New Treatment Options for Rheumatic Manifestations of HCV

August 04, 2017
New Treatment Options for Rheumatic Manifestations of HCV
Christin L. Melton, ELS 

The recent development of oral interferon (IFN)-free direct-acting antiviral agents (DAAs) has important implications for managing hepatitis C virus (HCV) in patients with rheumatic symptoms. Patients may have preexisting rheumatic disorders at the time of HCV infection or may develop an HCV-related autoimmune disorder that manifests rheumatic symptoms.¹ 

Most HCV-related extrahepatic manifestations are autoimmune or inflammatory disorders that commonly cause rheumatic symptoms. A high prevalence of patients with HCV experience rheumatic symptoms as the disease progresses. Between 6% and 20% develop arthralgia, which typically arises symmetrically in joints of the knees, back, and fingers; arthralgia of the ankles or elbows is rare.¹ Myalgia is less common, affecting 2% to 5% of patients.¹

Continue reading....

Navigate This Blog
Extrahepatic manifestations of HCV & Treatment
Rheumatologic manifestations of hepatitis C virus - is included in this collection of articles.

All Articles
A collection of research articles on ailments related to HCV
Categorized article directory on the extrahepatic manifestations of hepatitis C.

When liver immune cells turn bad

When liver immune cells turn bad
University Health Network
(April 21, 2017--Toronto) - A high-fat diet and obesity turn "hero" virus-fighting liver immune cells "rogue", leading to insulin resistance, a condition that often results in type 2 diabetes, according to research published today in Science Immunology.

Using cells from mice and human livers, Toronto General Hospital Research Institute researchers demonstrated for the first time how under specific conditions, such as obesity, liver CD8+ T cells, white blood cells which play an important role in the control of viral infections, become highly activated and inflammatory, reprogramming themselves into disease-driving cells.

Scientists have been trying for many years to discover why the liver continues to pump out too much glucose in people with diabetes. This paper sheds light on the markers of activation and inflammation in CD8+ T cells and the Interferon-1 pathway which helps stimulate their function.

The research is entitled, "Type 1 Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome," by first authors Magar Ghazarian, a former graduate student, Dr. Xavier Revelo, a post-doctoral fellow in the lab of Dr. Daniel Winer, and senior authors Dr. Shawn Winer, Laboratory Medicine, St. Michael's Hospital, Laboratory Medicine and Pathobiology, University of Toronto, and Dr. Daniel Winer, Diabetes Research Group and the Department of Pathology, Toronto General Hospital Research Institute and the Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto.

"We found that under conditions of obesity and a high-fat diet, the cells that typically strengthen our immune system by killing viruses and pathogens instead increase blood sugar. They become pathogenic and worsen insulin resistance," explains Dr. Dan Winer. In fact, the normal function of the immune cells becomes misdirected. The pathways they would typically use to fight infection create inflammation, unleashing a chemical cascade which impacts insulin and glucose metabolism.

"The immune system in the liver represents a key missing link in our understanding of how the liver malfunctions in obesity to dysregulate sugar levels," adds Dr. Revelo.

In the study, researchers fed mice a high-fat diet, 60% of which was saturated fat, for 16 weeks. Compared with normal chow diet-fed mice, the high-fat diet mice showed worsened blood sugar, increased triglycerides, a type of fat (lipid) in the blood, and a substantial increase in the numbers of CD8+ T cells in the liver.

Instead of responding to viruses or other foreign invaders in the body, the activated CD8+ T cells launch an inflammatory response to fat, and to bacterial components that migrate to the liver from the gut through the blood.

The activated T-cells divide rapidly, pumping out increased numbers of cytokines, proteins that assist them in an active and excessive immune response. This pro-inflammatory response in turn interferes with normal metabolism in the liver, specifically jamming up or blocking insulin signaling to the liver cells.

