Cirrhosis Research

People diagnosed with liver disease commonly experience malnutrition, according to experts. The reasons for this involve a multitude of factors.¹One of the main causes is that a damaged liver as a result of a disease like hepatitis cannot properly metabolize many of the nutrients that an individual consumes in his or her diet. As a result, some patients may need dietary therapy.²

How is the liver associated with nutrition? Eighty-five percent to 90% of the blood that leaves the stomach and intestines carries significant nutrients to the liver where they are converted into substances the body can use. The liver processes carbohydrates, proteins, fats, and minerals to be used in normal body function.³

Physicians May Miss the Signs
Despite medical practitioners' knowledge of liver disease-related malnutrition, the condition is often underdiagnosed, wrote a team of gastroenterologists at the State University of Rio de Janeiro in Brazil, in a new study. The aim of this study was to help physicians better identify the signs of malnutrition in these patients.

"Malnutrition is often underdiagnosed in cirrhosis because the parameters more frequently used to address malnutrition in these patients, such as weight, measurement of skinfolds, and blood tests, are affected by cirrhosis," explained Fatima Figueiredo, MD, PhD, a gastroenterologist at the university and the study's chief investigator, in an interview with Priority Healthcare. "Cirrhosis can increase the weight and the measurements of skinfolds because of the fluid retention and edema that occurs in cirrhosis. Therefore, the disease itself can change these nutritional parameters, delaying the diagnosis of weight loss, for example."

Malnutrition in cirrhotic patients increases their likelihood of a poor prognosis and has been associated with increases in general illness and death in patients undergoing liver transplantation, Figueiredo explained.

Nailing Down Definitive Signs
To evaluate the signs associated with liver disease-related malnutrition, Figueiredo and his group enrolled 79 patients with liver disease, comparing them with a group of 17 people without liver disease.

"The aims of this study were: to quantify body composition changes, to determine tissue loss pattern, and to assess the relation of these to the severity of [liver] dysfunction," wrote the researchers in their study paper.

The team first measured levels of total body water and extracellular water in each of the patients. Water makes up about one-half to two-thirds of our total body weight. It is divided into two components: water that is contained within our cells (intracellular water), and the water that floats in the space between our cells (extracellular water). Maintaining water balance is essential to normal body function.⁴

In determining total body water and extracellular water levels, the researchers measured intracellular water and total body cell mass. The team also measured total body fat in each of the patients. All of these assessments were combined to determine an individual patient's overall nutritional status.

At the end of the study, Figueiredo's team learned that extracellular water was increased and intracellular water was lower in people with liver disease. They also found that body cell mass and body fat were lower in these patients, mostly in those with moderate to severe liver disease.

The researchers established a pattern of tissue loss; in those with early-stage cirrhosis, the loss of body fat was predominate. In patients with moderate cirrhosis, there were losses in either body cell mass or body fat. But in those with advanced liver cirrhosis, the researchers noted losses in both body fat and body cell mass.

"Liver cirrhosis was characterized by a significant reduction in body cell mass and body fat, and by a redistribution of body water," Figueiredo's group concluded. "Significant losses occurred even in patients with mild disease."

The investigators say it's hoped their findings will help physicians better diagnose malnutrition and manage the nutritional status of their patients with liver disease.

Altering the Diet is Debatable
What are the treatment options when malnutrition is diagnosed in people with liver disease? Experts say those with advanced liver disease should be recommended a diet providing adequate calories, proteins, minerals and vitamins. These dietary recommendations should be given based on a certain individual's condition.⁵

However, Figueiredo says that is a topic of debate among physicians. "It makes sense that if we could properly refeed those patients, we would make a difference in their outcomes," he said. "However, no one has proven this theory yet."

Because physicians tend to inadvertently diagnose malnutrition much later in people with cirrhosis, re-designing a proper nutritional diet by then doesn't have much effect because the patients have already developed other related illnesses, which negatively affects their prognoses anyway, Figueiredo explained.

"With other [diagnostic] tools for nutritional assessment, we could demonstrate that nutritional depletion occurs very early even when there is no signal of it in clinical examination," he said. Still, these tools are very expensive and thus impractical in the clinical setting, Figueiredo said.

"If researchers plan a study refeeding patients very early (patients with no obvious signal of malnutrition) instead of patients diagnosed late, we could demonstrate that nutritional therapy would be a very important supportive therapy for these patients," he said.

1. Florez DA, Aranda-Michel J. Nutritional management of acute and chronic liver disease. Semin Gastrointest Dis 2002 Jul;13(3):169-78.
2. Bavdekar A, Bhave S, Pandit A. Nutrition management in chronic liver disease. Indian J Pediatr 2002 May;69(5):427-31.
3. American Liver Foundation. Diet & Your Liver. Available at: http://www.liverfoundation.org/db/articles/1022. Accessed February 16, 2005.
4. The Merck Manual. Disorders of Nutrition and Metabolism. Water Balance.
5. Tozun N. Influence of the metabolic complications of liver cirrhosis on dietary intake. Med Sci Monit 2000 Nov-Dec;6(6):1223-6.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

http://www.hepatitisneighborhood.com/content/in_the_news/archive_2247.aspx

WEDNESDAY, Feb. 23 (HealthDay News) -- A ray of hope may be emerging for the makers of cox-2 inhibitors, the class of drugs under such intense scrutiny at last week's government hearings.

