Liver disease plagues obese adolescents

By LINDA A. JOHNSON
08 sept 2008--In a new and disturbing twist on the obesity epidemic, some overweight teenagers have severe liver damage caused by too much body fat, and a handful have needed liver transplants.
Many more may need a new liver by their 30s or 40s, say experts warning that pediatricians need to be more vigilant. The condition, which can lead to cirrhosis and liver failure or liver cancer, is being seen in kids in the United States, Europe, Australia and even some developing countries, according to a surge of recent medical studies and doctors interviewed by The Associated Press.
The American Liver Foundation and other experts estimate 2 percent to 5 percent of American children over age 5, nearly all of them obese or overweight, have the condition, called nonalcoholic fatty liver disease.
"It's clearly the most common cause of liver disease," said Dr. Ronald Sokol, head of public policy at the liver foundation and a liver specialist at Children's Hospital and University of Colorado Denver.
Some experts think as many as 10 percent of all children and half of those who are obese may suffer from it, but note that few are given the simple blood test that can signal its presence. A biopsy is the only sure way to diagnose this disease.
As fat builds up, the liver can become inflamed and then scarred over time, leading to cirrhosis, a serious condition, which in years past was mostly caused by hepatitis or drinking too much alcohol. Liver failure or liver cancer can follow, but if cirrhosis has not yet developed, fatty liver disease can be reversed through weight loss.
The disease is most common in overweight children with belly fat and certain warning signs, such as diabetes or cholesterol or heart problems. However, it's been seen in a few children of normal weight.
Genetics, diet and exercise level all play a role. It is most prevalent among Hispanics, relatively rare among African-Americans, and more common among boys than girls.
"There are people in their 30s or early 40s that will require a liver transplant" from developing the condition as a kid, predicts Dr. Jose Derdoy, head of liver transplants at Cardinal Glennon Children's Medical Center in St. Louis. He's treated a 15-year-old, 530-pound boy and many others with the condition.
Experts blame obesity, with about two-thirds of all Americans overweight. With fatty liver disease becoming more common in adults, many experts predict it will become the top cause of liver transplants by 2020.
"There aren't enough livers to go around," says Dr. Philip Rosenthal of the University of California-San Francisco Children's Hospital.
His patient, Irving Shaffino, a 15-year-old Mexican-American who lives outside Lubbock, Texas, was lucky to get a transplant a year ago. He was in end-stage cirrhosis and, at 5-feet-4 1/2, weighed 180 pounds.
Irving had been fat since age 6, thanks to a high-starch, high-fat diet of Mexican food, pizza and burgers, said his mother, Guadelupe Shaffino. At age 8, she said, he had a distended stomach and by his early teens, breathing problems kept him tethered to an oxygen tank at home.
Without health insurance, the family couldn't find a local hospital that would do a transplant.
"My son begged me, 'Don't let me die, Mommy,' so I did everything in my power to find a place to help him. Thanks be to God, we found a way," said Guadelupe Shaffino, a restaurant cook.
UCSF Children's Hospital, with money from a state health program, agreed to do the transplant. Rosenthal, who oversees the hospital's pediatric liver transplant program, took over care of Irving. The doctor said without a new liver Irving would have died, maybe within months.
"He was in bad shape," said Rosenthal.
Soon after tests were completed and Irving got on a transplant waiting list, an organ was found.
"It felt like a miracle, because people say you could be on the transplant list for years," Irving said.
Within a couple of months of the July 26, 2007 operation, Irving had weaned himself from the oxygen tank and could go on walks, although he got winded quickly.
Back home in Texas, his medications are down from 11 to four and Irving said he's replaced soda and fast food with fruit, vegetables and whole grains.
"I want to get into sports again," he said. "I want to get down to maybe 150" pounds.
Sadly, however, Irving has made little progress in losing weight. While he's grown an inch and a half since his operation, he's still obese and his weight was up to 219 last month.
Specialists say many kids diagnosed with fatty liver disease come to subsequent checkups heavier, and at best, just one in four loses significant weight, the only treatment known to stop and even reverse the disease.
