Treatment of hepatic encephalopathy

Treatment of hepatic encephalopathy

Correspondence We would like to inform you of three points of correction and clarification to statements in your March 12 Editorial (p 912).1 First, t...

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We would like to inform you of three points of correction and clarification to statements in your March 12 Editorial (p 912).1 First, the recently released African Scenarios report2 by UNAIDS does not forecast that “10% of Africans might die [of AIDS] by 2005”. In fact, the Scenarios show that the annual death rate in the African continent will remain at less than 1% from 2004 to 2025. Second, the role of religion, religious leaders, and faith-based organisations is a continuing thread throughout the report and a full analysis of the role of religion is included on page 184. Participants who created the three scenarios belonged to various faiths, including Catholicism. The report clearly states that beliefs about how HIV is spread and how it can be prevented can be based on secular, traditional, or religious systems, or a mix of all three. Cultural and religious leaders have shown that they can influence belief systems to ensure that HIV is seen in a more positive way. The three scenarios bring to light some of the profoundly different roles that religion might have. In “Tough choices”, the actual and latent capacity of faith-based organisations is marshalled by national leaders as part of a national HIV/AIDS response. In “Traps and legacies”, religious institutions provide one of the few refuges available to communities suffering from the effects of AIDS, but the relationship between people of different faiths, and between faith-based and secular institutions, is often uncomfortable and sometimes extremely tense. In “Times of transition”, religious leaders and their congregations, both within and outside Africa, have a crucial role in shaping new global values and, specifically, the response to the AIDS epidemic. Collaboration between religious groups grows. We also have a longstanding partnership with Caritas Internationalis, one of the world’s largest Catholic Vol 365 April 16, 2005

tions, to provide prevention and care services, to reduce stigma and discrimination faced by people living with HIV, and to mobilise leadership. We have been actively engaged in a dialogue with the Catholic Church, at the highest levels in the Vatican, as well as in numerous countries. This involvement includes addressing issues such as AIDS-related stigma, prevention of sexual transmission of HIV including condom use, and engaging church-affiliated institutions in care. For example, earlier this year, the UNAIDS Executive Director met with African bishops when he participated in the World Day of the Sick activities in Cameroon, where a “Marshall Plan” against AIDS in Africa was launched by the Church. We also supported a theological workshop focusing on HIV and AIDS-related stigma held in Windhoek, Namibia, at the end of 2003. Although we recognise that there are differences on policy directions, we have seen real progress made on the ground through the engagement of the Catholic Church. The major issue now is to focus on common ground. We feel that the Editorial missed an opportunity to further the agenda and address the new challenges countries are facing as a result of this exceptional crisis. I declare that I have no conflict of interest.

Purnima Mane [email protected] Director, Social Mobilization and Information, Joint United Nations Programme on HIV/AIDS, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland 1 2

The Lancet. The Pope’s grievous errors. Lancet 2005; 365: 912. UNAIDS. AIDS in Africa: three scenarios to 2025. Geneva: UNAIDS, 2005. en/AIDS+in+Africa_Three+scenarios+to+2025. asp (accessed March 30, 2005).

Your Editorial “The Pope’s grievous errors”1 could well be added as a contemporary chapter to John Foxe’s Actes and Monuments.2 First published in 1563, this work had picked up on the idea of collecting the history of antipapal martyrs. You are harshly critical of John Paul II’s recently published book Memory

and identity because it does not address the HIV/AIDS problem. One would rather seek and find this information in, say, a WHO report on global health. You bring out the big guns to blame the Pope for not applauding polygamy, because of his lack of “any understanding of African history or culture”. Unlike the Pope, you side with the culture of the pill and condom, assuming that your position is solely right. You cannot wait for John Paul’s successor who “must replace his ecclesiastical error with clerical compassion”. It is the style of your Editorial that surprises me most. You take on a solemn, patronising, self-assured tone. You treat the subject of your writing with superiority and hostility, admonishing him from beginning to end. Is this really The Lancet, my favourite medical journal for many years? I can’t believe my eyes.

Rights were not granted to include this image in electronic media. Please refer to the printed journal AP

The Pope’s grievous errors

I declare that I have no conflict of interest.

Andrew Szczeklik [email protected] Department of Medicine, Jagiellonian University School of Medicine, Skawiska 8, 31-066 Kraków, Poland 1 2

The Lancet. The Pope’s grievous errors. Lancet 2005; 365: 912. Davies N. The Isles: a history. London: Macmillan, 2000: 397.

