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Cysteamine Will Be Tested As Treatment For Fatty Liver Disease In Children

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NIH study to test treatment for fatty liver disease in children

With the launch of a new clinical trial supported by the National Institutes of Health, researchers are working to determine whether treating children diagnosed with the most severe form of fatty liver disease with a drug called cysteamine will help improve the liver.

The trial, called Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh),will enroll 160 boys and girls ages 8 to 17 with nonalcoholic fatty liver disease (NAFLD).  The participants will receive cysteamine or placebo by mouth twice a day for a year.  There are no weight cutoffs or percentiles for the children participating in CyNCh.  However, more than 90 percent of the children are expected to be overweight or obese.  Participants need a baseline biopsy that confirms severe NAFLD to be eligible for the study.   Children with poorly managed diabetes, heart disease, and other chronic liver diseases will be excluded.

NAFLD covers a range of severity from simple liver disease without injury, called steatosis, to the more concerning nonalcoholic steatohepatitis, or NASH, which includes fat accumulation, inflammation, and liver injury.  Most children with fatty liver disease are overweight and resistant to insulin, a hormone that regulates energy.  The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy.

“We did not see fatty liver disease in children until recently,” said Edward Doo, M.D., NASH Clinical Research Network project scientist and director of the Liver Diseases Program at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is funding the study in collaboration with Raptor Pharmaceutical of Novato, Calif., which makes the drug and will provide it to the trial. “Fatty liver disease affects about 17 percent of children in the United States. This rise in the number of children with NAFLD most likely mirrors the increase in obesity, which affects more than 16 percent of American children and teens,” Dr. Doo said.

Results from a small pilot study using cysteamine in 11 children with NASH suggest that it improves liver enzymes by reducing toxins that can damage the liver.  Cysteamine is approved to treat cystinosis, a genetic disease that causes the amino acid cystine to accumulate in the kidneys, liver, eyes, brain, and white blood cells.  Modest weight loss through diet and physical activity may help some children with fatty liver disease, but it is a treatment option that seldom helps people meet their goals.  “We know that following a weight loss plan for many children and adults can be daunting, especially if they have limited access to healthy food options that are low in fat, added sugars, and calories, and infrequent opportunities for physical activity,” said Joel E. Lavine, M.D., Ph.D., a CyNCh principal investigator and professor of pediatrics at Columbia University, New York City.  “Hopefully, this trial will move us closer to finding a safe and effective treatment that helps children with fatty liver disease.”

NAFLD can be a precursor to NASH, which may progress to cirrhosis, liver failure and liver cancer.  NAFLD may also increase a patient’s risk of developing heart disease.  A healthy liver helps the body remove harmful chemicals from the blood, fight infection and digest food.  If too much scar tissue forms, the liver could fail.  Then a liver transplant is required.   “We are concerned that the disease may advance as children become adults and increase their risk for cirrhosis, liver failure, liver transplantation, and death as adults,” said Stephen P. James, M.D., director of the NIDDK’s Digestive Diseases and Nutrition Division.  “This multicenter, double-blind trial offers researchers and NIDDK an opportunity to rigorously assess how safe and effective cysteamine is in treating children with NASH, as well as to reveal new avenues worthy of scientific study.”

The following clinical centers are conducting the CyNCh trial:

  • Children’s Memorial Hospital, Chicago
  • Cincinnati Children’s Hospital Medical Center
  • Columbia University, New York City
  • Indiana University, Indianapolis
  • Mount Sinai Medical Center, New York City
  • St. Louis University
  • Texas Children’s Hospital, Houston
  • University of California, San Diego
  • University of California,  San Francisco
  • University of Washington, Seattle

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The NIDDK, a component of the NIH, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe and disabling conditions affecting Americans. For more information about the NIDDK and its programs, see www.niddk.nih.gov. Education programs for diabetes and kidney disease offer information and resources for patients and health professionals.

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Novel Approach To View Inner Workings Of Viruses, Identified By NIH Scientists

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Since the discovery of the microscope, scientists have tried to visualize smaller and smaller structures to provide insights into the inner workings of human cells, bacteria and viruses.  Now, researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, have developed a new way to see structures within viruses that were not clearly seen before.  Their findings are reported in the Jan. 13 issue of Science.