Since the liver stores and manufactures glucose or sugar depending upon the body's need, the hormone insulin signals whether the liver should store or release glucose. This system keeps circulating blood sugar levels in check. If that signal is disrupted or blocked, the liver continues to make more sugar, pouring it into the bloodstream. If the liver is over-producing glucose, it becomes difficult to regulate blood sugar.

"This response never manifested itself until humans started to eat high-sugar, high-fat, high-calorie diets," says Magar Ghazarian, now a medical student in Ireland.

Adds Dr. Shawn Winer: "We're moving from studying diabetes as a metabolic syndrome - a combination of nutritional and hormonal imbalances - to include the role of the immune system and inflammation. That's the developing link. Inflammation is emerging to be a major mediator of insulin resistance."

Insulin resistance is a pathological condition linked to obesity, in which cells fail to respond normally to the hormone insulin which helps the body metabolize glucose. This results in poor absorption of glucose by cells, causing a buildup of sugar in the blood. Long-term insulin resistance eventually leads to diabetes.

The findings were confirmed in genetically-modified mice, as well as in human liver cells.

The researchers found that in genetically-modified mice lacking Interferon-1, who were also fed a high-fat diet, the CD8+ T cells did not produce an inflammatory response, and the mice had near normal blood sugar levels.

In further investigations of human liver cells from nearly 50 donor tissues of humans with varying degrees of body mass index (BMI) and liver fat, higher levels of CD8+ T cells were linked with higher levels of blood sugar or more advanced fatty liver disease. Donor tissues were obtained from Saint Louis University Hospital, Washington University School of Medicine and Mid-American Transplant Services from St. Louis and University Health Network.

The researchers note that CD8 + T cells could potentially be used as markers for the progression of fatty liver disease, which is expected to become the leading indication for liver transplantation within the next one or two decades.

Type 2 diabetes is one of the fastest growing diseases in Canada with more than 60,000 new cases yearly. Nine out of ten people with diabetes have type 2 diabetes. Being overweight or obese is an important risk factor for diabetes. It is estimated that 3.5 million or about 9% of Canadians have diabetes.

The study was funded by the Canadian Institutes of Health Research, the Canadian Diabetes Association, the J.P. Bickell Foundation, and the Ontario Ministry of Research, Innovation & Science.

About Toronto General Hospital
Toronto General Hospital is a partner in University Health Network, along with Toronto Western, the Princess Margaret Cancer Centre, the Toronto Rehabilitation Institute and the Michener Institute for Education. The scope of research and complexity of cases at Toronto General Hospital have made it a national and international source for discovery, education and patient care. It has one of the largest hospital-based research programs in Canada, with major research in cardiology, transplantation, diabetes, regenerative medicine, infectious diseases, genomic medicine, psychosocial care and health systems. Toronto General Hospital is a research and teaching hospital affiliated with the University of Toronto. http://www.uhn.ca

http://immunology.sciencemag.org/content/2/10/eaai7616

Understanding the links between inflammation and chronic disease

Northwestern University
Understanding the links between inflammation and chronic disease Early exposure to microbes reduces inflammation related to chronic disease later

EVANSTON, Ill. --- American parents may want to think again about how much they want to protect their children from everyday germs.
A new Northwestern University study done in lowland Ecuador remarkably finds no evidence of chronic low-grade inflammation -- associated with diseases of aging like cardiovascular disease, diabetes and dementia.

In contrast, about one-third of adults in the United States have chronically elevated C-reactive protein (CRP). Acute elevations in CRP -- a protein in the blood whose levels rise as part of the inflammatory response -- are important for protecting us against infectious disease. But when CRP is chronically produced, it is associated with chronic diseases.

"In other words, CRP goes up when you need it, but it is almost undetectable when you don't, after the infection resolves," said Thomas W. McDade, professor of anthropology at Northwestern and faculty fellow at the university's Institute for Policy Research. "This is a pretty remarkable finding, and very different from prior research in the U.S., where lots of people tend to have chronically elevated CRP, probably putting them at higher risk for chronic disease."

