect. Since disturbances of gastrointestinal motility
are frequent in patients with cirrhosis which seem to aggravate certain
complications of cirrhosis such as hepatic encephalopathy and infections, an
analysis of the effect of erythromycin upon severity and clinical course of HE is
very interesting.
However, the study contains several methodological problems which have to be
answered very carefully before the manuscript should be evaluated for
publication.
The most striking problem is the fact that the diagnostic procedures to evaluate
the severity and the clinical course of HE seem to be insufficient in this study.
While ammonia is considered as one of the major pathogenetic factors of
cerebral dysfunction in CLD (1) the utility and correct interpretation of blood
ammonia levels in patients with liver cirrhosis presenting with HE has been a
long-standing source of confusion since prospective clinical studies evaluating
the impact of ammonia for monitoring HE have revealed controversial results (2).
The accuracy of ammonia determination is influenced by many factors including
phlebotomy technique, rapid laboratory analysis on ice, arterial or venous
sampling and fasting periods which should be always considered when
interpreting results (3). Additionally, ammonia levels can be influenced by many
nonhepatic conditions, e.g. chronic renal disease, cigarette smoking or heavy
exercise. Therefore, ammonia determination is not a usef ul screening test for HE
while its correlation with grading of mental state according to West Haven Criteria
is arbitrary (4, 5).
Psychometric testing is only usefull to separate patients with minimal hepatic
encephalopathy from cirrhotics without HE, but not a procedure to divide HE in
several stages such as the West Haven criteria 1-4. Therefore, the separation of
patients in different severity stages of HE as it was done in the present study is
simply not correct.
At the same time, the authors should have used an objective diagnostic method
such as critical flicker frequency which represents the golden standard for
diagnosis of HE, especially in subtile stages. In two recently published articles
the value of critical flicker frequency (CFF) was described in patients with liver
cirrhosis and minimal hepatic encephalopathy (MHE), compared with
neuro-psychometric tests (6-7). CFF is a well-established neurophysiological
technique which measures the ability of the central nervous system to detect
flickering light. In the studies by Romero-Gómez and Sharma et al. the mean
CFF was a highly sensitive and reliable parameter for quantification of MHE
severity in cirrhotic patients with little age, day-time, and training dependency. A
convincing advantage of CFF towards alternative diagnostic testing e.g.
psychometric tests or neurophysiologic techniques which are time-consuming
and costly is its simple application which requires no experience d personnel.
Furthermore, the basic therapy of HE like rehydration, specific therapy of
complications, etc . should be described more precisely.
Additionally, there is a relationship between motility abnormalities and the
presence of certain complications such as ascites due to mechanic alteration of
the small bowel by intraabdominal fluids, etc. Therefore, some cirrhotics have
more motility problems than the others and might have a better effect of
erythromycin than patients without motility disturbances. This point should be
also reflected by the authors of the present manuscript.
Last but not least, the effect of H pylori infection and its eradication on
hyperammonemia and hepatic encephalopathy in cirrhotic patients was
investigated in several studies before. H pylori infection is an important factor for
inducing high blood ammonia concentration and HE in cirrhotic patients. H pylori
eradication may be helpful for treatment and prevention of HE. Since
clarithromycin represents a part of the antibiotic regime in Hp-eradication and
belongs to the same antibiotic class as erythromycin, the authors of the present
manuscript should discuss the published literature in that respect.
1. Butterworth RF, Giuere JF, Michaud J, et al. Ammonia: a key factor in the
pathogenesis of hepatic encephalopathy. Neurochem Pathol 1987;6:1-12.
2. Arora S, Martin CL, Herbert M, and al. Myth: Interpretation of a single
ammonia level in patients with chronic liver disease can confirm or rule out
hepatic encephalopathy. Can J Emerg Med 2006;8:433-435.
3. Wang V, Saab S. Ammonia levels and the severity of hepatic encephalopathy.
Am J Med 2003;114:237-238.
4. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy – definition,
nomenclature, diagnosis, and quantification: final report of the working party at
the 11th World Congress of Gastroenterology, Vienna, 1998. Hepatology 2002;
35:716-721.
5. Gundling F, Seidl H, Schmidt T, Schepp W. Blood ammonia level in liver
cirrhosis: a conditio sine qua non to confirm hepatic encephalopathy? Eur J
Gastroenterol Hepatol. 2008 Mar;20(3):246-7.
6. Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: Diagnostic
tool for minimal hepatic encephalopathy. J Hepatol. 2007;47:67-73.
7. Romero-Gómez M, Córdoba J, Jover R, del Olmo JA, Ramírez M, Rey R, de
Madaria E, Montoliu C, Nuñez D, Flavia M, Compañy L, Rodrigo JM, Felipo V.
Value of the critical flicker frequency in patients with minimal hepatic
encephalopathy. Hepatology. 2007;45:879-885.