"My patients that are successful, the whole family has bought in," increasing exercise and changing diet, said Dr. Stephanie Abrams, a liver and obesity specialist at Texas Children's Hospital. "The problem is that we aren't changing society in favor of becoming lean."
The scope of the disease has only been realized in recent years. Just a handful of cases were reported in medical journals in the 1980s, and in the past, many adult patients were thought to be lying when they denied drinking alcohol.
Only three liver transplants on American children with nonalcoholic fatty liver disease were recorded from 1990 through 2002; two were done last year.
"It really has been only in the last two or three years that this has become more commonplace," said Dr. Ann Scheimann, a pediatric gastroenterologist at Johns Hopkins Children's Center. "It is scary."
Like heart disease, liver disease is silent. Kids may feel fine for years. Any early symptoms, like fatigue and loss of appetite, are vague and usually eclipsed by more conspicuous problems, from diabetes to high blood pressure.
"The majority of children with this still go undiagnosed," said Dr. Jeffrey Schwimmer, head of the Fatty Liver Clinic at Rady Children's Hospital in San Diego. "Some kids have died."
The number of patients at his clinic has roughly tripled over its six years, and he's seen one with cirrhosis just 8 years old.
"Many of these children, their parents have it (fatty liver disease) and don't know it," said Schwimmer.
Experts say the best way to combat the problem is to intervene early, while it can still be reversed, with a medical team working with the whole family, including liver and hormone specialists, a dietitian and counselors.
Last spring, the American Academy of Pediatrics recommended doctors do a blood test of liver enzymes every two years on obese children and overweight ones with high blood pressure or cholesterol or family history of heart disease. A trade group for children's hospitals last year gave similar advice.
Within the last several months, there's been an explosion of research published on it and the role genes may play.
Surprisingly, some research comes from countries not known for high obesity rates: China, India and Iran. More reports come from Australia, England, Greece, Ireland, Israel, Italy and Japan. Doctors say globalization has given even poor countries fast food chains and sedentary pastimes: TV, Internet, video games.
Scientists now are seeking the best ways to treat it.
A small study in Rome showed weight loss helped. The U.S. government is testing the diabetes drug metformin and vitamin E and is funding about 20 other studies, including one that aims to determine how the disease progresses and who is most likely to develop cirrhosis or liver failure.
When her son was diagnosed with advanced liver disease three years ago, Susan Siegfried recalls being "devastated." Curtis, then 12, was just over 5-feet-5 and weighed 179 pounds. About 40 percent of his liver was scarred.
Her husband, Mike, decreed the whole family would change its diet, and all high-fat and junk food was removed from their home in Chester, Ill.
Susan Siegfried said her son went from being the "sit-in-front-of-the-TV, play-video-games kind of kid," tired and sickly, to full of energy and very active. He now bales hay and does other chores on his uncles' nearby farm. Initially, he dropped about 20 pounds. He's shot up 4 inches but only gained 8 pounds in the past two years.
A new liver biopsy last fall showed huge improvement in his liver.
"I'm definitely a lot thinner than I would have been if I hadn't done anything," said Curtis, who found exercising and cutting out sugar and fat wasn't that hard. "If you stick with it, you'll get used to it."

Baclofen Aids in Alcohol Abstinence in Cirrhosis Patients

Susan Jeffrey
December 7, 2007 — Results of a randomized trial show alcohol-dependent patients with liver cirrhosis were able to attain alcohol abstinence at a higher rate with baclofen, an anticraving agent with a low liver metabolism, than with placebo.
"In conclusion, our results suggest that baclofen, because of its anticraving action and safety, could have an important role for treatment of alcohol-dependent patients with advanced liver disease," the researchers, with first author Giovanni Addolorato, MD, from the Institute of Internal Medicine, Catholic University of Rome, Italy, write. "We have shown that a pharmacological agent can promote alcohol abstinence and prevent alcohol relapse in individuals with alcoholic liver disease."
Further studies are needed to define the optimal duration of treatment, assess possible tolerance to the drug in a more prolonged regimen, and define the role for baclofen in clinical practice, they added.