McDade said the findings build on his previous research in the Philippines, which found that higher levels of microbial exposure in infancy were associated with lower CRP as an adult. Similar exposures during infancy in lowland Ecuador, where rates of infectious disease continue to be high, may have a lasting effect on the pattern of inflammation in adulthood.

"In my mind the study underscores the value of an ecological approach to research on the immune system, and it may have significant implications for our understanding of the links between inflammation and chronic disease," McDade said. "This may be particularly important since nearly three-quarters of all deaths due to cardiovascular disease globally now occur in low- and middle-income nations like the Philippines and Ecuador."

The new research, which was conducted as part of the Shuar Health and Life History Project (http://www.bonesandbehavior.org/shuar/), suggests that higher levels of exposure to infectious microbes early in life may change how we regulate inflammation as adults in ways that prevent chronic inflammation from emerging. Infectious microbes have been part of the human ecology for millennia, and it is only recently that more hygienic environments in affluent industrialized settings have substantially reduced the level and diversity of exposure.

A growing body of research has shown that higher levels of chronic inflammation are associated with diseases of aging like cardiovascular disease, diabetes and dementia. But current research is based almost exclusively on people living in affluent industrialized countries like the United States.
"We simply do not know what chronic inflammation looks like in places like the Ecuadorian Amazon and other parts of the world where infectious diseases are more common," McDade said.

As a result, McDade, director of the Lab for Human Biology Research and director of Cells to Society (C2S): The Center on Social Disparities and Health, and collaborators at the University of Oregon set out to investigate what factors in the environment and during development influence how people regulate inflammation as adults. The study was conducted in lowland Ecuador – in a group of 52 adults between the ages of 18 and 49.

Based on current clinical criteria, McDade and colleagues did not find a single case of chronic low-grade inflammation among adults living in the Ecuadorian Amazon. McDade said people in these places are still dying of diseases such as cardiovascular disease, but probably not through processes that involve inflammation.

In terms of population health, McDade said these findings suggest that the association between inflammation and cardiovascular disease frequently reported in the United States may only apply in ecological settings characterized by low levels of exposure to infectious disease.
"It builds on research on chronic inflammation and cardiovascular disease in the U.S. and other affluent, industrialized settings and suggests that patterns seen here may not apply globally," McDade said. "It also suggests that the levels of chronic inflammation we see in the U.S. are not universal, and may be a product of epidemiological transitions that have lowered our level of exposure to infectious microbes."

###

"Analysis of Variability of High Sensitivity C-Reactive Protein in Lowland Ecuador Reveals No Evidence of Chronic Low-Grade Inflammation" is currently available online in the Early View section of the American Journal of Human Biology (http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291520-6300/earlyview). The study's co-authors are Paula S. Tallman, Department of Anthropology, Northwestern University; and Felicia C. Madimenos, Melissa A. Liebert, Tara J. Cepon, Lawrence S. Sugiyama and J. Josh Snodgrass, all with the Department of Anthropology at the University of Oregon and its Institute of Cognitive and Decision Sciences. Sugiyama is also affiliated with the Center for Evolutionary Psychology, University of California, Santa Barbara.

http://www.eurekalert.org/pub_releases/2012-05/nu-utl053012.php

Yogurt Drink Good for Diabetes

By Chris Kaiser, Cardiology Editor, MedPage Today
Published: March 30, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

Action Points

A Middle Eastern yogurt drink known as doogh and fortified with vitamin D was found to decrease inflammatory markers in people with type 2 diabetes.

Note that those drinking the fortified concoctions had significantly higher levels of adiponectin, a hormone known to have anti-inflammatory properties.

A Middle Eastern yogurt drink known as "doogh" and fortified with vitamin D was found to decrease inflammatory markers in people with type 2 diabetes, researchers found.

