Wednesday, October 12, 2011

Hepatitis News Ticker: Will the increased prevalence of (NASH) in the age of better HCV therapy make NASH the Deadlier Disease?

Girl Reading By A Window By Edmund Charles Tarbell

New On The Blog

Approximately one-third of the US population is presumed to have nonalcoholic fatty liver disease (NAFLD), with a similar prevalence reported in other parts of the world. Liver-related morbidity stems almost entirely from those individuals with nonalcoholic steatohepatitis (NASH).

The prevalence of NASH in the United States is estimated to be 3%-5%, or roughly 9 million to 15 million persons, of whom up to 20% will develop cirrhosis. As a comparator, hepatitis C virus (HCV) infection, which is the leading indication for liver transplantation, had a prevalence of 1.6% between 1999 and 2002, representing approximately 4.1 million Americans.1

Although the incidence of HCV has plateaued and will possibly decrease over the long term, the incidence of NAFLD is on the rise. Thus, it is not surprising that NASH is predicted to surpass HCV as an indication for liver transplantation in the next 20 years.

The study by Bhala et al.2, in this issue of HEPATOLOGY, makes an important contribution to our understanding of the natural history of NASH. It is a large, multinational study that incorporates patients with advanced but compensated NASH or HCV. Somewhat not surprisingly, Bhala et al. showed that liver-related decompensation and incident hepatocellular carcinoma (HCC) were higher in patients with untreated or refractory HCV, compared to those with advanced NASH.

This article also draws our attention to the development of HCC in patients with HCV or NASH who have not yet developed cirrhosis. There are currently sparse data addressing this in the literature, and this study further underscores the importance of better understanding the potential risk of HCC in patients without cirrhosis.

Several publications have provided insight into the natural history of NAFLD and NASH. In a large population study with a 15-year follow-up, NAFLD was independently associated with liver-related mortality as well as with cardiovascular (CV) disease and HCC, although the effect on the latter two conditions could not be dissociated from insulin resistance.3 To better put into perspective what will happen to our patients with advanced NASH, it is logical to compare it to HCV, a disease with a well-established natural history.

In a small prospective cohort study of Australian patients published in HEPATOLOGY nearly a decade ago, Hui and colleagues compared 23 patients with NASH-derived cirrhosis to 23 patients with untreated HCV-derived cirrhosis and 23 nonresponders with HCV-derived cirrhosis. The authors found that patients with NASH cirrhosis experienced less hepatic decompensation, but a similar mortality to their HCV cirrhosis counterparts.4

In this issue of HEPATOLOGY, Bhala et al. extend their findings to a multinational prospective cohort study that includes patients from Italy, the United States, the United Kingdom, and Australia. They investigated the long-term outcome of patients with NASH or HCV and advanced fibrosis (stage 3 or 4). They compared 247 patients with NASH to 264 patients with HCV (nonresponders or untreated) in the analysis and followed them for a mean of 85.6 and 74.9 months, respectively. The findings demonstrate that whereas the HCV cohort had more liver-related morbidity and incident HCC than the NASH cohort, rates of CV events and overall mortality were no different. Importantly, the current study differs from prior work in that it included patients with stage 3 fibrosis, in addition to those with compensated cirrhosis.

This is a timely study that sheds light on some aspects of the natural history of NAFLD. However, it has limitations that should be considered when interpreting the results. Given the heterogeneity of what we currently refer to as NASH, it is unlikely that any study would be generalizable to the entire NASH population. Ethnic differences in the susceptibility to develop NAFLD or progressive liver injury are well documented.5

For example, Hispanics and Asians (particularly the Indian subcontinent and southeast Asia), are at increased risk for advanced NASH, whereas African Americans are relatively protected despite the presence of similar metabolic risk factors.6-8 Although the current study is a multinational study from four countries (Australia, Italy, the United States, and the United Kingdom), 92% of the patients with NASH were Caucasian. Thus, as the authors concede, it is not clear whether these findings are applicable to other races. Although this is a potential weakness of the study, one could argue that given the heterogeneity of the NASH population at large, studies of ethnic-specific cohorts are important.

It is known that HCV treatment response deters the rate of decompensation and the development of HCC.9 Thus, the natural history of the HCV group chosen by Bhala et al. was at less risk of being influenced by external factors such as viral clearance. However, the disadvantage of this as a comparison group is that it is not representative of the population of patients with HCV-derived cirrhosis that one would encounter in clinical practice, which would include relapsers and those with sustained viral clearance.

Patients in this cohort either did not respond to treatment or were untreated, namely representing the HCV subgroup with the poorest outcome. Were some patients not treated because they were sicker as suggested by a lower platelet count in the HCV-infected cohort?

Moreover, compared to those that respond to treatment, HCV nonresponders have a higher risk of decompensation. Both NASH and HCV are common and often occur together. Unfortunately, data on concomitant fatty liver or insulin resistance was not systematically collected.

The recent approval of the direct-acting antivirals for treatment of HCV raises many questions. Although the natural history of HCV as we know it is likely to change, drug interactions and side effects may limit broad use of direct-acting antivirals. Even so, with more patients achieving viral clearance, one could speculate that this will translate into less liver-related morbidity and mortality, including incident HCC in the years to come.

