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Liver clinic targets silent epidemic with team approach

After watching the cafeteria lady’s husband die under his team’s care, Thomas Jensen, MD, began focusing on preventing the scenario from happening again. The patient, who had been unknowingly suffering from liver disease, had lost all function of the organ, leaving Jensen and his colleagues nearly helpless.

Wieland and Jensen
Amanda Wieland, MD, and Thomas Jensen, MD, flank a FibroScan® machine, which they often use to quickly and non-invasively assess patients’ liver health. The pair teamed up to launch the Multidisciplinary Nonalcoholic Fatty Liver Disease Clinic (NAFLD) in hopes of slowing an increasing epidemic.

Today, as an assistant professor on the University of Colorado Anschutz Medical Campus, Jensen’s memory fuels his outreach aimed at detecting what has become the most prevalent chronic liver disease in the United States. Rising in tandem with the obesity epidemic, Nonalcoholic Fatty Liver Disease (NAFLD) now strikes children as well as adults and is soon expected to become the top reason for liver transplants in this country.

“It was one of the toughest cases I saw in residency,” said Jensen, who joined the School of Medicine’s Division of Endocrinology, Metabolism and Diabetes in 2016. “He was intubated and on multiple medications and was very difficult to manage. I just remember thinking to myself: We need to have a better way of finding these people before it’s too late.”

Answering a call

Today, Jensen and Amanda Wieland, MD, of the Division of Gastroenterology and Hepatology, have launched the Multidisciplinary NAFLD Clinic, using a team approach that combines their expertise with that of top experts across the campus in decreasing the disease’s burden on patients and the health care system.

Red flags for NAFLD in patients

 

Obesity

Visceral fat (increased waist circumference)

Metabolic syndrome

Insulin resistance

Type 2 diabetes

High blood pressure

Sleep apnea

Some lipid disorders

High triglycerides

Some medications (e.g., some HIV drugs, Tamoxifen, Methotrexate, some steroids)

“Roughly 30 percent of the population has Fatty Liver Disease, doubling in incidence since the 1990s,” Jensen said. “We know that it’s not only preventable, but it also can be reversible largely through diet and exercise,” said Jensen, who hopes to extend the clinic hours with the addition of SOM’s Emily Schonfeld, MD, a gastroenterologist, to the staff this fall.

NAFLD – which results when fatty deposits (steatosis) collect in the liver because of something other than alcohol consumption – has strong links to obesity and heart and metabolic disease. While it strikes 8 percent of the lean population, NAFLD affects nearly 70 percent of diabetics and 80 percent of the morbidly obese.

If the cause goes unaddressed, liver inflammation, scarring and cell death (nonalcoholic steatohepatitis, or NASH) can result, ultimately leading to permanent tissue damage, or cirrhosis.

Missing a silent killer

With top-of-the-line screening equipment, the clinic’s team can identify cases and determine the severity, generally non-invasively, steering patients down the road to reversal. Jensen hopes more patients and primary care doctors, who often don’t have the knowledge, ability or time to effectively treat NAFLD patients, will seek expert care for themselves or their patients.

While primary care physicians routinely check liver function with blood tests, the Dallas Heart Study found the lab work was not a reliable marker, leaving patients undiagnosed, Jensen said. “On ultrasound, researchers found that up to 80 percent of those patients who did have fatty liver had normal-looking enzymes,” Jensen said.

Because doctors once thought simple steatosis would never progress to inflammation and scarring, non-specialists sometimes downplay early NAFLD, Jensen said. But studies now suggest within a six-year period, up to 40 percent of those patients do develop NASH.

“So, our sense is that it’s not only important to screen but to look at the risk factors that might suggest patients are susceptible and to monitor those patients.”

Life-changing diagnosis

Having lost his brother 10 years his junior last year to long-undiagnosed NAFLD, Aurora resident Dennis Ipsen considers himself lucky that his doctor sent him to Jensen and Wieland. The pair quickly detected the disease and began monitoring Ipsen.

“That’s what I liked the most,” Ipsen said of Jensen’s expertise and team approach. “He was Johnny-on-the-spot looking for this, and he knew what he was dealing with, and he brought in the other doctor very quickly,” said Ipsen, who has diabetes and heart disease. “The sooner it’s detected, the better off you are.”