Those who drank the doogh fortified with vitamin D, or vitamin D plus calcium, had decreased levels of highly sensitive C-reactive protein and several interleukin proteins, among other markers of inflammation, reported Tirang Neyestani, PhD, of Beheshti University of Medical Sciences in Tehran, Iran, and colleagues.

In addition, those drinking the fortified concoctions had significantly higher levels of adiponectin, they reported online in the Journal of Clinical Endocrinology and Metabolism.
Adiponectin is a hormone known to have anti-inflammatory properties and to regulate the metabolism of glucose. A 2009 review of the literature found that higher levels of adiponectin were associated with a lower risk of type 2 diabetes (JAMA 2009; 302(2): 179-188).

Neyestani and colleagues noted that animal studies have shown vitamin D to have a beneficial effect in various autoimmune disorders. These researchers also reported last year the positive effect vitamin D has in diabetics on endothelial biomarkers (BMC Medicine 2011; 9:125) and on glycemic control (Am J Clin Nutr 2011; 93: 764-771), again using fortified doogh.

However, they said that the evidence in humans showing this particularly unique effect of vitamin D is scarce.

In this study, researchers conducted a double-blind, randomized, controlled trial over 12 weeks in 90 patients with type 2 diabetes. Participants were randomized equally either to plain doogh, doogh fortified with vitamin D, or doogh fortified with vitamin D and calcium.

Baseline characteristics between the groups were similar, with an age range of 30 to 60. Participants drank two bottles of the liquid yogurt per day. The average body mass index was 29 kg/m²
"The prevalence of overweight and obesity is escalating in Iran," Neyestani told MedPage Today via email. "Moreover, obesity and abdominal adiposity have a close association with development of type 2 diabetes; in other words, most cases of type 2 diabetes are overweight or obese."

Both groups with fortified drinks showed significant improvement of vitamin D status at the end of 12 weeks, "confirming high bioavailability of vitamin D in doogh," researchers said.
The inflammatory markers that significantly decreased at the end of 12 weeks were C-reactive protein, interleukin(IL)-1 beta, IL-6, fibrinogen and retinol binding protein (RBP)-4.

"This is the first study to show that vitamin D with or without extra calcium resulted in a significant decrease in these particular inflammatory biomarkers, as well as an increase in adiponectin and RBP-4," Neyestani and colleagues concluded.

Vitamin D studies of healthy people have typically not shown beneficial effects. "It is possible that the immunomodulatory effect of vitamin D can be more clearly observed when the immune system is stimulated," they said.

The findings, however, are not inconsistent with animal studies, they noted.
"Our study showed for the first time that adiponectin, a substance secreted by fat tissue that has an anti-inflammatory effect, increased when calcium and vitamin D-fortified doogh was consumed," said Neyestani.

Unlike vitamin D, calcium can be obtained through diet, mostly dairy products. Vitamin D, however, has very limited food sources.

"People usually do not have sufficient direct sun exposure for many reasons, including cultural, as women in Iran are veiled since age 9, Neyestani told MedPage Today. "In Iran, this problem is more complicated by the fact that there is no fortification program at the time. We therefore must rely mostly on vitamin D supplementation for now."

A limitation of the study was that three-quarters of participants were deficient in vitamin D, and that longer-term studies need to be done to adequately capture all vitamin D-dependent functions.

The work was funded by the National Nutrition and Food Technology Research Institute at Shahid Beheshti University of Medical Sciences in Tehran, Iran.
The authors reported they had nothing to disclose.

From the American Heart Association:

Antioxidant Vitamin Supplements and Cardiovascular Disease

Primary source: Journal of Clinical Endocrinology and Metabolism

                    Source reference:
"Improvement of vitamin D status via daily intake of fortified yogurt drink either with or without extra calcium ameliorates systemic inflammatory biomarkers, including adipokines, in the subjects with type 2 diabetes" J Clin Endocrinol Metab 2012; DOI: 10.1210/jc.2011-3465.