Treatment of hepatic encephalopathy In their Rapid Review (Jan 29, p 431),1 Debbie Shawcross and Rajiv Jalan highlight conceptual advances in our understanding of the pathogenesis of hepatic encephalopathy. However, such advances have not yet been translated into new medications available for therapy. In the meantime, the weakness of the evidence base for the use of non-absorbable disaccharides as a treatment for hepatic encephalopathy leads Shawcross and Jalan to suggest that they are a therapeutic “myth”. They call for clinical studies in which such drugs (including lactulose) are tested against placebo. Since their conclusions concur with the results of a previously published

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meta-analysis,2 both articles deserve comment. Criticism of the design of studies done in the early 1970s may be completely valid. However, the mechanisms of action of non-absorbable disaccharides have been extensively studied.3 Deficiencies in the design of trials should not be equated with the dismissal of compounds with biological effects and plausible explanations for their benefit. Have the users of nonabsorbable disaccharides for 30 years been victims of autodeception? Clinical trials in hepatic encephalopathy are particularly difficult to do. Confounding variables such as the degree of hepatic failure, the nature of the precipitating event, and the extent of portal-systemic shunting have not been well controlled for in many studies. An example of the difficulties in this area of research is the testing of a drug in precipitant-induced encephalopathy, since control of the precipitating event can be therapeutic in itself.4 The challenge lies in defining distinct clinical problems within the spectrum of hepatic encephalopathy where placebo-controlled trials are likely to yield clear results. Appropriate endpoints need to be defined, and the tools required to monitor drug effects reexamined. Ethics committees will need to be convinced, and multicentre and probably multinational collaborations will be required. An important task lies ahead. Although a positive result from a trial of lactulose versus placebo would be expected by a long list of major investigators,5 researchers should not be dissuaded from pursuing studies of other clinical problems within hepatic encephalopathy, where comparison of a new drug against placebo is well justified. I declare that I have no conflict of interest.

Andres T Blei [email protected] Northwestern University, Chicago, IL 60611, USA 1


Shawcross DL, Jalan R. Dispelling myths in the treatment of hepatic encephalopathy. Lancet 2005; 365: 431–33.





Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004; 328: 1046–50. Clausen MR, Mortensen PB. Lactulose, disaccharides and colonic flora: clinical consequences. Drugs 1997; 53: 930–42. Sanaka MR, Ong JP, Mullen KD. Challenges of designing hepatic encephalopathy treatment trials. Hepatology 2003; 38: 527–28. Conn HO, Bircher J, eds. Hepatic encephalopathy: management with lactulose and related carbohydrates. East Lansing: Medi-Ed Press, 1988.

In their provocative Rapid Review,1 Debbie Shawcross and Rajiv Jalan discuss how the conclusions of two recent studies dispel therapeutic myths about lactulose and protein restriction in the treatment of hepatic encephalopathy.2,3 The origins of therapeutic myths in medicine comprise a combination of a logical background and the perception of a beneficial effect of the therapy used. We did a survey among hepatologists belonging to the Spanish Society for the Study of the Liver to find out common treatment practices in patients with hepatic encephalopathy. We mailed a questionnaire to 578 members of the society. 128 (22%) responded, most of whom had a large amount of clinical experience (mean 19 years of specialised practice). Most (94%) used oral lactulose or lactitol as the mainstay of treatment for episodic encephalopathy, combined with protein restriction (74%). The benzodiazepine receptor antagonist flumazenil was seldom used (12·5%); in most cases (73%) it was reserved for suspected pharmacological intoxication. After an episode of hepatic encephalopathy, most patients (84%) received oral lactulose or lactitol to prevent recurrence. Similar practices were reported for treating recurrent or chronic encephalopathy. The results of this survey indicate that there is an important gap between recommendations of societies,4,5 results of clinical studies,2,3 and clinical practice. Although there is not enough evidence from placebo-controlled trials of the efficacy of lactulose or lactitol, current guidelines favour its

use because of the logical rationale behind it, a large amount of clinical experience, and good tolerability. The European Society for Clinical Nutrition and Metabolism recommends transient protein restriction, followed by adequate nutrition after a few days. However, no study has shown a benefit of reducing protein intake in episodic encephalopathy. Conversely, although several studies and a metaanalysis indicate that flumazenil improves hepatic encephalopathy in about a quarter of patients, flumazenil is not widely recommended and is seldom used in clinical practice owing to the perception of a non-relevant benefit for any situation other than pharmacological intoxication. The cause of these discrepancies may be the importance of liver function in determining the outcome of hepatic encephalopathy. Most patients with low bilirubin concentrations recover within a few days, whereas those with jaundice usually progress to death, except if there is a reversible cause (ie, acute alcoholic hepatitis, autoimmune hepatitis, or septic jaundice). The development of new therapeutic approaches requires precise definitions of the state of liver function. The main endpoint for cirrhotic patients without jaundice is reduced duration of episodes and decreased number and duration of recurrences. Patients with jaundice and terminal disease should be excluded from clinical trials, since treatment will have no benefit. For jaundiced cirrhotics with the potential for recovery (ie, acute-on-chronic liver failure), treatment should be focused on improving liver function. In these trials, midterm survival (months after admission) is more important than the short-term effect on encephalopathy. The new therapeutic challenge is to combine progress in neurosciences with that in liver biology. Before newer treatments are available, rational use of the current ones might still be valid. We declare that we have no conflict of interest. Vol 365 April 16, 2005