Ipsen’s only new directive so far: maintain his chosen Weight Watchers diet plan. “I’m hoping that’s all I need,” he said.

“I just remember thinking to myself: We need to have a better way of finding these people before it’s too late.” – Thomas Jensen, MD

Rx: Weight loss

A healthy diet, exercise and weight loss is often the only prescription necessary with early diagnosis, Jensen said. “We know that with a 5 percent weight loss, you can reverse the level of fat in the liver,” he said. “And with a greater-than 10 percent weight loss, you can even start seeing reversal of fibrosis (early stages of scarring).”

At the NAFLD clinic, patients receive counseling on controlling related conditions and on ways of achieving weight loss, from fitness apps to bariatric surgery. “I had an obese patient with moderate steatosis,” Jensen said. She was a candidate for bariatric surgery and opted for that route. One month and 15 pounds later, a recheck found her fatty liver was completely resolved, Jensen said.

In addition to the Metabolic and Bariatric Program for severely overweight cases, the NAFLD clinic works closely with the CU Anschutz Health and Wellness Center in helping patients master lifestyle changes and achieve weight loss.

Keeping the faith

Valerie Frank family
Valerie Frank stands front and center of her family, which includes eight grandsons. Frank travels from her Sterling home to the CU Anschutz Medical Campus for specialist care for liver disease.

Although Valerie Frank’s disease had progressed to cirrhosis by the time she found the clinic, the Sterling resident dropped more than 40 pounds since diagnosis and holds out hope that Jensen’s and Wieland’s care can keep complications at bay.

“It’s still good to know,” said Frank, who has diabetes and spent more than a year seeing doctors and undergoing tests trying to find an answer for fatigue and abnormal blood work. She finally told her doctor she gave up. “And he said: Let’s try one last thing. Let’s have you see Dr. Jensen and Dr. Wieland at UCHealth.”

Three weeks later, after making the two-plus-hour trip from her Sterling home, Frank was diagnosed. Now, despite the drive and higher out-of-pocket costs, Frank said she will continue under the doctors’ care for as long as they can help her and would encourage other liver patients to do the same.

“Absolutely. From the minute I walked in, I felt a connection with them both,” said the mother of three and grandmother of eight grandsons. With cirrhosis, her prognosis is not certain, but she’s sure of one thing: The doctors are doing everything they can to give her the best outcome. “I’m feeling well. I’m doing well. You can’t give up on hope,” she said. “I have total faith in them.”

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Insights into liver disease caused by intravenous nutrition

Research by physician-scientists at the University of Colorado Anschutz Medical Campus offers hope for improved quality of life for people who rely on intravenous nutrition due to intestinal damage.

Kasmi and Sokol
Karim C. El Kasmi, MD, PhD, and Ronald Sokol, MD, professor of pediatrics

Karim C. El Kasmi, MD, PhD, assistant professor of pediatrics, and Ronald Sokol, MD, professor of pediatrics, both of the CU School of Medicine, are authors of an article in the April 2018 Nature Communications that sheds light on the underlying cause of intestinal failure-associated liver disease and suggests new therapeutic approaches.

Intestinal failure is a condition that occurs when a person’s intestines are injured, damaged, or surgically shortened resulting in the need for the person to receive daily intravenous (IV) nutrition to sustain health. This IV nutrition, called parenteral nutrition, can be given in the hospital or at home through semi-permanent IV catheters.

Side effects of this form of nutrition are jaundice, liver injury called cholestasis, and eventually scarring in the liver. Intestinal failure-associated liver disease could eventually become so severe that the person would need a liver transplant or a combined liver and intestinal transplant to survive.

Until recently, there has been no effective therapy because of a poor understanding of how intestinal failure related to the development of the liver disease. Over the past decade, investigators have learned that reducing or changing the IV lipids can have a beneficial effect on some, but not all, patients.

Drs. El Kasmi and Sokol developed a mouse model that mimics the situation in humans with intestinal failure who depend on IV nutrition. Mice with intestinal injury that are given PN through a central venous catheter for 7 to 28 days develop decreased liver function, called cholestasis, and liver injury.