Hepatitis C -The Brain on Fire: Inflammation and Depression

The Brain on Fire: Inflammation and Depression

Inflammation and Its Effects on Mood

Published on November 23, 2011
by James M. Greenblatt, M.D.

Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection. Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.

We have all had the flu or at least know what it feels like.

The miserable collection of symptoms includes lack of energy, difficulty concentrating, sleepiness, loss of appetite, and general malaise.

For most of us these symptoms disappear within a few days. For some, it takes much longer. Although we tend to blame the influenza virus for making us feel miserable, the symptoms are actually a result of our immune system trying to combat the virus.

The symptoms of the flu are brought on by proteins, pro-inflammatory cytokines, our bodies produce in order to fight the flu and other infections.

When the immune system is under attack from physical injury, infections, or toxins, the immune system generates an inflammatory response. Inflammation is a normal physiological process that is now understood to play a major role in many chronic medical illnesses, including cancer, heart disease, diabetes, asthma, and obesity. In each of these cases inflammation causes the release of cytokines. Cytokines, which come in many different classes, including anti- and pro-inflammatory, behave as messengers and signal cells of the immune system.

The effects of pro-inflammatory cytokines can cause a diverse array of physical and psychological symptoms. When this happens it is referred to as sickness behavior.

Recently, scientists have been able to demonstrate how the symptoms of sickness behavior mirror those of depression. Researchers and health professionals are now beginning to understand the connection between inflammation and depression.

One study found that patients with major depressive disorder had significantly higher levels of the pro-inflammatory cytokine TNF-alpha than their non-depressed counterparts. In addition, patients with depression had low levels of anti-inflammatory cytokines.
Researchers have also found that eight weeks of Zoloft treatment was able to decrease some pro-inflammatory cytokines seen in depressed patients. On Zoloft, the depressed patients also saw an increase in anti-inflammatory cytokines.

A study involving depressed patients classified as non-responders supplemented the patients' standard antidepressant treatment with the addition of aspirin, an anti-inflammatory. More than 50% of these patients responded to this combination treatment. At the end of the study more than 80% of the group responsive to the anti-inflammatory went into remission.
Cytokines, the messengers during inflammation, are also used to treat infections and autoimmune disorders. So-called autoimmune disorders are clear examples of how an unregulated immune system can cause destructive damage to many different organs and tissues. Some of the most common autoimmune diseases include rheumatoid arthritis, multiple sclerosis, thyroid disease, and celiac disease.

Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection. Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.

In one study, nearly a third of patients with chronic hepatitis C who received interferon treatment displayed psychiatric symptoms after four weeks of treatment. Symptoms included mania, hypomania, and depression. Over the years I have had to admit patients for inpatient psychiatric treatment for depression and suicidal behavior following interferon therapy.

It appears that inflammation and the complicated collection of immune system chemical messengers called cytokines play an important role in brain function and may cause psychological symptoms.

When the brain is aggravated by any source-stress, infections, trauma, stroke, poisons, or nutritional deficiencies-inflammation spurs the release of pro- inflammatory cytokines, which may affect mood. Scientists have proposed many mechanisms as to how this may occur.

One mechanism as to how an unregulated immune system may contribute to depression is quite well understood. Cytokines activate an enzyme, indoleamine 2,3-dioxygenase (IDO), which degrades serotonin resulting in low levels of the neurotransmitter. IDO also degrades the precursor to serotonin, tryptophan. Decreased levels of the neurotransmitter serotonin are likely the contributing factor to the development of depressive symptoms. The inflammatory process' contribution to the constant destruction of serotonin decreases the chances of recovery.

For too many years we have tried to correlate depression with a deficiency of serotonin and related neurotransmitters in the brain. Using medications based on this theory has yielded dismal results, barely better than a placebo. If we understand the underlying physiological abnormalities contributing to mood disorders, then we are likely to benefit from more effective solutions.