Their results appear in the December 8 issue of The Lancet.
Abstinence Most Effective
Intervention aimed at achieving alcohol abstinence represents the most effective treatment for patients with liver cirrhosis, the authors write. However, some anticraving agents are metabolized by the liver and can worsen liver disease. Naltrexone, for example, is contraindicated in patients with liver disease. Other drugs, such as acamprosate and topiramate, have shown promise but have not, to their knowledge, been studied in patients with cirrhosis.
Baclofen is a gamma aminobutyric acid (GABA) B-receptor agonist that has low liver metabolism (about 15%) and is mainly eliminated unmodified by the kidney. It has been shown in preliminary studies to reduce alcohol craving and intake and enhance abstinence in alcohol-dependent patients, and no hepatic adverse effects have been reported, either in patients dependent on alcohol or in those with neurologic disorders. "As a result, baclofen could represent a useful drug to augment alcohol abstinence in individuals affected by alcoholic liver cirrhosis," they write.
To find out, the researchers conducted a trial of 84 alcohol-dependent patients with liver cirrhosis who were referred to the Institute of Internal Medicine between October 2003 and November 2006. They were randomly assigned to receive either oral baclofen or placebo. For the first 3 days, baclofen was given 3 times per day at a dose of 5 mg; for the subsequent 12 weeks, baclofen was given 3 times per day at a dose of 10 mg.
Outcomes of interest were total alcohol abstinence and cumulative abstinence duration, assessed during outpatient visits. Relapse was defined as alcohol intake of more than 4 drinks per day or 14 or more drinks per week over a period of at least 4 weeks.
Significantly more patients allocated to baclofen achieved and maintained abstinence than patients on placebo, the authors report.
The number of patients who terminated treatment did not differ significantly between groups, with 14% of baclofen patients and 31% of placebo patients stopping treatment (P = .12). No hepatic adverse effects were recorded, they noted.
Cumulative abstinence duration was about twice as high in patients receiving baclofen (mean, 62.8 days) as it was in those receiving placebo (mean, 30.8 days; P = .001).
"Our results show that oral administration of baclofen is significantly more effective than placebo at achieving and maintaining alcohol abstinence and at increasing cumulative abstinence duration in alcohol-dependent patients with liver cirrhosis," they concluded. "This reduction in self-reported alcohol use was associated with significant reductions in clinical markers of liver injury (alanine aminotransferase, gamma glutamyltransferase, bilirubin, and international normalized ratio), findings that confirm self-reported data and suggest that the reduction in alcohol consumption was sufficient to lessen liver injury."
"Surprisingly Robust" Findings
In a Commentary accompanying the publication, James C. Garbutt, MD, from the University of North Carolina at Chapel Hill, and Barbara Flannery, PhD, from the Transdisciplinary Behavioral Science Program, RTI International, in Baltimore, Maryland, called the findings by Dr. Addolorato and colleagues "surprisingly robust in favor of baclofen, with nearly three quarters of patients on baclofen maintaining sobriety compared with about a quarter of placebo patients."
More patients assigned to placebo dropped out and, because dropouts were counted as failures in the sobriety survival analysis, these would have affected the primary outcome measure, the editorialists noted. "However, the higher retention rate in the baclofen group is of interest in its own right," they write.
At 12 weeks, the study was relatively brief, so longer and larger studies of populations with varying inclusion and exclusion criteria will be required to assess whether baclofen has true value in patients with cirrhosis who continue to drink, they noted. "Nevertheless, the findings are welcome because they could spur further efforts to identify drug treatments for alcoholism complicated by cirrhosis.
The study was supported by the Italian Ministry for University, Scientific and Technological Research (MURST), and by the European Research Advisory Board (ERAB). Neither the authors nor the editorialists have disclosed any relevant financial relationships.
Lancet. 2007; 370:1915-1922,1884-1885.

AASLD: Proton Pump Inhibitors May Be Problematic for Cirrhosis Patients

BOSTON, Nov. 5 -- Use of proton pump inhibitors (PPIs) in patients with cirrhosis was associated with a risk of spontaneous bacterial peritonitis and Clostridium difficile-associated disease, according to two retrospective studies.
