Therapeutic window is narrow for steroids in alcoholic hepatitis

 

PHILADELPHIA – The main lesson for discordant data regarding the benefit of corticosteroids for alcoholic hepatitis is that mortality reductions accrue only to those patients who have advanced hepatitis but have not yet developed end-stage disease, according to a detailed look at published studies presented at Digestive Diseases: New Advances, held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education.

The relative benefit even in appropriate candidates is modest, according to Kevin Mullen, MD, chief of digestive diseases, West Virginia University, Morgantown. By his calculations, there is a survival benefit for one of every five to seven patients treated, and that survival benefit endures only 6-12 months.

These calculations were extrapolated from a long list of studies published over the last 45 years, some of the largest of which concluded that steroids are ineffective, according to Dr. Mullen. The likely source of the conflicting data is the timing of steroids over the course of the disease and the disparity in the scales used to define severity.

Of the scales employed to select candidates for steroid therapy, the Maddrey Discriminant Function (MDF) may be the best supported, according to Dr. Mullen. He suggested that other options, such as the MELD (Model for End-Stage Liver Disease) score and the presence or absence of hepatic encephalopathy are also likely to have discriminatory value in selecting patients for steroid therapy, but these have been largely evaluated in retrospective studies using disparate methodologies.

“The problem arises from so many trials using different criteria for patient selection,” Dr. Mullen explained.

Nevertheless, drawing on the preponderance of data, Dr. Mullen concluded that there is likely to be a therapeutic window within which steroids are beneficial. Using one prednisolone study that stratified patients by MDF score to illustrate this point, he noted that 6-month survival on active therapy was no better than placebo in patients with an MDF less than 25 and numerically but not necessarily clinically significantly better in those scoring 25-34. In the groups with an MDF score of 35-44 or 44-54, the survival at 6 months was several times higher (greater than 60% vs. less than 20%), but there was no advantage with scores greater than 54. In this latter group, the mortality rate at 6 months was 100% in those receiving steroids but only 80% among those given placebo.

“In my mind, there is no question that steroids can be of benefit, but it is a question of picking the right patient. If steroids are given too late in the disease process, it can exacerbate end-stage problems, leading to death,” Dr. Mullen said.

The potential mechanisms of benefit from steroids in alcoholic hepatitis include a reduction in collagen formation and an increase in albumin production, according to Dr. Mullen. In addition, steroids have the potential to suppress the cytokine-mediated inflammation that drives progressive liver dysfunction. However, steroids also have the potential of exacerbating existing infections by suppressing immune function. Moreover, he cautioned that steroids are contraindicated in patients with gastrointestinal bleeding or pancreatitis.

Importantly, patients with alcoholic hepatitis who are going to respond to steroids typically demonstrate a reduction in bilirubin within the first week, according to Dr. Mullen. He cautioned that continuing steroids in the absence of a change in bilirubin should be weighed again potential harms, including the exacerbation of liver disease or comorbidities. Even in responders, he recommended no more than 3 weeks to preserve a favorable benefit-to-risk ratio.

“Four weeks may be too long,” Dr. Mullen advised, but he also suggested that the management of advanced alcoholic hepatitis may be best left to specialists.

“Patients with severe alcoholic hepatitis should be referred and the referral should be to a hepatologist accustomed to managing these patients,” said Dr. Mullen, who cautioned that this is a challenging disease. “We have not been making a huge amount of progress” in the treatment of alcoholic hepatitis, which can be a frustrating disease because of alcoholic recidivism and poor prognosis in advanced stages, he said.

“I would argue that severe alcoholic liver disease has been one of the barriers for recruiting physicians into hepatology, because it is a very arduous group of people to look after, they get very sick, and the treatments are often not very successful,” he noted.

Global Academy and this news organization are owned by the same company. Dr. Mullen had no disclosures to report.

 

PHILADELPHIA – The main lesson for discordant data regarding the benefit of corticosteroids for alcoholic hepatitis is that mortality reductions accrue only to those patients who have advanced hepatitis but have not yet developed end-stage disease, according to a detailed look at published studies presented at Digestive Diseases: New Advances, held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education.

The relative benefit even in appropriate candidates is modest, according to Kevin Mullen, MD, chief of digestive diseases, West Virginia University, Morgantown. By his calculations, there is a survival benefit for one of every five to seven patients treated, and that survival benefit endures only 6-12 months.

These calculations were extrapolated from a long list of studies published over the last 45 years, some of the largest of which concluded that steroids are ineffective, according to Dr. Mullen. The likely source of the conflicting data is the timing of steroids over the course of the disease and the disparity in the scales used to define severity.

Of the scales employed to select candidates for steroid therapy, the Maddrey Discriminant Function (MDF) may be the best supported, according to Dr. Mullen. He suggested that other options, such as the MELD (Model for End-Stage Liver Disease) score and the presence or absence of hepatic encephalopathy are also likely to have discriminatory value in selecting patients for steroid therapy, but these have been largely evaluated in retrospective studies using disparate methodologies.

“The problem arises from so many trials using different criteria for patient selection,” Dr. Mullen explained.

Nevertheless, drawing on the preponderance of data, Dr. Mullen concluded that there is likely to be a therapeutic window within which steroids are beneficial. Using one prednisolone study that stratified patients by MDF score to illustrate this point, he noted that 6-month survival on active therapy was no better than placebo in patients with an MDF less than 25 and numerically but not necessarily clinically significantly better in those scoring 25-34. In the groups with an MDF score of 35-44 or 44-54, the survival at 6 months was several times higher (greater than 60% vs. less than 20%), but there was no advantage with scores greater than 54. In this latter group, the mortality rate at 6 months was 100% in those receiving steroids but only 80% among those given placebo.