A new study finds the cox-2 drug Celebrex may be safe and effective to use on a short-term basis in patients with stable cirrhosis of the liver.

The news comes less than a week after a U.S. Food and Drug Administration advisory panel recommended the cox-2 drugs stay on the market -- but with the addition of a black-box label warning of potential cardiovascular risks.

"This study provides an important, potential niche usage for selective cox-2 inhibitors in people with chronic liver diseases, based on their better safety profile in very short term use versus non-selective NSAIDs," said Dr. Scott Friedman, chief of the division of liver disease at Mount Sinai School of Medicine in New York City.

Friedman was not involved with the study, which appears in the March issue of the journal Hepatology.

Forbes magazine reported this week that Celebrex's manufacturer, Pfizer, Inc., is planning a study to compare Celebrex's safety profile with another anti-inflammatory pill. According to the magazine, that other pill is likely to be naproxen (Aleve) -- the same drug Celebrex is pitted against in the cirrhosis study.

These moves may signal a change in Pfizer's handling of Celebrex, as the company moves away from previous trials that attempted to prove the drug's superiority to other products in protecting the heart. Instead, according to the Forbes article, it now appears the company may be satisfied with trials aimed at proving Celebrex simply poses no greater cardiovascular risk than its rivals.

Members of the FDA advisory panel did indicate that the black box could be removed from Celebrex labeling if future trials showed a favorable safety profile.

This latest study in Hepatology focuses on a whole new safety issue, however: kidney problems.

The drugs known as nonsteroidal anti-inflammatories have long been associated with kidney failure in patients with cirrhosis of the liver. But there's been some evidence indicating that cox-2 inhibitors -- a subclass within the category of NSAIDs -- may be exempt from this problem.

In their study, the researchers from Barcelona's Hospital Clinic compared Celebrex with the traditional NSAID naproxen and a placebo in 28 patients with cirrhosis of the liver. Cirrhosis, which is often linked to excessive drinking, occurs when scar tissue impedes normal liver function.

All the study participants were randomly assigned to receive five doses of Celebrex, naproxen or placebo over a period of five days. The final analysis was based on data from 18 individuals.

Based on this short-term data, Celebrex turned out to be safer than naproxen, having no effect on kidney function.

"Most physicians and patients also recognize that these drugs, whether they're selective or non-selective, should only be given when absolutely indicated," Friedman said.

The long-term effects of the drugs are still an open question and the study authors did acknowledge the need for more research in this area.

"They did not assess long-term safety, but if there was a clear indication for a cox-2 for short-term use -- for example, patients who had musculoskeletal or orthopedic issues that required short-term treatment -- the data would suggest that a cox-2 would be safer than a traditional NSAID," Friedman said.

Also, all of the patients in the study had very stable disease, he added. "It would not be appropriate to extrapolate this to the use of cox-2 selective antagonists in patients with more advanced liver disease," Friedman said. "These patients had stable cirrhosis and were otherwise healthy."

The data, Friedman added, is not really all that surprising since prior animal studies had indicated that the kidney problems associated with NSAIDs were attributable to the blockage of the cox-1 enzyme rather than the cox-2 enzyme.

Traditional NSAIDs such as naproxen block both enzymes, while the cox-2 inhibitors, as their name suggests, block only the cox-2 variant.

The National Institutes of Health (digestive.niddk.nih.gov ) has more on cirrhosis of the liver.

	Safety and Efficacy Of Antiviral Therapy in Patients With Decompensated Cirrhosis Associated With Chronic Hepatitis C Infection Treatment of Cirrhotic HCV Patients with a Low Ascending Daily Dosing Regimen of Consensus Interferon and Ribavirin Association Between Liver Histology, Viral Kinetics and Outcome of Therapy with Peginterferon Alfa-2a (Pegasys) Combination Therapy with Ribavirin Previous studies have shown that the presence of liver cirrhosis is associated with lower sustained viral response (SVR) rates after peginterferon-ribavirin therapy. Pegylated Interferon Maintenance Therapy Positively Impacts on Portal Hypertension Secondary to HCV-related Cirrhosis Treatment of HCV in Cirrhotic Patients
	Trial of acarbose in hepatic encephalopathy
	Coagulation tests unlikely to reflect thrombin generation in cirrhosis
	Malnutrition and Liver Cirrhosis: Scoping Out the Signs
	Short-Term Celebrex Safe Against Cirrhosis

Safety and Efficacy Of Antiviral Therapy in Patients With Decompensated Cirrhosis Associated With Chronic Hepatitis C Infection

Trial of acarbose in hepatic encephalopathy

Coagulation tests unlikely to reflect thrombin generation in cirrhosis