Action Points
Explain to patients with cirrhosis that this study suggests that they be monitored carefully while on proton pump inhibitors for spontaneous bacterial peritonitis and Clostridium difficile-associated disease.
Note that these studies were published as an abstract and presented at a conference. The data and conclusions should be considered to be preliminary until published in a peer-reviewed publication.
PPI therapy was independently associated with peritonitis, despite a higher antibiotic prophylaxis rate among patients who developed the condition compared with patients who did not, Jasmohan S. Bajaj, M.D., M.S., of the Medical College of Wisconsin at Milwaukee, told attendees at the American Association for the Study of Liver Diseases meeting here.
Dr. Bajaj and colleagues also used the same 985 hospitalized patients with cirrhosis in a case-control study to learn if PPI therapy increases the rate of Clostridium difficile in that population.
Patients with cirrhosis are often prescribed a PPI because of their propensity to develop upper GI symptoms and bleeding, Dr. Bajaj said. But the medications promote bacterial overgrowth and have been associated with infection.
In the first study, univariate logistic regression showed that Child's (CTP) score (P=0.0001, OR: 9.9, CI: 3.4 to 28.8) and PPI use (P=0.0001, OR: 7.8, CI: 3.4 to 18) were significantly higher among the peritonitis patients than in those who did not have peritonitis. The two patient groups were matched by age alone and by age and CTP score.
On multivariate analysis, CTP score (P=0.0001, OR: 9.3, CI: 4 to 30) and PPI use (P=0.0001, OR 6.4, CI: 2.5 to 16) were also significant.
More than a third of the peritonitis patients (36%) had received antibiotic prophylaxis compared with less than a quarter (22%) of the controls.
More than two-thirds of peritonitis patients (68%) were on a PPI compared with about a third (32%) of the patients who did not have peritonitis.
The researchers also found that inappropriate use of PPIs was higher in the peritonitis patients (53%) than in patients who did not have peritonitis (32%). Use was defined as appropriate when PPIs were taken for GERD, Barrett's esophagus, nonvariceal GI bleed, and peptic ulcer; other uses were defined as inappropriate.
In the C. difficile study, both PPI use and antibiotic use (primarily for pneumonia and suspected septicemia) were associated with a higher risk of Clostridium difficile-associated disease, said Dr. Bajaj.
The study's variables included age, CTP score, race, reason for admission that was liver-related, antibiotic use, prophylaxis against sudden bacterial peritonitis, and PPI use.
On univariate logistic regression with Clostridium difficile-associated disease as the outcome, only antibiotic use (P0.0001, OR: 6.7, CI: 3.2 to 14) and PPI use (P0.0001, OR: 8, CI: 3.4 to 19) were significant predictors.
On multivariate analysis, PPI use (P0.0001, OR: 6.1, CI: 3 to 14) and antibiotic use (P0.0001, OR 7.8, CI: 3.2 to 19) were again significantly associated with C. difficile disease.
The researchers noted neither funding source for the study nor financial conflicts.Primary source: American Association for the Study of Liver DiseasesSource reference: Bajaj JS, et al "Proton Pump Inhibitor Use is Associated with a High Risk of Spontaneous Bacterial Peritonitis" Abstract 740 presented Nov. 4. Additional source: American Association for the Study of Liver DiseasesSource reference: Bajaj JS, et al "Clostridium Difficile Infection Is Associated with Proton Pump Inhibitors in Patients with Cirrhosis" Abstract 773 presented Nov. 4.

Alcoholic Cirrhosis Alters Gene Expression and Worsens Brain Dysfunction

AUSTIN, Tex., Aug. 27 -- Cirrhosis may worsen alcohol-induced brain dysfunction by altering neural gene expression, according to investigators here.
Comparison of gene expression patterns in cirrhotic and noncirrhotic alcoholics revealed widespread differences in the frontal cortex, R. Dayne Mayfield, Ph.D., of the University of Texas, and colleagues, reported in the September issue of Alcoholism: Clinical and Experimental Research.