Cryo-electron microscopy (cryo-EM) is a technique that allows scientists to image very small particles, like structures on the surface of viruses. This method has been useful in helping researchers understand how vaccines work.  But, despite the success of cryo-EM, scientists have been unable to clearly visualize structures inside of viruses, because radiation is used to image them.   “With lower doses of radiation, it is not possible to see inside the organism,” said lead author Dr. Alasdair Steven of the NIAMS Laboratory of Structural Biology Research.  “However, higher doses of radiation damage the virus, destroying the very structures that we would like to view.”

Working in collaboration with the group of Dr. Lindsay Black at the University of Maryland Medical School, Baltimore, Steven and his team were able to turn the problem of radiation damage into an asset.  Viruses, one of the simplest life forms, are made up of nucleic acids (DNA or RNA) and the proteins encoded by the nucleic acid instruction manual.  The researchers realized that proteins inside the virus are more sensitive to damage than DNA.

“We first used low doses of radiation and recorded images in which the inner structure of the virus was invisible,” said Steven. “Next, we used high doses of radiation, and found that the inner structure could be seen as a cylinder of bubbles.”  While the inner structure was damaged, the team was able to superimpose the images, using three-dimensional computer reconstruction.  As a result, they were able to clearly visualize the viral structure. The investigators call this technique bubblegram imaging.

Moving forward, the team members anticipate many uses of bubblegram imaging.  Ideally, this technique will allow a better understanding of the inner workings of viruses, providing more opportunities for developing novel therapies. Beyond studying viral structure, cryo-EM could be used to visualize interactions of proteins with DNA in human cells. One exciting prospect lies in using this approach to visualize differences in cancer vs. non-cancer cells. “This new cryo-EM procedure renders previously invisible proteins visible and, thus, will provide new understanding of cell biology,” said  Steven.

For more information on the NIAMS Laboratory of Structural Biology Research, visit http://www.niams.nih.gov/Research/Ongoing_Research/Branch_Lab/Structural_Biology/default.asp.

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

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NIH Scientists Find The Cause Of Cold Urticaria

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Genetic mutation leads to cold allergy, immune deficiency and autoimmunity

Investigators at the National Institutes of Health have identified a genetic mutation in three unrelated families that causes a rare immune disorder characterized by excessive and impaired immune function. Symptoms of this condition include immune deficiency, autoimmunity, inflammatory skin disorders and cold-induced hives, a condition known as cold urticaria.

The study was led by Joshua Milner, M.D., in the Laboratory of Allergic Diseases at the National Institute of Allergy and Infectious Diseases (NIAID), and Daniel Kastner, M.D., Ph.D., scientific director at the National Human Genome Research Institute (NHGRI). It will appear in the online edition of the New England Journal of Medicine on Jan. 11, 2012.

The mutation discovered occurs in a gene for phospholipase C-gamma2 (PLCG2), an enzyme involved in the activation of immune cells. The investigators have named the condition PLCG2-associated antibody deficiency and immune dysregulation, or PLAID. “Investigating rare diseases gives researchers more clues about how the healthy immune system functions,” says NIAID Director Anthony S. Fauci, M.D. “More importantly, identifying the genetic cause of these disorders opens up possibilities for better disease management and potentially a cure for people who may have spent their entire lives debilitated by severe and unexplained symptoms.”

The NIH study involved 27 people from three separate families who all suffered from an inherited form of cold urticaria, an allergic disease characterized by the formation of itchy, sometimes painful hives, episodes of fainting and, in certain cases, life-threatening reactions in response to cold temperatures.

Blood sample analysis revealed that many patients produced antibodies to their own cells and tissues (autoantibodies), making them more susceptible to developing autoimmune disease. More than half had a history of recurrent infections, and laboratory tests revealed that most had low levels of infection-fighting antibodies and low numbers and reduced activity of circulating immune B cells — all symptoms of immune deficiency disease. In three cases, patients had common variable immunodeficiency, a disease that requires frequent intravenous infusions of immune globulin to prevent severe infections. Seven patients suffered from granulomas, inflamed masses of tissue, which formed on their fingers, ears, nose and other parts of their skin.

“This is one of few examples in which the allergy symptom directed us to a genetic syndrome,” says Dr. Milner. “In trying to understand the link between this group of conditions — autoimmunity, chronic infections and cold urticaria—we not only identified a disease-causing mutation but uncovered a unique and fascinating genetic mechanism at the crux of allergy, immune defense and self-tolerance.”