Although the natural evolution of disease in the HCV cohort was fairly predictable, the NASH cohort may have been influenced by several factors. In the article by Bhala et al., the use of metformin and statins was reported, but no mention was made of thiazolidenediones or vitamin E use. This is particularly relevant, because 50% of the NASH cohort had diabetes, and thiazolidenediones are commonly used in this setting.

Furthermore, there are no data provided on the use of new medications or changes in body weight during the follow-up period. The short-term data on the effects of sustained weight loss, vitamin E, and pioglitazone are compelling, and future studies will be needed to determine their influence on the natural history of NASH.10, 11 While we await these data, we need to, at a minimum, consider the role of such factors as potentially altering the course of NASH for the better.

Given the observational nature of the study, the assessment of liver decompensation was left to the discretion of the investigators. Thus, the “development of varices” as a major outcome of hepatic morbidity could have been ascertained by screening endoscopy or by the development of a variceal hemorrhage. Screening practices for the detection of HCC or varices of the individual centers were not reported. Differences in how these endpoints were reported could be relevant, because the majority of patients with HCV came from Australia and Italy, and the majority of patients with NASH came from the United States and the United Kingdom, suggesting that different screening practices or definitions between the participating centers could have influenced outcome.

HCC does occur in patients with NASH-derived cirrhosis, and others have identified factors such as diabetes that confer an increased risk (1.3- to 2.4-fold) of HCC.12

Some have estimated the risk attributable to HCV to be four- to five-fold higher, and the data reported by Bhala and colleagues do support previous publications.13 Patients with advanced HCV unresponsive to treatment still comprise a large portion of the HCV-infected population, and this subgroup develops decompensated liver disease and HCC at an accelerated rate.14

However, in contrast, a recent prospective cohort study comparing patients with NASH-derived cirrhosis to an unselected group of patients with HCV-derived cirrhosis found that the annual incidence of HCC in patients with NASH compared to those with HCV was no different.1

The authors report equivalent CV outcomes in the two cohorts. Although this is intriguing, such an assertion may be premature. The data supporting the association between NASH and CV disease are fairly robust and have recently been reviewed.16 Prospectively collected data with well-defined cardiac endpoints and longer follow-up are needed to make a definitive statement about differences in CV outcomes between HCV and NASH.

Interestingly, despite comparing patients with advanced NASH to the subset of HCV patients with the worse prognosis, mortality rates were similar. These data suggest that over time, liver-related morbidity, including HCC and mortality due to NASH, may exceed that of the HCV population at large. The combination of the increasing burden of liver disease from NASH and more effective treatments for HCV (and NASH) are sure to change the landscape in how we approach our patients with cirrhosis arising from NASH or HCV. Future studies will be needed to redefine these dynamic populations and assess relative differences in risk as we enter this new era.


Stem Cells

Stem Cell Therapy for Liver Disease Takes Step Forward
By Michael Smith, North American Correspondent, MedPage Today

Published: October 12, 2011Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine.

Action Points

Note that in this study, a proof of concept, a combination of techniques was used in human induced pluripotent stem cells to correct a point mutation in the alpha-1 antitrypsin gene that is responsible for alpha-1 antitrypsin deficiency.

Point out that genetic correction restored the structure and function of the alpha-1 antitrypsin gene in subsequently derived liver cells in vitro and in vivo, validating the concept that genetic correction can be used to generate clinically relevant cells for autologous cell-based therapies

Researchers are reporting they can correct the mutation that causes an inherited liver disease, at least in the lab and in animals.
The report, online in Nature, is "proof of principle" that stem cells can be used as therapy for alpha-1 antitrypsin deficiency and perhaps for other diseases caused by a single mutation, according to Ludovic Vallier, PhD, of Cambridge University, one of the co-authors of the study.
Vallier and other authors told reporters at a London press briefing that more research needs to be done before the novel approach they used can be used to treat patients with the condition – about 100,000 in the U.S.

But, they noted, their approach is a step forward – they were able to correct both copies of the defective gene without introducing potentially dangerous genetic changes elsewhere in the genome.

"We needed to correct both copies of the bad gene," said co-author Allan Bradley, PhD, of the Wellcome Trust Sanger Institute in Cambridge, England. And it had to be done, he added, in such a way that "the genome of the cells was not damaged in any way."
The researchers began with skin cells from patients afflicted with alpha-1 antitrypsin deficiency, which affects one in 2,000 people of Northern European descent and is the most common inherited metabolic disease of the liver.
The condition arises from a single point mutation in both copies of the gene that codes for alpha-1 antitrypsin -- a mutation that causes the protein to form ordered polymers in hepatocytes, eventually leading to cirrhosis.

The only treatment is a liver transplant.

The skin cells were transformed into induced pluripotent stem cells, which have the potential to become any type of cell.
The researchers used a novel approach to modify the stem cells. So-called zinc finger nucleases were used to cut out the mutated base pair, and a DNA sequence dubbed piggyBAC – a so-called transposon -- was used to insert the correct base pair.
One of the important features of piggyBAC, the researchers said, is that it can be removed again without leaving bits of DNA behind.
About 11% of the resulting stem cells had the correct base pair on both copies of the gene, the researchers reported. They also maintained their ability to differentiate into cells expressing markers of the three germ layers.
In a "reassuring" finding, three-quarters of the modified cells with two repaired copies of the gene had the same genomes otherwise as their parental stem cell lines, the researchers reported.

In the lab, the researchers forced the stem cells to differentiate into hepatocytes, which showed characteristics similar to normal liver cells, including glycogen storage, low density lipoprotein-cholesterol uptake, albumin secretion, and cytochrome P450 activity.