The researchers were able to show that products from bacteria in the intestine of the mice, called lipopolysaccharides (LPS), are absorbed through the injured intestine and activate the immune system in the liver to produce a cytokine, IL-1 beta, leading to cholestasis. The combination of IV lipids and intestinal injury lead to the intestinal failure-associated disease.

With this understanding, the researchers identified three possible new targets for drug intervention to prevent or treat intestinal failure-associated disease. Several drugs that target these disease-causing pathways are already approved or in development. Further testing in clinical trials with affected patients is required, but this research opens the possibility of treating patients who need long-term IV nutrition without the worry of developing serious liver damage.

Guest contributor: Mark Couch, CU School of Medicine.

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Ronald Sokol, MD, named president of American Association for the Study of Liver Diseases

Ronald Sokol, MD, a professor of pediatrics-gastroenterology, hepatology and nutrition in the University of Colorado School of Medicine, has been named president of the American Association for the Study of Liver Diseases (AASLD).

Sokol was introduced as AASLD president in a recent article in Hepatology magazine. “Ron has made significant contributions to the field of hepatology through his clinical expertise, research, mentoring, advocacy and service within national organizations,” the article states.

In addition to his hospital affiliations at Children’s Hospital Colorado and the University of Colorado Hospital, the article notes, Sokol is the vice chair of clinical and translational research in the Department of Pediatrics and director of the Colorado Clinical and Translational Sciences Institute (CCTSI) at the CU Anschutz Medical Campus. CCTSI recently received a $46.5 million NIH grant to continue its work of accelerating research discoveries and new health care treatments.

The article in Hepatology went on to say that Sokol has been an NIH-funded investigator since 1986 “and has received an astonishing $200 million in grant support to date. His major clinical interests are pediatric hepatology and liver transplantation. Ron’s scientific interests include the mechanisms of vitamin E deficiency and cholestasis; the role of mitochondria and oxidative stress in liver injury; the mechanisms of liver cell injury in cholestasis; fatty liver, and parenteral nutrition-associated liver injury; the pathogenesis of biliary atresia; and the development of predictive models for rare childhood liver diseases.

“To that end, Ron has published 250 original articles pertaining to basic science, translational and clinical research studies in pediatric hepatology.”

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Common antioxidant may guard against development of liver disease

A common antioxidant found in human breast milk and foods like kiwi fruit can protect against nonalcoholic fatty liver disease (NAFLD) in the offspring of obese mice, according to researchers at the  University of Colorado Anschutz Medical Campus.

“Pyrroloquinoline quinone, or PQQ, is a natural antioxidant found in soil and many foods and enriched in human breast milk,” said the study’s lead author Karen Jonscher, PhD, an associate professor of anesthesiology and a physicist at CU Anschutz. “When given to obese mouse mothers during pregnancy and lactation, we found it protected their offspring from developing symptoms of liver fat and damage that leads to NAFLD in early adulthood.”

Dr. Karen Jonscher
Karen Jonscher, PhD, associate professor of anesthesiology and a physicist at CU Anschutz.

The study, published online last week in the Journal of the Federation of American Societies for Experimental Biology, is the first to demonstrate that PQQ can protect offspring of obese mothers from acceleration of obesity-induced liver disease.

NAFLD is the most common liver disease in the world, affecting 20-30 percent of all adults in the U.S. and over 60 percent of those who are obese. It heightens the risk of cardiovascular disease, type 2 diabetes and liver cancer.

Scientists have found that mice fed a high fat, Western-style diet give birth to offspring with a higher chance of getting the disease.

“We know that infants born to mothers with obesity have a greater chance of developing NAFLD over their lifetime, and in fact one-third of obese children under 18 may have undiagnosed fatty liver disease that, when discovered, is more likely to be advanced at the time of diagnosis,” Jonscher said. “The goal of our study, which we carried out using a mouse model of obese pregnancy, was to determine whether a novel antioxidant given to mothers during pregnancy and breastfeeding could prevent the development of NAFLD in the offspring.”

Jonscher and her colleagues fed adult mice healthy diets or Western-style diets heavy on fat, sugar and cholesterol. They gave a subset of both groups PQQ in their drinking water.