“This study illustrates the power of multidisciplinary teamwork involving clinicians, geneticists and basic immunologists to get to the heart of seemingly insoluble medical mysteries,” says Dr. Kastner. “Our team and colleagues working in the field now have much better odds of improving health outcomes for people with PLAID and for understanding this gene’s role in other disorders.”

The NIAID investigators teamed up with gene hunting experts in Dr. Kastner’s laboratory and found the PLCG2 mutation after performing gene analysis and DNA sequencing studies. The mutation caused the PLCG2 enzyme to function without shutting off. Despite the fact that the enzyme was constantly turned on, immune cells ignored its signaling and did not activate normally.

Investigators performed a series of laboratory experiments to understand how the PLCG2 mutation affects B cells and mast cells, immune cells that contain histamine and other chemicals that are released during an allergic response. Patients’ B cells containing the mutated gene fail to turn on normally, leading to their inability to produce antibody, but also an inability to sense when they are producing autoantibodies. Laboratory-developed mast cells containing the mutated gene released chemicals on exposure to cool temperatures, which could explain why the patients developed cold-induced hives.

According to the investigators, their findings suggest that inhibiting PLCG2 activity could be a therapeutic strategy to treat cold-induced hives, autoimmunity and immune deficiency in people with PLAID, but more studies are needed. The study findings also suggest that people previously diagnosed with common variable immunodeficiency disease or with granulomatous diseases could have a PLCG2 gene mutation. Further study is needed to understand PLAID and how mutations in PLCG2 could contribute to other allergic and immunologic disorders.

“These findings are gratifying both for researchers and for people with this disorder,” says NHGRI Director Eric Green, M.D., Ph.D. “Furthermore, this study illustrates how genome-analysis methods can empower efforts to unravel the molecular basis of rare genetic diseases.”

Additional support for this work was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the NIH.

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

NIAID conducts and supports research  — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.

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Autoantibodies Are Affecting About 32 Million Americans, NIH Study Shows

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NIH study shows 32 million Americans have autoantibodies that target their own tissues

More than 32 million people in the United States have autoantibodies, which are proteins made by the immune system that target the body’s tissues and define a condition known as autoimmunity, a study shows. The first nationally representative sample looking at the prevalence of the most common type of autoantibody, known as antinuclear antibodies (ANA), found that the frequency of ANA is highest among women, older individuals, and African-Americans. The study was conducted by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health. Researchers in Gainesville at the University of Florida also participated.

Earlier studies have shown that ANA can actually develop many years before the clinical appearance of autoimmune diseases, such as type 1 diabetes, lupus, and rheumatoid arthritis. ANA are frequently measured biomarkers for detecting autoimmune diseases, but the presence of autoantibodies does not necessarily mean a person will get an autoimmune disease. Other factors, including drugs, cancer, and infections, are also known to cause autoantibodies in some people.

“Previous estimates of ANA prevalence have varied widely and were conducted in small studies not representative of the general population,” said Frederick Miller, M.D., Ph.D., an author of the study and acting clinical director at NIEHS. “Having this large data set that is representative of the general U.S. population and includes nearly 5,000 individuals provides us with an accurate estimate of ANA and may allow new insights into the etiology of autoimmune diseases.” The findings appear online in the Jan. 11 issue of the Journal Arthritis and Rheumatism.

Miller, who studies the causes of autoimmune diseases, explains that the body’s immune system makes large numbers of proteins called antibodies to help the body fight off infections. In some cases, however, antibodies are produced that are directed against one’s own tissues. These are referred to as autoantibodies.

A multi-disciplinary team of researchers evaluated blood serum samples using a technique called immunofluorescence to detect ANA in 4,754 individuals from the 1994-2004 National Health and Nutrition Examination Survey (NHANES). The overall prevalence of ANA in the population was 13.8 percent, and was found to be modestly higher in African-Americans compared to whites. ANA generally increased with age and was higher in women than in men, with the female to male ratio peaking at 40-49 years of age and then declining in older age groups.

“The peak of autoimmunity in females compared to males during the 40-49 age bracket is suggestive of the effects that the hormones estrogen and progesterone might be playing on the immune system,” said Linda Birnbaum, Ph.D., director of NIEHS and an author on the paper.