Crucially, they also secreted the normal form of alpha-1 antitrypsin, which had similar activity to the protein derived from normal adult hepatocytes.

When the cells were injected into the livers of mice, they quickly became distributed throughout the organ and integrated into the mouse parenchyma. There was no sign of tumor formation, which has been a concern with such genetic manipulation, but there were indications of normal function.

A key hurdle remaining is how to use the cells in treatment, since even in the animals, they still formed only a minority of the liver cells.
One possibility, according to co-author David Lomas, MD, PhD, also of Cambridge, is that the transplanted cells would have a selective advantage over the resident defective cells and over time would take over the liver.
But that, he cautioned is "speculation."

The research shows that stem cells can be used to correct the defect and produce hepatocytes that function normally, he said. "Now we can start to consider how we're going to get them" into patients.

The study was supported by the Wellcome Trust, the MRC Senior nonclinical fellowship and the Cambridge Hospitals National Institute for Health Research Biomedical Research Center, the Medical Research Council and Papworth NHS Trust, the Bill and Melinda Gates Foundation, Inserm and Institut Pasteur, and the Japan Science and Technology Agency.
The authors did not report potential conflicts.
Primary source: NatureSource reference:Yusa K, et al "Targeted gene correction of a1-antitrypsin deficiency in induced pluripotent stem cells" Nature 2011; DOI: 10.1038/nature10424.

Liver Cancer
By: MARY ANN MOON, Internal Medicine News Digital Network
In patients with hepatitis C who develop hepatocellular carcinoma, the serum alpha-fetoprotein level around the time when the cancer is diagnosed is an independent predictor of mortality, Dr. Gia L. Tyson and her colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

Serum alpha-fetoprotein (AFP) level has been incorporated into at least three of the major staging and prognostic scoring systems for hepatocellular carcinoma, all of which were developed in patient populations outside the United States. But until now it was unknown whether AFP level would be predictive in U.S. patients in general, or in U.S. patients whose HCC is related to hepatitis C in particular.

This retrospective cohort study of 1,480 patients shows that these staging and prognostic systems are relevant in the United States, and that testing for serum AFP when HCC is diagnosed would be useful. Such testing is inexpensive, widely available, and easily interpretable, said Dr. Tyson of the Houston VA Health Services Research and Development Center of Excellence and Baylor College of Medicine, and her associates.

The investigators reviewed the records of adults enrolled in a national VA registry of hepatitis C patients who developed HCC between 1998 and 2007, and followed them through 2009 to determine whether serum AFP level correlated with mortality (Clin. Gastroenterol. Hepatol. 2011 November [doi: 10.1016/j.cgh.2011.07.026]).

As veterans, most of the patients (99%) were men and about half (56%) were white. The mean age was 58 years, and 40% of the subjects had cirrhosis. The interval between hepatitis C diagnosis and liver cancer diagnosis was a mean of 3.86 years.

Overall mortality was 87% during a mean follow-up of 1.8 years. After HCC diagnosis, median 1-year survival was 43%, median 3-year survival was 19%, and median 5-year survival was 12% in the study population as a whole.
Median survival was found to be significantly shorter in patients who had high AFP levels around the time of HCC diagnosis.

Specifically, the median survival was 709 days for patients with an AFP level less than 10 ng/mL, 422 days for those with an AFP level of 10-99 ng/mL, 208 days for those with an AFP level of 100-999 ng/mL, and 68 days for those with an AFP level of 1,000 ng/mL or more. Similarly, survival rates at 1 year, 3 years, and 5 years after HCC diagnosis were progressively lower as AFP levels increased.

The 5-year survival rate for HCC was low overall at only 12%, but it was extremely low, at 1%, in patients with serum AFP levels of 1,000 ng/mL or more. In comparison, those with AFP levels less than 10 ng/mL had a 24% survival rate at 5 years, Dr. Tyson and her colleagues said.

The risk of death increased with increasing AFP level independently of patient factors such as age, sex, and race/ethnicity; independently of clinical factors such as the presence of ascites, encephalopathy, and congestive heart failure; and independently of treatment received, including liver transplantation, resection, radiofrequency ablation, or transarterial chemoembolization.

The results of two sensitivity analyses confirmed that mortality increased significantly with increasing AFP level, with hazard ratios of 1.51 for an AFP level of 10-99 ng/mL, 2.29 for an AFP level of 100-999 ng/mL, and 4.22 for an AFP level of 1,000 ng/mL or more, compared with an AFP level less than 10 ng/mL.

"This is the largest study in a United States HCV-infected cohort to report serum AFP levels are predictive of mortality after HCC diagnosis," the investigators noted.
The dose-response relationship between AFP level and mortality risk further strengthens the role of AFP as a predictor of prognosis, they added. These findings are consistent with results from Italian, French, and Chinese patient populations.

"The main limitation" of this study was the lack of data concerning tumor size and staging. However, numerous studies elsewhere, including those in Italy, France, and China, have demonstrated that AFP as a prognostic factor is independent of tumor size and stage, Dr. Tyson and her associates noted.

This study also was limited in that nearly all of the patients were men and most were white, so the findings may not be generalizable to women and other racial/ethnic groups.

This study was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, and the Houston Veterans Affairs Health Services Research and Development Center of Excellence. No financial conflicts of interest were reported.