Their offspring were kept on the diets for 20 weeks. Those fed a Western diet gained more weight than those on a healthy diet. PQQ did not change the weight gain but it did reduce the fat in the livers, even before the mice were born. The antioxidant also reduced inflammation in the livers of mice fed the Western diet. The researchers found that PQQ protected adult mice from fatty liver, even when it  was stopped after three weeks when the mice quit breastfeeding.

Jonscher believes the antioxidant may work by impacting pathways critical to the early onset of diseases associated with maternal obesity, high fat diets and inflammation.

PQQ is found in human breast milk, soy, parsley, celery, kiwi and papaya. It’s also found in soil and interstellar dust. Jonscher said it could possibly be used as a prenatal or lactation supplement to protect children of obese mothers from developing liver and cardiovascular disease in adulthood, but cautioned that pregnant women should always consult their doctor before taking any supplement.

“Perhaps supplementing the diet of obese pregnant mothers with PQQ, which has proven safe in several human studies, will be a therapeutic target worthy of more study in the battle to reduce the risk of NAFLD in babies,” Jonscher said.

 

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Mice flown in space show nascent liver damage

In a discovery with implications for long-term spaceflight and future missions to Mars, a researcher at the University of Colorado Anschutz Medical Campus has found that mice flown aboard the space shuttle Atlantis returned to Earth with early signs of liver disease.

“Prior to this study we really didn’t have much information on the impact of spaceflight on the liver,” said the study’s lead author Karen Jonscher, PhD, an associate professor of anesthesiology and a physicist at CU Anschutz. “We knew that astronauts often returned with diabetes-like symptoms but they usually resolved quickly.”

Dr. Karen Jonscher, associate professor of anesthesiology and a physicist at CU Anschutz

But the prospect of liver damage raises new concerns.

The mice studied spent 13.5 days aboard the space shuttle. When they returned, Jonscher and her colleagues were able to collect liver samples. They found that spaceflight appeared to activate specialized liver cells that may go on to induce scarring and cause long-term damage to the organ.

We saw the beginning of nascent liver damage in just 13.5 days,” Jonscher said. “The mice also lost lean muscle mass. We have seen this same phenomenon in humans on bedrest – muscles atrophy and proteins break down into amino acids. The question is, how does that affect your liver?”

For years scientists have studied the impact of spaceflight on human physiology but most of the research has focused on bone, muscle, brain and cardiovascular function. Yet studies suggesting that astronauts who spent time in space developed diabetes-like symptoms link microgravity with metabolism and point toward the liver, the major organ of metabolism, as a possible target of the space environment.

Whether or not the liver itself is vulnerable to damage has remained an open question. And this research may help answer that.

The mice spent time orbiting the Earth on the final space shuttle flight in 2011. Once they returned home, teams of  scientists were allowed to share and study their internal organs.

Jonscher’s team found that spaceflight resulted in increased fat storage in the liver, comparing pair-fed mice on Earth to those on the shuttle. This was accompanied by a loss of retinol, an animal form of Vitamin A, and changes to levels of genes responsible for breaking down fats. As a result, mice showed signs of nonalcoholic fatty liver disease (NAFLD) and potential early indicators for the beginnings of fibrosis, which can be one of the more progressive consequences of NAFLD.

Space Shuttle Orbiting Earth stock photo

“It generally takes a long time, months to years, to induce fibrosis in mice, even when eating an unhealthy diet,” Jonscher said. “If a mouse is showing nascent signs of fibrosis without a change in diet after 13 ½ days, what is happening to the humans?”

With NASA planning longer deep space missions, including one to Mars which would take at least a year, these findings are significant.

“Whether or not this is a problem is an open question,” Jonscher said. “We need to look at mice involved in longer duration space flight to see if there are compensatory mechanisms that come into play that might protect them from serious damage.”

She pointed out that the stress of spaceflight and reentry to Earth might have also played a role in the liver damage.

“Further study in this area is merited and analysis of tissues harvested in space from mice flown aboard the International Space Station for several months may help determine whether long-term spaceflight might lead to more advanced hepatic injury and whether damage can be prevented,” she said.

The study appeared today in the journal PLOS ONE.

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