Understanding the connection between depression and inflammation gives researchers and pharmaceutical companies incentive to look for alternative medications to treat depression. In the meantime there are, however, well-researched lifestyle and nutritional interventions that are known to decrease inflammation and improve mood: exercise, stress reduction, nutritional supplements (i.e. omega-3 fatty acids), and optimizing vitamin D levels. Chronic stress is one of the major preventable contributors to inflammation and immune dysregulation.

For each individual the inflammatory response is likely precipitated by a unique and complex interaction of causative agents. Infection, stress, nutritional deficiencies, and sedentary lifestyles are the most common factors. Individual, personalized understanding of inflammation and its contributions to the physiology of mood disorders is a critical, but often neglected component of integrative therapies for depression. By neglecting the underlying cause of depression, recovery is less likely.

In case you missed it:
Video- Psychiatric Complications of Hepatitis C Treatment - Part 1 and Part 2

The Role of Inflammation In Causing GI Cancers

The Role of Inflammation In Causing GI Cancers

Inflammation has been linked with various diseases, including many types of malignancies. This association has become well enough known that a cover of Time magazine in recent years pronounced inflammation the “surprising killer,” noting the “surprising link” between inflammation and cancer.

The fact that cancer was deemed to be the leading cause of death worldwide in 2008 by the World Health Organization is less known and speaks to the importance of understanding mechanisms that lead to cancer. It’s also important to note that the five cancers causing the most deaths worldwide – lung, gastric, colon, liver, and breast – include three malignancies of the digestive system.

Chronic inflammatory conditions of the entire digestive tract have been associated with malignancy, ranging from tobacco use and gingivitis in oropharyngeal carcinomas to inflammatory bowel disease–associated colitis and colon cancer. Other well known associations include GERD and Barrett’s esophagus associated with esophageal adenocarcinoma, and H. pylori infection associated with gastric adenocarcinoma.

Chronic inflammation associated with celiac disease predisposes to enteropathy associated T cell lymphoma. Inflammatory conditions of other organs of the digestive system, including chronic forms of hepatitis, cholangitis, and pancreatitis are associated with malignancies of the liver, biliary tract, and pancreas.

Inflammation impacts key steps involved in cancer biology including mutagenesis, tumor progression, and metastasis.

Factors that contribute to the development of GI cancers that arise from inflammation include infectious agents such as H. pylori, gut microbiota, and dietary factors, as well as host factors such as genetics, obesity, and the nature of the immune response. Not all individuals with a given risk factor, whether it be GERD, IBD, or H. pylori infection, develop cancer.

A complex interaction of host, environment, and luminal factors is the likely determinant of the clinical outcome arising from the potentially carcinogenic agent or condition. A variety of cell types produce mediators such as reactive oxygen and nitrogen species that damage DNA, and cytokines and growth factors that affect proliferation, cell death, and repair processes. Subsets of immune cells including cytotoxic T cells, helper T cells, and NK cells are involved in immunosurveillance.

Together, the components of the immune/inflammatory response modulate proliferation, differentiation, angiogenesis, stem cell recruitment, and mutation – events that are integral in the process of carcinogenesis. H. pylori infection has been well studied in an attempt to understand factors that may result in gastric adenocarcinoma.

Research indicates that host genetics, dietary factors, bacterial genotype, and the inflammatory response all contribute. Signaling pathways activated by chronic IBD that may lead to colon cancer have also been elucidated and it is thought that some of these mechanisms may relate to more common forms of colon cancer.

Further research is needed, as a better understanding of the inflammatory events regulating carcinogenesis may identify new biomarkers or therapies that change the detection and management of inflammatory diseases that can lead to malignancy.

■ SHEILA E. CROWE, M.D., FRCPC, FACP, FACG, AGAF, is Professor of Medicine and Director of Research, Division of Gastroenterology, Department of Medicine, University of California, San Diego.