VA Researcher Promotes Better Care for Liver Cancer Patients

“During the past two decades, the incidence of hepatocellular carcinoma in the United States has tripled, while the five year survival rate has remained below 12 percent,” said El-Serag.

Each year, more than half a million people worldwide receive a diagnosis of hepatocellular carcinoma, the most common form of primary liver cancer. Hepatocellular carcinoma related to the hepatitis C virus is the fastest rising cause of U.S. cancer-related deaths. A researcher at the Michael E. DeBakey VA Medical Center (MEDVAMC) has summarized recent advances in prevention, surveillance, diagnosis, and treatment in order for physicians everywhere may be better educated and improve care for their patients.

The review article, by Hashem B. El-Serag, M.D., M.P.H., chief of Gastroenterology and Hepatology, appeared in the September 22, 2011 issue of the New England Journal of Medicine.

“Approximately 20,000 new cases of hepatocellular carcinoma are diagnosed every year in the United States,” said El-Serag. “During the past two decades, the incidence of hepatocellular carcinoma in the United States has tripled, while the five year survival rate has remained below 12 percent.”

Listed for the past few years as one of the best doctors in the nation in the field of gastroenterology, an elected member of the American Society for Clinical Investigators, and a recipient of the Blue Faerry Award for Excellence in Liver Cancer Research, El-Serag is also a professor of medicine and the chief Gastroenterology and Hepatology Section at Baylor College of Medicine, the director of Cancer Prevention and Population Sciences at the Dan Duncan Cancer Center, and chief of Clinical Epidemiology and Outcomes at the Houston Center for Quality of Care and Utilization.

El-Serag has received extensive research grant funding from the Department of Veterans Affairs, the National Institutes of Health, numerous foundations, as well as private industry. His clinical interests include Barrett’s esophagus, chronic liver disease, and liver cancer.

A study in November's issue of Gut investigates the impact of HIV-associated enteropathy and B cell dysfunction on the high-affinity systemic antibody responses to gut commensal bacteria.
Human systemic antibody responses to commensal microbiota are not well characterised during health and disease.

Dr Anna Haas and colleagues from Switzerland analyzed their potential modulation caused by chronic HIV-1 infection which is associated with sustained enteropathy, and systemic B cell disturbances reflected by impaired B cell responses and chronic B cell hyperactivity.

The team report that the mechanisms underlying B cell hyperactivation and the specificities of the resulting hypergammaglobulinaemia are only poorly understood.
Titres of high affinity antimicrobiota antibodies were increased in IBD patients


By a technique referred to as live bacterial FACS (fluorescence-activated cell sorting), the present study investigated systemic antibody responses to several gut and skin commensal bacteria as well as Candida albicans in longitudinal plasma and serum samples from healthy donors, chronic HIV-1-infected individuals with or without diarrhea and patients with inflammatory bowel disease (IBD).

The data show that systemic antibody responses to the commensal microbiota were abundantly present in humans and remained remarkably stable over years.

Overall systemic antibody responses to gut commensal bacteria were not affected during chronic HIV-1 infection, with titres decreasing when normalised to elevated plasma immunoglobulin G (IgG) levels found in patients with HIV.
In contrast, the team observed that increases in the titres of high affinity antimicrobiota antibodies were detected in patients with IBD, demonstrating that conditions with known increased intestinal permeability and aberrant mutualism can induce changes in antibody titres observed in these assays.

Dr Haas' team commented, "Neither HIV-associated enteropathy nor B cell dysfunction impact on the high-affinity systemic antibody responses to gut commensal bacteria."

"HIV-associated hypergammaglobulinemia is therefore unlikely to be driven by induction of antimicrobiota antibodies."
Gut 2011; 60: 1506-1519 11 October 2011

Unsuccessful interferon-based therapy for chronic hepatitis C virus (HCV) infection appeared to improve or slow liver fibrosis progression in HIV/HCV coinfected people, but this was usually temporary, according to 2 studies presented the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011) last month in Chicago.

Michael Carter Published: 12 October 2011

The life expectancy of patients receiving antiretroviral therapy in the UK improved significantly between 1996 and 2008, research published in the British Medical Journal shows. Patients who initiated HIV therapy when their CD4 cell count was in the region of 350 cells/mm3 had an average life expectancy of approximately 75 years.

However, starting HIV therapy with a CD4 cell count below 200 cells/mm3 was associated with a poorer prognosis, highlighting the importance of improved HIV testing and the prompt initiation of therapy.

“Life expectancy is strongly related to the CD4 count at which individuals start treatment,” write the investigators from the UK Collaborative HIV Cohort (UK CHIC). “This highlights the need to identify people infected with HIV early in the course of their infection, before substantial CD4 loss has occurred.”

Results also showed that, overall, the average life-expectancy of patients with HIV was about 13 years lower than that for the general UK population. However, all the average life expectancy figures reported by the researchers necessarily include patients who started treatment late. This group of patients are known to have a worse prognosis.

HIV is now considered a chronic, manageable condition, and with the right treatment and care the prognosis of many patients is excellent. Although several studies have examined mortality rates in the era of effective HIV therapy, few have examined how long patients with HIV can now expect to live.“Estimates of life expectancy are important to individuals who want to plan their lives better, to service providers, and to policy makers,” explain the investigators. They therefore used data collected between 1996 and 2008 to estimate the life expectancy of patients who started HIV therapy when their CD4 cell count was below 350 cells/mm3, the current threshold for starting antiretroviral treatment in the UK.