The paper also found that the prevalence of ANA was lower in overweight and obese individuals than persons of normal weight. “This finding is interesting and somewhat unexpected,” said Edward Chan, Ph.D., an author on the study and professor of the Department of Oral Biology at the University of Florida.

“It raises the likelihood that fat tissues can secrete proteins that inhibit parts of the immune system and prevent the development of autoantibodies, but we will need to do more research to understand the role that obesity might play in the development of autoimmune diseases,” said Minoru Satoh, M.D., Ph.D., another author on the study and associate professor of rheumatology and clinical immunology at the University of Florida.

The researchers say the paper should serve as a useful baseline for future studies looking at changes in ANA prevalence over time and the factors associated with ANA development. The paper is the first in a series analyzing this data from the NHANES dataset, and exploring possible environmental associations with ANA.

The NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists (www.niehs.nih.gov/news/releases/newslist/index.cfm) to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

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Vitamin D May Improve Bone Health In Those Taking Anti-HIV Drug

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NIH study suggests benefits for young people on long-term tenofovir treatment

Vitamin D may help prevent hormonal changes that can lead to bone loss among those being treated for HIV with the drug tenofovir, according to the results of a National Institutes of Health network study of adolescents with HIV.

Tenofovir is widely used to treat HIV infection.  However, the drug causes symptoms that resemble those of vitamin D deficiency ods.od.nih.gov/factsheets/VitaminD-QuickFacts, causing bones to lose calcium and reducing bone density.  The study found that large monthly doses of vitamin D reduced blood levels of a hormone that stimulates calcium release from bones.

“What we’ve found suggests vitamin D could be used to counteract one of the major concerns about using tenofovir to treat HIV,” said Rohan Hazra, M.D., of the Pediatric, Adolescent and Maternal AIDS Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute that funds the networks.  “People in their teens and twenties may be on anti-HIV treatment for decades to come, so finding a safe and inexpensive way to protect their long-term bone health would be a major advance.”

The findings were published online in Clinical Infectious Diseases.

Vitamin D helps the body absorb calcium to build bones.  When the body is deficient in vitamin D, levels of a hormone called parathyroid hormone rise.  This rise triggers activity that draws calcium from bones.  As a result, the bones become more fragile and can break more easily.  Parathyroid hormone also tends to be elevated in people taking tenofovir, whether or not they have sufficient vitamin D.

Because parathyroid hormone levels are elevated in people taking tenofovir in much the same way as they are in people with vitamin D deficiency, the researchers theorized that vitamin D might counteract the bone-depleting effects of tenofovir.

The study was conducted by first author Peter L. Havens, M.D., of the Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee; Dr. Hazra; Kathleen Mulligan, Ph.D., of the University of California at San Francisco; and other researchers affiliated with the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) and the International Maternal–Pediatric–Adolescent AIDS Clinical Trials (IMPAACT) Group.

In addition to funding from NICHD, funding was also provided by the National Center for Research Resources, the National Institute on Drug Abuse, and the National Institute of Mental Health.

About 200 18- to 25-year-olds on antiretroviral therapy took part in the study. Study participants included young adults taking tenofovir and those receiving other forms of anti-HIV treatment.  Each month, the adolescents and young adults in the study took a 50,000-unit dose of vitamin D or placebo.  At the end of the three months, parathyroid hormone levels had fallen about 14 percent among participants taking tenofovir and vitamin D but remained unchanged in participants taking other kinds of anti-HIV medication.  However, youth taking tenofovir still had higher parathyroid hormone levels than those on other anti-HIV drugs.  The researchers don’t know if longer treatment with vitamin D would further reduce parathyroid hormone levels.

The recommended daily dose of vitamin D is 600 units.  The authors noted that they observed no adverse effects from the vitamin D treatment during the 3 months of this study.

The researchers are now making plans for a two-year follow-up study to examine the longer-term safety of vitamin D in a similar group of HIV-infected youth taking antiretroviral regimens containing tenofovir, and to determine if the changes in parathyroid hormone result in improvements in bone density.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.  For more information, visit the Institute’s website at http://www.nichd.nih.gov/.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers  and is a component of the U.S. Department of Health and Human Services. NIH  is the primary federal agency conducting and supporting basic, clinical, and  translational medical research, and is investigating the causes, treatments,  and cures for both common and rare diseases. For more information about NIH  and its programs, visit www.nih.gov.

 

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