Both astrocytes and neuronal cells were affected at the transcriptional level in cirrhotic alcoholics.
"Genes involved in neurite growth, neuronal cell adhesion, and synaptic transmission were inhibited at the mRNA level in cirrhotic alcoholics," the authors stated.
Collectively, the alterations in gene expression are consistent with more severe brain dysfunction in cirrhotic versus noncirrhotic alcoholics, they concluded.
In cirrhotic patients, neurotoxins that cannot be removed from circulation cross the blood-brain barrier and cause brain dysfunction that include hepatic encephalopathy. Imaging and pathology studies have suggested that chronic alcohol abuse causes brain damage that is more severe in alcoholics with cirrhosis. The reasons for the worse brain dysfunction in cirrhotic alcoholics have not been completely explained.
Dr. Mayfield and colleagues had previously reported extensive transcriptional reprogramming in the cortex of noncirrhotic alcoholics. In the current study, they used 47,000-element cDNA microarray technology to examine gene expression profiles in the frontal cortex of cirrhotic alcoholics and to compare the profiles with those of noncirrhotic alcoholics.
The study involved seven cirrhotic and 14 noncirrhotic alcoholics. RNA from the frontal cortex of all 21 participants was analyzed by means of cDNA microarray, and investigators compared the transcriptome (entire set of RNA molecules) of the cirrhotic and noncirrhotic alcoholics.
The total number of spots detected on each array was similar between the two groups. Of 15,833 genes detected in both groups, 1,125 met criteria for differential expression (increased or decreased in cirrhotic patients). These genes were compared with 531 genes expressed in a control group versus noncirrhotic alcoholics (reported in a previous study).
In general, the magnitude of different expression between cirrhotic and noncirrhotic alcoholics exceeded that of the comparison between controls and noncirrhotic alcoholics.
By computerized analysis, the investigators grouped differentially expressed genes into biologically relevant themes. Genes involved in cell adhesion, mitochondrial function, and synaptic transmission were overrepresented among down-regulated genes. Upregulated genes had overrepresentation of genes involved in apoptosis and mitosis.
"Interestingly, all of the stress-response genes that were upregulated in uncomplicated alcoholics compared with nonalcoholic controls were further upregulated in the current cirrhotic alcoholic cases," the authors observed.
The investigators summarized the state of knowledge about alcohol-induced brain damage, including findings from the current study:
Long-term alcohol exposure causes persistent liver inflammation and elevated serum cytokine levels.
As liver damage progression, some neurotoxins cannot be removed from circulation, and the supply of some necessary elements is reduced.
Progressive cirrhosis adversely affects neuronal and glial-cell functions, including cell communication, signal transduction, ion transport, and mitochondrial function.
In glial cells (astrocytes), apoptosis is induced, leading to increased brain atrophy and proliferation of progenitor cells.
In neuronal cells synaptic transmission is inhibited, potentially causing more severe cognitive dysfunction.
The authors had no disclosures. The study was supported by the National Institute of Alcoholism and Alcohol Abuse.Primary source: Alcoholism: Clinical and Experimental ResearchSource reference: Liu J et al. "Altered gene expression profiles in the frontal cortex of cirrhotic alcoholics." Alcohol Clin Exp Res 2007; 31: 1-7.

Mild Cirrhosis is Not a Bar to Cardiac Surgery

NEW YORK, July 5 -- Cardiac surgery can be performed safely in many patients with mild liver cirrhosis, and in select patients with moderate cirrhosis, according to investigators here.
In a series of 27 patients with cirrhosis of the liver who underwent heart surgery, the operative mortality rate for patients with stage A disease, the mildest form, according to the Child-Turcotte-Pugh classification system was 11%, and the patients had an 80% one-year survival rate, reported Farzan Filsoufi, M.D., and colleagues, of Mount Sinai Hospital.
In contrast, four of six patients (67%) with Child-Turcotte-Pugh class C died during surgery, and only one survived a year, the authors reported in the July issue of Liver Transplantation.