The life expectancy of patients with HIV was compared with the life expectancy of the general UK population, and the investigators also calculated the impact of late initiation of HIV therapy on prognosis.

A total of 17,661 individuals aged 20 and above were included in the study. Most of the patients were men (75%), white (58%), and their median age was 37 years. Overall, 42% of patients started HIV treatment late – defined as a CD4 cell count below 200 cells/mm3.Patients were followed for a median of 5 years, and during 91,203 person years of follow-up a total of 1248 (7%) of individuals died. The overall mortality rate was 13.7 per 1000 person years. However, this fell from 28.8 per 1000 person years in 1996-99 to 9.5 per 1000 years between 2006-08. Improvements in HIV treatment in care over the period largely account for this fall in the mortality rate.

The investigators calculated that a 20-year-old receiving HIV therapy in 1996-99 would live on average a further 30 years. This life expectancy increased to 46 years in the period 2006-08.

Life expectancy for a 35-year-old was an additional 20 years of life in 1996-99, and 31 years in the period 2006-08.

However, prognosis differed by gender, and was significantly better for women than men. Overall, life expectancy for a 20-year-old woman was an additional 50 years compared to 40 years for men.

HIV-positive patients had a significantly shorter life expectancy than individuals in the general population. A HIV-negative 20-year-old woman would be expected to survive until she was 82 years old and an HIV-negative man until he was 78.

“Compared with the same sex in the general UK population, for patients undergoing treatment for HIV infection, life expectancy at age 20 was 18.3 years less for men and 11.4 years less for women,” write the investigators.

They note “the prevalence of smoking, drug misuse, and alcoholism are all higher among people with HIV, which leads to increased deaths from cardiovascular disease, cancer, liver disease, suicide, overdose and injury.”But further analysis showed that starting HIV treatment promptly significantly improved prognosis – which approached normal levels for patients who initiated therapy at a level indicated by current guidelines.

Patients who started therapy with a CD4 cell count between 200 and 350 cells/mm3 had an average life expectancy of 75 years, but this fell to 61 years for individuals who initiated therapy when their CD4 cell count was between 199 and 100 cells/mm3 and to 58 years for those who started treatment with a CD4 cell count below 100 cells/mm3.

“Patients should start antiretroviral therapy once their CD4 cell count has fallen below 350 cells/mm3,” emphasise the investigators.“Life expectancy among people with HIV has considerably improved in the UK between 1996 and 2008, and we should expect further improvements for patients starting antiretroviral therapy now with improved drugs and new guidelines recommending earlier treatment,” conclude the authors. “The clear impact of low CD4 cell count on life expectancy implies that it is particularly important to diagnose HIV infection at an early stage.”


May M et al. Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) study. BMJ 343, doi: 10.1136/bmj.d6016, 2011 (click here for the open access article).

Barham K. Abu Dayyeh, Namrata Gupta, Kenneth E. Sherman, Paul I. W. de Bakker, Raymond T. Chung, for the Aids Clinical Trials Group A5178 Study Team
Research Article, published 07 Oct 2011

IL28B SNPs have an additive allele dose effect in predicting HCV treatment outcomes in HCV/HIV coinfected persons and can be incorporated into a simple pretreatment prediction score that could minimize the risk of exposure to PEG/RBV therapy for persons with unfavorable scores.


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Marcelo Papelbaum, Rodrigo O Moreira, Walmir Coutinho, Rosane Kupfer, Leao Zagury, Silvia Freitas and Jose C Appolinario

Diabetology & Metabolic Syndrome 2011, 3:26 doi:10.1186/1758-5996-3-26
Published: 7 October 2011

Abstract (provisional)

View Full Text Here

Comorbid depression in diabetes has been suggested as one of the possible causes of an inadequate glycemic control. The purpose of this study was to investigate the association between major depression and the glycemic control of type 2 diabetes mellitus (T2DM).


Seventy T2DM patients were evaluated. They underwent a psychiatric examination using the following instruments: Structured Clinical Interview for DSM-IV and Beck Depression Inventory. The diabetes status was assessed in the short-term (glycemia, glycated hemoglobin) clinical control.


The presence of current depression was observed in 18.6% (13/70). In addition, type 2 diabetes patients who displayed depression evidenced higher levels of glycated hemoglobin (8.6 +/-2.0 vs. 7.5 +/-1.8; p=0.05) when compared to those who did not exhibit a mood disorder.


In our sample, the presence of depression seems to impact on the short-term control of T2DM. The authors discuss the clinical utility of these findings in the usual treatment of diabetes.

The complete article is available as a provisional PDF

Autoimmune Disease/Women

The War Within: Women and Autoimmunity
Released: 10/12/2011 12:20 PM EDT

Society for Women's Health Research (SWHR)
Newswise — WASHINGTON, D.C. (October 12, 2011) —

50:1, 9:1, 2:1 these are just some ratios of autoimmune disease disparities between women and men.

The Society for Women’s Health Research (SWHR) hosted the Capitol Hill briefing, The War Within: Women and Autoimmunity, on Tuesday, October 11 to address these concerns. The briefing featured two panelists who spoke about autoimmune diseases in women, and the efforts needed to advance the understanding and treatment of these often serious conditions.

