Date sent: 22-04-2013
Date comments sent back:

Name of peer reviewer: Fernando Gomes Romeiro

General comments:

The article is fairly justified, not only because previous articles recommended the use of dopamine agents in cases of hepatic encephalopathy. These previous articles were written a long time ago, and they have other recommendations that are now considered outdated. The main reason for the present article is the large number of patients suffering of severe hepatic encephalopathy, and in many of them the symptoms are refractory to the treatments available. Being so, any treatment that could be useful for them deserves an accurate research, and the author’s did a good job in this review. As far as I am concerned, their task was difficult because they worked with a few articles comparing dopamine agents with placebo. Regarding the treatment used, two of these articles included patients receiving bromocriptine and three included patients receiving levodopa. All of these articles compared the dopamine agents with placebo, because the authors decided to exclude two other articles comparing dopamine agents to lactulose and neomycin. However, two of the five articles analysed included only patients without cirrhosis and the three remaining articles included only cirrhotic patients. Thus, the few articles analysed evaluated a different disease profile, and it was a clear drawback in the present review. According to the author’s opinion, the excluded articles would not improve their findings, since they are small and low-quality studies, and there are no other articles that could be included. Despite the problems caused by the low number of trials evaluated and the big differences among them, the review describes its limitations and explains their causes.

Major comments

I) In the abstract and in the background (pages 1 and 2), the authors commented on extrapyramidal symptoms and changes in basal ganglia of patients with hepatic encephalopathy. In fact, these findings are not exclusively seen in hepatic encephalopathy, and many of these patients can also have another disease that was not mentioned in the text, named acquired hepatocerebral degeneration. The disease is not rare (11), and deserves some comments in this review. Manifestations in acquired hepatocerebral degeneration vary from Parkinsonism to dystonia. The patients can have extrapyramidal symptoms, changes in basal ganglia and hepatic encephalopathy, and dopaminergic agents (like levodopa) are very useful for them (5,6,11,12). The multiple bouts of hepatic coma are the only known risk factor for this disease (15). Therefore, patients with hepatic encephalopathy are the main population that can have acquired hepatocerebral degeneration, and these two conditions can coexist in the same patients (11,12). As dopamine agents are mainly used to control movement disorders in diseases like the acquired hepatocerebral degeneration and the authors cited findings that can be seen in both conditions, the text must include a short comment explaining that the review is limited to hepatic encephalopathy without acquired hepatocerebral degeneration. Otherwise this review can lead to misinterpretations by doctors who are not familiar with these two conditions. The use of dopamine agents in acquired hepatocerebral degeneration would be an issue for another review.

II) In “Types of participants” (page 3), the authors wrote “The diagnostic criteria could include psychometric tests, clinical scoring systems (such as the West-Haven Criteria), electroencephalography (Guerit 2009), or biochemical findings (including ammonia levels).” Ammonia levels or any other biochemical findings cannot be used as diagnostic criteria of hepatic encephalopathy (1,2,8,10,13,14). The text must be corrected.

Minor comments

I) In some parts of the text (“Description of the condition”, “Description of the intervention” and “Types of participants” - pages 2 and 3) the authors divided the hepatic encephalopathy course as episodic or chronic. Actually, the classification is of episodic or persistent hepatic encephalopathy (3,4). The text should be corrected.

II) In the first paragraph of the “Plain language summary” (page 2), the authors wrote that the symptoms often were developed after infections, dehydration and bleeding. They did not include hyponatremia, which is a relevant trigger factor that should be mentioned. Furthermore, it has been considered a special form of encephalopathy in cirrhotic patients, so it is advisable to include hyponatremia as a common trigger factor for this condition (7,9).

III) On page 6 the authors explained why they excluded two trials with active comparison groups. Personally, I disagree with the authors because maybe some of the articles excluded could improve the results of this review. I agree that the excluded articles had low quality, but two articles comprised in this review contained only patients with fulminant hepatitis (without cirrhosis), and two articles with cirrhotic patients included only 6 or 7 patients. Therefore, I think that a more reasonable explanation should be described, because the limit between the included and excluded articles seems to be not clear enough.

IV) On the last lines of page 6, after the reference “(Blei 2009)” the new sentence should be initiated with a capital letter: “In agreement with more recent recommendations…”.

V) In the table with information about the reference “Michel 1980” on page 8, the authors decided to use an abbreviation to hepatic encephalopathy. The abbreviation should be written with capital letters and must be defined in the text.

VI) On page 12 there is a lot of “?” that I really did not understand, but I think it is only a mark to a final modification.

References

1) Abdo AA. An evidence-based update on hepatic encephalopathy. Saudi J Gastroenterol. 2006 Jan-Mar;12(1):8-15.

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) Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF & Morgan MY. Review article: the design of clinical trials in hepatic encephalopathy – an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther 2011; 33: 739–747.

4) Bajaj JS. Review article: the modern management of hepatic encephalopathy. Aliment Pharmacol Ther 2010; 31, 537–547.

5) Burkhard PR, Delavelle J, Du Pasquier R, Spahr L. Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol. 2003 Apr;60(4):521-8.

6) Butterworth RF. Parkinsonism in cirrhosis: pathogenesis and current therapeutic options. Metab Brain Dis. 2012 Oct 20. [Epub ahead of print]

7) Córdoba J, García-Martinez R, Simón-Talero M. Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence. Metab Brain Dis. 2010 Mar;25(1):73-80.

8) 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.

9) Guevara M, Baccaro ME, Ríos J, Martín-Llahí M, Uriz J, Ruiz del Arbol L, Planas R, Monescillo A, Guarner C, Crespo J, Bañares R, Arroyo V, Ginès P. Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration. Liver Int. 2010 Sep;30(8):1137-42.

10) 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, 20(3):246–247.

11) Noone ML, Kumar VG, Ummer K, Achambat L, Salam KA. Cirrhosis presenting as Parkinsonism. Ann Indian Acad Neurol. 2008 Jul;11(3):179-81.

12) Romeiro FG, Américo MF, Yamashiro FS, Caramori CA, Schelp AO, Santos AC, Silva GF. Acquired hepatocerebral degeneration and hepatic encephalopathy: correlations and variety of clinical presentations in overt and subclinical liver disease. Arq Neuropsiquiatr. 2011 Jun;69(3):496-501.

13) Suk KT, Baik SK, Yoon JH, Cheong JY, Paik YH, Lee CH, Kim YS, Lee JW, Kim DJ, Cho SW, Hwang SG, Sohn JH, Kim MY, Kim YB, Kim JG, Cho YK, Choi MS, Kim HJ, Lee HW, Kim SU, Kim JK, Choi JY, Jun DW, Tak WY, Lee BS, Jang BK, Chung WJ, Kim HS, Jang JY, Jeong SW, Kim SG, Kwon OS, Jung YK, Choe WH, Lee JS, Kim IH, Shim JJ, Cheon GJ, Bae SH, Seo YS, Choi DH, Jang SJ; Korean Association for the Study of the Liver. Revision and update on clinical practice guideline for liver cirrhosis. Korean J Hepatol. 2012 Mar;18(1):1-21.

14) Wang V, Saab S. Ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003;114:237-238.

15) Wijdicks EF, Wiesner RH. Acquired (non-Wilsonian) hepatocerebral degeneration: complex management decisions. Liver Transpl. 2003 Sep;9(9):993-4.

Date 05/05/2013