Liver cirrhosis has been shown to be a major risk factor for death among patients undergoing abdominal surgery, with outcomes directly correlating with Child-Turcotte-Pugh disease stage, a measure originally used to estimate perioperative mortality in liver transplant candidates, but now also used to stage cirrhosis.
Although there are few such studies of heart surgery outcomes in patients with cirrhosis, observational reports have suggested that patients with liver disease fare worse during cardiac procedures, the authors noted.
"Patients with cirrhosis who require open heart surgical procedures are among the most challenging and complex patients seen in cardiac surgery," agreed Gonzalo Gonzalez-Stawinski, M.D., of the Cleveland Clinic, in an accompanying editorial.
"Liver disease results in physiologic derangements that are only exacerbated by surgery and cardiopulmonary bypass," Dr. Gonzalez-Stawinski said.
To get a better handle on the challenges of liver co-morbidity in heart surgery patients, the Mount Sinai investigators conducted a retrospective review of 4,952 patients who had cardiac surgery at their hospital from 1998 through 2004.
During that period, 20 men and 27 women with cirrhosis, mean age 58 + 10, underwent cardiac surgery, 18 with the use of cardiopulmonary bypass, and nine without.
The procedures included pericardiectomy, cardiopulmonary bypass grating (five performed off-pump), single or double valve replacement, and aortic repairs.
Ten of the patients had Child-Turcotte-Pugh class A disease, 11 had class B disease, and six had class C. The mean preoperative Model for End-stage Liver Disease (MELD) score was 14.2 + 4.2.
Seven patients (26%) died during surgery. When the deaths were stratified by Child-Turcotte-Pugh class, the authors found that death occurred in only 11% of patients with class A disease, compared with 18% of patients with class B, and 67% of patients with class C cirrhosis.
None of the deaths occurred in the five patients who had revascularization without the use of cardiopulmonary bypass.
One-year survival was 80% among patients with Class A disease, 45% in patients with class B cirrhosis, and 16% in patients with class C disease (P=0.02).
Postoperative complication rates followed a similar pattern, occurring in 22% of patients with class A disease, 56% with class B, and 100% of patients with class C disease.
The authors also found that the Child-Turcotte-Pugh classification was a better predictor of in-hospital death than the MELD score (P=0.02 versus P=0.065, respectively).
There was also a statistically significant inverse relationship between preoperative platelet count and hospital mortality (P<0.04), the authors noted. In addition preoperative platelet count was inversely related to the severity of cirrhosis as determined by the Child-Turcotte-Pugh class. There were no hospital deaths among patients with normal platelets count.
"Operative mortality remains high in Child-Turcotte-Pugh class C patients," the investigators wrote. "Careful patient selection is critical in order to improve surgical outcome in patients with cirrhosis."
In his editorial, Dr. Gonzalez-Stawinski wrote that the study affirms that surgeons need to be cautious in their approach to patients with cirrhosis of the liver.
"Filsoufi et al. report that the expected survival for Child-Pugh class B patients with cirrhosis is 50% at eight months. More importantly, the survival when considering patients with Child-Pugh class C is merely 50% at four months," he wrote. "These data are particularly important to take into account and explain to patients with cirrhosis at the time of consenting for surgery so that an informed decision is made without raising any false hopes or expectations."
Dr. Filsoufi and colleagues acknowledged that their study was limited by its retrospective, observational design, a patient population that was heterogenous and selected by referring specialists as potential heart surgery candidates, and the small sample size, which precludes an accurate assessment of the MELD score (a relative newcomer) as a tool for predicting cardiac surgery outcomes in patients with cirrhosis.
Neither study funding source nor author conflicts of interest were reported.Primary source: Liver TransplantationSource reference: Filsoufi F et al. "Early and Late Outcome of Cardiac Surgery in Patients With Liver Cirrhosis." Liver Transpl 2007; 13:990-995. Additional source: Liver TransplantationSource reference: Gonzalez-Stawinski G. "Early and Late Outcomes of Cardiac Surgery in Patients With Liver Cirrhosis." Liver Transpl 2007; 13:956.