Autoimmune disease occurs when the body’s immune system attacks its own organs, cells and tissues. There are approximately 80-90 autoimmune diseases that affect 20-50 million Americans, many of which are debilitating. While autoimmune diseases affect both men and women, many diseases are more prevalent in women. Hashimoto’s thyroiditis, for example, which impairs functioning of the thyroid, affects 50 times more women than it does men and systemic lupus affects nine times more women than men.

Both a patient and an advocate, Kathleen Ann Arnsten has been diagnosed with eight different autoimmune diseases and must take 30 medications daily in order to function. She describes her experiences with autoimmune diseases as “devastating,” and warns that even though patients may appear healthy, pain is ravaging them within; we cannot be apathetic towards research for better treatments.

Due to the various symptoms of an autoimmune disease and the fluctuating severity of those symptoms, care is highly individualized according to the patient’s needs. Often, a patient must try many different treatments before an effective one is found. Some autoimmune diseases, like lupus, are incurable and can be fatal. Additionally, there is a great shortage of treatments available, causing many patients to turn to expensive off-label drugs to manage their conditions. Arnsten stressed the need for further research and clinical trials surrounding autoimmune diseases, with the potential to discover and patent new treatments.

Panelist Annette Rothermel, PhD, Program Officer at the Autoimmunity and Mucosal Immunology Branch at the National Institutes of Allergy and Infectious Diseases (NIAID), spoke about NIAID and its ongoing autoimmunity research efforts. The National Institutes of Health (NIH) Autoimmune Disease Coordinating Committee, chaired by NIAID and founded in 1998, promotes research of autoimmune diseases by NIH, federal agencies, advocacy groups, and private organizations. Current autoimmunity research funded by NIAID aims for greater understanding of the role of immune systems in initiating and maintaining autoimmune disease, improvement of experimental systems and diagnostics, and development of advanced therapies and prevention strategies for autoimmune conditions.

The fact that most patients suffer for five to 10 years from an autoimmune disease before receiving an accurate diagnosis supports the conclusion that the general public, and even healthcare professionals, remain largely unaware of autoimmune disease symptoms and the severity of such conditions. While the cure for autoimmune diseases may still be out of reach, Arnsten and Rothermel agree that large improvements can and must be made in diagnosis and treatment.

For more information on the Society for Women’s Health Research please contact Rachel Griffith at 202-496-5001 or

The Society for Women’s Health Research (SWHR), a national non-profit organization based in Washington D.C., is widely recognized as the thought leader in women’s health research, particularly how sex differences impact health. SWHR’s mission is to improve the health of all women through advocacy, education and research. Visit SWHR’s website at for more information.


L.A. firm recalls 377,775 pounds of ground beef in E. coli scare

Commercial Meat Co. is calling back 377,775 pounds of meat after routine testing discovered the bacterium.

The beef was processed between Sept. 7 and Oct. 7 and shipped to restaurants in California and Nevada in the form of bulk ground beef, patties, taco meat and chili, according to the U.S. Department of Agriculture’s Food Safety and Inspection Service.

Off The Cuff
Posted: 2011-10-11 14:35

Papers trumpeting new drug targets are a staple of biomedical journals such as Nature Medicine, but their claims are viewed skeptically by many drug development professionals. This skepticism has only been reinforced by a recent attempt to put some numbers on the reproducibility of such reports in a real-world setting (Nat. Rev. Drug Discov. 10, 712, 2011). The authors, from Bayer Healthcare, surveyed their in-house scientists tasked with experimentally validating publications on new drug targets. For only 21% of the 67 cases examined did they find results considered to be completely in line with the literature.
  • A reproducibility rate of 21% seems remarkably low, and the Bayer authors didn't find any obvious trends to explain this. Given the limited information provided in their report, it's difficult to make an independent evaluation of their findings, and a more fine-grained look at each of the cases might yield further insights. Notably, 70% of the cases examined involved oncology drug targets, so the situation might be different in other therapeutic areas.

    Why should published research on new drug targets be so challenging to replicate? Although it doesn't seem plausible that outright fraud could account for a high fraction of the failure rate, less serious forms of bias—so-called 'questionable research practices', such as selective presentation of data—are likely a more pervasive problem (see PLoS ONE 4, e5738, 2009). Statistical errors made by authors, such as the use of insufficient sample sizes, may arise simply from ignorance but have the potential to undermine the conclusions of many papers. Even a basic statistical procedure—comparing the difference between two experimental effects—is widely botched (Nat. Neurosci. 14, 1105, 2011). (Click here to continue reading.)

A new University of British Columbia study finds that Black Canadians with darker skin are more likely to report poorer health than Black Canadians with lighter skin. The study also suggests that a mismatched racial identity can negatively affect health.

The study, published online in the current issue of Social Science & Medicine journal, provides the first Canadian evidence of the health effects of "colourism," discrimination targeted more strongly at darker-skinned than lighter-skinned people of colour, says the author.

Researchers surveyed the self-reported racial identities -- Asian, Black, South Asian and White -- of nearly 1,500 participants from Vancouver and Toronto across four key health indicators: high blood pressure, depression, mental health and overall health.

While some findings support existing research -- that Black Canadians are more likely than others to report high blood pressure and that Asian Canadians are most likely to report poorer mental health -- the study found that Black Canadians with darker skin were as much as four times more likely than Black Canadians with lighter skin to report poor overall health.