“In my mind, there is no question that steroids can be of benefit, but it is a question of picking the right patient. If steroids are given too late in the disease process, it can exacerbate end-stage problems, leading to death,” Dr. Mullen said.

The potential mechanisms of benefit from steroids in alcoholic hepatitis include a reduction in collagen formation and an increase in albumin production, according to Dr. Mullen. In addition, steroids have the potential to suppress the cytokine-mediated inflammation that drives progressive liver dysfunction. However, steroids also have the potential of exacerbating existing infections by suppressing immune function. Moreover, he cautioned that steroids are contraindicated in patients with gastrointestinal bleeding or pancreatitis.

Importantly, patients with alcoholic hepatitis who are going to respond to steroids typically demonstrate a reduction in bilirubin within the first week, according to Dr. Mullen. He cautioned that continuing steroids in the absence of a change in bilirubin should be weighed again potential harms, including the exacerbation of liver disease or comorbidities. Even in responders, he recommended no more than 3 weeks to preserve a favorable benefit-to-risk ratio.

“Four weeks may be too long,” Dr. Mullen advised, but he also suggested that the management of advanced alcoholic hepatitis may be best left to specialists.

“Patients with severe alcoholic hepatitis should be referred and the referral should be to a hepatologist accustomed to managing these patients,” said Dr. Mullen, who cautioned that this is a challenging disease. “We have not been making a huge amount of progress” in the treatment of alcoholic hepatitis, which can be a frustrating disease because of alcoholic recidivism and poor prognosis in advanced stages, he said.

“I would argue that severe alcoholic liver disease has been one of the barriers for recruiting physicians into hepatology, because it is a very arduous group of people to look after, they get very sick, and the treatments are often not very successful,” he noted.

Global Academy and this news organization are owned by the same company. Dr. Mullen had no disclosures to report.

 

PHILADELPHIA – The main lesson for discordant data regarding the benefit of corticosteroids for alcoholic hepatitis is that mortality reductions accrue only to those patients who have advanced hepatitis but have not yet developed end-stage disease, according to a detailed look at published studies presented at Digestive Diseases: New Advances, held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education.

The relative benefit even in appropriate candidates is modest, according to Kevin Mullen, MD, chief of digestive diseases, West Virginia University, Morgantown. By his calculations, there is a survival benefit for one of every five to seven patients treated, and that survival benefit endures only 6-12 months.

These calculations were extrapolated from a long list of studies published over the last 45 years, some of the largest of which concluded that steroids are ineffective, according to Dr. Mullen. The likely source of the conflicting data is the timing of steroids over the course of the disease and the disparity in the scales used to define severity.

Of the scales employed to select candidates for steroid therapy, the Maddrey Discriminant Function (MDF) may be the best supported, according to Dr. Mullen. He suggested that other options, such as the MELD (Model for End-Stage Liver Disease) score and the presence or absence of hepatic encephalopathy are also likely to have discriminatory value in selecting patients for steroid therapy, but these have been largely evaluated in retrospective studies using disparate methodologies.

“The problem arises from so many trials using different criteria for patient selection,” Dr. Mullen explained.

Nevertheless, drawing on the preponderance of data, Dr. Mullen concluded that there is likely to be a therapeutic window within which steroids are beneficial. Using one prednisolone study that stratified patients by MDF score to illustrate this point, he noted that 6-month survival on active therapy was no better than placebo in patients with an MDF less than 25 and numerically but not necessarily clinically significantly better in those scoring 25-34. In the groups with an MDF score of 35-44 or 44-54, the survival at 6 months was several times higher (greater than 60% vs. less than 20%), but there was no advantage with scores greater than 54. In this latter group, the mortality rate at 6 months was 100% in those receiving steroids but only 80% among those given placebo.

“In my mind, there is no question that steroids can be of benefit, but it is a question of picking the right patient. If steroids are given too late in the disease process, it can exacerbate end-stage problems, leading to death,” Dr. Mullen said.

The potential mechanisms of benefit from steroids in alcoholic hepatitis include a reduction in collagen formation and an increase in albumin production, according to Dr. Mullen. In addition, steroids have the potential to suppress the cytokine-mediated inflammation that drives progressive liver dysfunction. However, steroids also have the potential of exacerbating existing infections by suppressing immune function. Moreover, he cautioned that steroids are contraindicated in patients with gastrointestinal bleeding or pancreatitis.

Importantly, patients with alcoholic hepatitis who are going to respond to steroids typically demonstrate a reduction in bilirubin within the first week, according to Dr. Mullen. He cautioned that continuing steroids in the absence of a change in bilirubin should be weighed again potential harms, including the exacerbation of liver disease or comorbidities. Even in responders, he recommended no more than 3 weeks to preserve a favorable benefit-to-risk ratio.

“Four weeks may be too long,” Dr. Mullen advised, but he also suggested that the management of advanced alcoholic hepatitis may be best left to specialists.

“Patients with severe alcoholic hepatitis should be referred and the referral should be to a hepatologist accustomed to managing these patients,” said Dr. Mullen, who cautioned that this is a challenging disease. “We have not been making a huge amount of progress” in the treatment of alcoholic hepatitis, which can be a frustrating disease because of alcoholic recidivism and poor prognosis in advanced stages, he said.

“I would argue that severe alcoholic liver disease has been one of the barriers for recruiting physicians into hepatology, because it is a very arduous group of people to look after, they get very sick, and the treatments are often not very successful,” he noted.

Global Academy and this news organization are owned by the same company. Dr. Mullen had no disclosures to report.