Although U.S. scholars have researched the wide-ranging effects of colourism for African Americans, including effects on health, the UBC study's author Prof. Gerry Veenstra, Dept. of Sociology, says this is the first study to suggest that colourism can affect the health of Canadians as well.

"The findings indicate that, for Black Canadians, levels of discrimination can depend on the relative darkness or lightness of their skin," says Veenstra. "For health researchers and policymakers, this means that the broad racial classifications typically used by health researchers may actually underestimate the magnitude of racial health inequalities in this country."

"This is a first step to understanding colourism's manifestations in Canada and the degree to which and for whom it affects health and well-being," adds Veenstra, who plans to study whether colourism affects other Canadian racial identities.

The study also finds that mistaking an individual's racial identity can have significant negative physical or mental impacts. Participants who reported higher levels of racial identity mismatches were found to be at greater risk of high blood pressure, poorer self-rated mental health and poorer self-rated overall health.

"For instance, people who considered themselves to be White but believed others tend to think they are something else -- perhaps that they were of mixed race, for example -- were at a higher risk of high blood pressure and poor mental health," Veenstra says.

While the study did not investigate the causes of this phenomenon, Veenstra says previous studies have suggested that people experience stress when the cues provided by others do not match their conceptions of themselves, a stress that can be strong enough to elicit adverse health outcomes.

When it comes to vitamins, it appears you could have too much of a good thing, say researchers who report a link between their use and higher death rates among older women.

Experts have suspected for some time that supplements may only be beneficial if a person is deficient in a nutrient.

And excess may even harm, as the study in Archives of Internal Medicine finds.

All of the women, in their 50s and 60s, were generally well nourished yet many had decided to take supplements.

Multivitamins, folic acid, vitamin B6, magnesium, zinc, copper and iron in particular appeared to increase mortality risk.

The researchers believe consumers are buying supplements with no evidence that they will provide any benefit.

Healthy You

Vitamins linked with higher death risk in older women

Based on existing evidence, we see little justification for the general and widespread use of dietary supplements”

They are quick to stress that their study relied on the 38,000 US women who took part in it recalling what vitamins and minerals they had taken over the previous two decades.

And it is difficult to control for all other factors, like general physical health, that might have influenced the findings.

But they say their findings suggest that supplements should only be used if there is a strong medically-based cause for doing so because of the potential to cause harm.

"Based on existing evidence, we see little justification for the general and widespread use of dietary supplements," Dr Jaakko Mursu of the University of Eastern Finland and his research colleagues said.

Less is more
In the study, iron tablets were strongly linked with a small (2.4%) increased death risk, as were many other supplements. The link with iron was dose-dependent, meaning the more of it the individual took, the higher their risk was.

Too much can be toxic and it is easy to inadvertently take more than the recommended daily amount”End Quote Helen Bond British Dietetic Association

Conversely, calcium supplements appeared to reduce death risk. However, the researchers say this finding needs more investigation and they do not recommend that people take calcium unless advised to by a doctor in order to treat a deficiency.
Drs Christian Gluud and Goran Bjelakovic, who review research for the Cochrane Database of Systematic Reviews to evaluate best evidence, said: "We think the paradigm 'The more the better' is wrong."

They say dietary supplementation has shifted from preventing deficiency to trying to promote wellness and prevent diseases, and caution: "We believe that for all micronutrients, risks are associated with insufficient and too-large intake."

Helen Bond of the British Dietetic Association said some people, like the elderly, might need to take certain supplements. For example, vitamin D is recommended for people over the age of 65.

But she said that generally, people should be able to get all the vitamins and minerals they needed from a healthy, balanced diet.

She said some took supplements as an insurance policy, wrongly assuming that they could do no harm. "But too much can be toxic and it is easy to inadvertently take more than the recommended daily amount."

Reporting on new study findings that vitamin supplements can cause harm, the BBC News cites the Cochrane authors of reviews on vitamin D and antioxidant supplementation.

Pain characteristics suggest higher benefit from gallbladder surgery

According to a new study in Clinical Gastroenterology and Hepatology, better understanding of a patient's abdominal pain could help physicians know which patients will benefit most from surgical removal of the gallbladder. Clinical Gastroenterology and Hepatology is the official journal of the American Gastroenterological Association.

Nearly 800,000 gallbladder removal surgeries, or cholecystectomies, are performed annually in the U.S. at a cost exceeding $6 billion. Surgeries are often performed on patients whose gallstones are discovered via imaging tests after patient complaints of abdominal pain. Considering that abdominal pain persists in up to 50 percent of patients after cholecystectomy, physicians need a better way to determine who will benefit from surgery.

"Given the number of cholecystectomies that are performed, this study underscores the importance of taking a detailed history when selecting patients for surgery," said Johnson L. Thistle, MD, of Mayo Clinic and lead author of this study. "About 80 percent of gallstones never become symptomatic. Identifying the features of episodic gallbladder pain and differentiating them from symptoms of gastroesophageal reflux disease and irritable bowel syndrome should lead to improved symptom relief and value for patients with abdominal pain."

Researchers prospectively studied 1,008 patients with upper abdominal pain who had elective cholecystectomy for uncomplicated gallstone disease. The following pain characteristics, especially if multiple, were most predictive of pain relief after surgery: episodic pain (usually once a month or less), lasting 30 minutes to 24 hours, occurring during the evening or at night, and onset one year or less before presentation.

Gallstones form in the gallbladder and are composed predominately of cholesterol, which has separated out of solution in bile and formed crystals, much as sugar may form in the bottom of a syrup jar. Gallstones may be as small as a grain of sand or as large as a golf ball, and the gallbladder may contain anywhere from one stone to hundreds. It is not entirely known why some people develop gallstones and others do not.

Many people with gallstones have no symptoms, and often, the gallstones are found when tests are performed to evaluate other problems. In this case, no treatment is usually recommended. When symptoms do arise, gallbladder removal is the most widely used therapy.

For more information on gallstones, please read the AGA brochure "Understanding Gallstones."

About the AGA Institute

The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization.

About Clinical Gastroenterology and Hepatology

The mission of Clinical Gastroenterology and Hepatology is to provide readers with a broad spectrum of themes in clinical gastroenterology and hepatology. This monthly peer-reviewed journal includes original articles as well as scholarly reviews, with the goal that all articles published will be immediately relevant to the practice of gastroenterology and hepatology. For more information, visit

Of Interest ?

Biolectrics developing pain-free severe gingivitis treatment device

Cirrhotics have a higher degree of severity of gingival inflammation or gum disease. The gum infection can leak bacteria into the blood stream, causing potentially severe infections in those with cirrhosis. This device may be a welcome addition for treating gum disease in the many thousands of people suffering with cirrhosis.

From HCV Advocate

Dental examination: Gingivitis or infection of the gums can seed bacteria into the blood stream. In healthy individuals this is of minor consequence, but in cirrhotics, it can cause severe infections. Moreover, if a patient with cirrhosis needs a liver transplant, the presence of gingivitis will prevent him or her from receiving a liver. We recommend our patients with cirrhosis to visit a dentist once a year. As the liver disease becomes more advanced (CPT Class B or C) we recommend dental exams every 6 months.

Biolectrics developing pain-free severe gingivitis treatment device

A Cleveland-area startup is developing a battery powered device that’s aimed at treating severe gingivitis and other forms of gum disease with less pain and at a lower cost than current therapies.

Biolectrics recently received more than $200,000 in nondilutive funding from Lorain County Community College and Cuyahoga County that it will use to build prototypes of its device and begin in vitro testing, said Chief Operating Officer Bill Leimkuehler.

Citing ongoing work on patent applications, Leimkuehler was hesitant to reveal much about how the company’s OraFlow device works. He did allow that the company plans to have the device on the market by the first quarter of 2013 and that it’ll be targeted at dentists.

The company appears to have a large potential market for its periodontitis treatment device. Advanced gum disease affects between 4 and 12 percent of U.S. adults, according to the Centers for Disease Control and Prevention. Once it rolls out its device, Biolectrics would do well to target geographic areas with high rates of smoking, given that the prevalence of gum disease is three times higher among smokers than among people who have never smoked, according to the CDC.

Biolectrics’ own research indicates that 56 million Americans suffer from severe gum disease, with a large portion of that number going untreated. “This is a tool that can be used to capture that untreated market,” he said.

The company’s primary advantage over current therapies for severe gum disease is twofold: cost and ease of use. In other words, Biolectrics’ OraFlow device is aimed at reducing the pain in patients’ gums as well as their wallets. However, because the company is reluctant to reveal details, it’s difficult to assess Biolectric’s claims of cost-effectiveness and pain reduction.

Severe gum disease is typically treated with scaling and root planing – scraping plaque from a patient’s gumline and tooth roots with a sharp device — or worse, flap surgery or bone grafting. Flap surgery involves cutting and folding back portions of the gums to access and clean diseased tissue. Both approaches, especially surgery, can be costly and painful.

“The existing treatments are somewhat barbaric in that they’re a brute-force attack on the plaque buildup,” Leimkuehler said.

The company is hoping to raise an unspecified amount of angel funding to further product development, and to make that investment more enticing, Biolectrics recently was approved for the Ohio Technology Investment Tax Credit.

For Your Reading Pleasure

Grand Rounds

Grand Rounds is a weekly summary of the best health blog posts on the Internet. Each week a different blogger takes turns hosting Grand Rounds, and summarizing the best submissions for the week.

This Weeks Host Is Healthcare Economist
This is a great time to be the Healthcare Economist. Not only am I hosting Grand Rounds for the first time, but Wisconsin sports are enjoying a renaissance. The Milwaukee Brewers are in the NLCS, the Green Bay Packers are Super Bowl Champs and undefeated, and the Wisconsin Badgers also have not lost.

How does this relate to this week’s edition of Grand Rounds? I have no idea. But I know if you’ve made it this far, you might as well take a few more minutes to review the best medical posts on the blog-o-sphere during the past week. Enjoy!

A few submissions from this weeks grand rounds below, to read more click here

Best post on health-related legal issues
. There is research suggesting that 7% of all abnormal labs are never reported to patients. Why is this? One reason is that certain state laws do not require providers to make lab test results available to patients. Would federal laws allowing all lab results to be made available to patients reduce this number? The Health Care Law Blog investigates.

Best post on worst hospitals. Characteristics of the worst hospitals: smaller, for-profit or public, and located in the South. Characteristics of the best hospitals: nonprofit, in the Northeast, major teaching hospitals and in urban areas. The ACP hospitalist review the results in more detail and also notes that the worst hospitals are much more likely to treat minorities and poor patients than the best hospitals (Question to the reader: is this a causal relationship and if so in which direction?)

To read more click here


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