HCV New Drug Research

Bacterial imbalance may be behind liver disease

2012-02-02T17:11:00.001-05:00

Bacterial imbalance may be behind liver disease

Unhealthy liver panel test results are generally thought to be the consequence of lifestyle factors. Obesity and excessive alcohol consumption can damage the organ and impair its function.

However, a new study from a team of Yale University researchers suggests that liver damage and obesity may frequently be caused by contagious microbial imbalances.

The research team showed that mice that lacked two key proteins that regulate inflammatory responses developed imbalances of microorganisms in their guts. This led to an increase in obesity and liver disease.

Furthermore, the study showed that when mice with these microbial imbalances were placed in confinements with normal mice, the healthy animals ended up developing the same disturbances, suggesting that the problem may be contagious.

On the bright side, the problems appeared to be relatively easy to treat and to reverse.

"We found, in mice, that targeted antibiotic treatment brought the microbial composition back to normal, and thus eased the liver disease," said lead researcher Richard Flavell. "Our hope is that our findings may eventually lead to a treatment for humans."

The findings could lead to a new understanding of the causes of obesity and unhealthy liver panel tests, which may lead to improved treatments.

ADNFCR-2248-ID-800698785-ADNFCR

Strategies for Success: Management of Telaprevir-Associated Rash and Anorectal Symptoms

2012-02-02T16:33:00.001-05:00

Strategies for Success: Management of Telaprevir-Associated Rash and Anorectal Symptoms

Scott Cotler , M.D.

Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.

Despite increased sustained virologic response (SVR) rates associated with protease inhibitor–based therapy, challenges exist, including adverse events. Rash and anorectal symptoms are among the more common adverse events associated with telaprevir,^[1] although the mechanism of action resulting in these adverse effects is currently unknown. Although there is an increase in adverse events associated with telaprevir, these events are rarely serious, may be managed, and should not dissuade clinicians from giving patients the best possible treatment for hepatitis C virus (HCV) infection to increase the chance of SVR.
This commentary reviews what is known about telaprevir-associated rash and anorectal symptoms and how these events can be managed to help patients successfully complete a course of treatment.

Rash
Data from controlled clinical trials of telaprevir indicate that approximately 56% of patients experienced rash.^[1] Telaprevir-associated rash is eczematous, associated with dry skin and pruritus, and in some cases has a maculopapular component. The rash is similar in appearance and histology to that observed with peginterferon/ribavirin but can be more extensive or severe. Rash onset typically occurs within the first 4 weeks of telaprevir treatment, with a median time to onset of 25 days; however, it is important to recognize that rash can develop any time during telaprevir therapy.^[1,2] In most cases the rash does not progress and it tends to resolve gradually over weeks after telaprevir is discontinued. At our center, my colleagues and I have seen some transient cases of telaprevir-associated rash that resolved while patients continued to take telaprevir.
Severe rash, which is generalized and covers more than 50% of body surface area or which shows evidence of skin breakdown (eg, vesicles, ulcerations), was reported in 4% of patients receiving telaprevir in controlled clinical trials.^[1] Potentially life-threatening events, including Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) syndrome and Stevens-Johnson syndrome, were rarely reported. An analysis of more than 1200 patients treated with telaprevir during the clinical development program identified 11 cases of DRESS (< 1%) and 2 cases of Stevens-Johnson syndrome (< 0.2%).^[2] These diagnoses were judged as probable or possible by a dermatology expert panel. On a positive note, these syndromes resolved with telaprevir discontinuation in all cases. Thus, although severe events can occur, they are quite rare. Nevertheless, clinicians need to remain vigilant for the development of these syndromes.

Clear guidance for managing telaprevir-associated rash is detailed in the prescribing information.^[1,2] Management of rash that is mild (localized) or moderate (more diffuse, but covering < 50% body surface area) involves continuing all medication, monitoring for progression, and using symptomatic therapy consisting of topical corticosteroids and/or oral antihistamines. Systemic corticosteroids are contraindicated given the potential for drug-drug interactions with telaprevir. For severe rash, the management approach is to discontinue telaprevir, continue peginterferon/ribavirin, and monitor patients closely over the course of 7 days. If the rash does not improve or worsens, consideration should be given to discontinuing ribavirin and/or peginterferon. If a patient shows evidence of either DRESS or Stevens-Johnson syndrome, all treatment should be immediately stopped, with favor given to patient hospitalization and consultation from a dermatologist. It is very important not to reduce the dose of telaprevir in response to rash—or any adverse event, for that matter—as dose reduction may result in the emergence of telaprevir-resistant HCV variants.

This rash management plan was implemented in the phase III studies of telaprevir with success.^[2] Although the overall incidence of rash remained similar in the phase III trials to that seen in the phase II trials, the rate of discontinuation of all medications due to rash fell to 1.1% in the phase III trials compared with a rate of 6.2% in the phase II trials. Thus, by using this management plan, most cases of rash can be effectively handled, allowing patients to remain on telaprevir therapy and maximizing the potential response to treatment.

Anorectal Symptoms
In the controlled trials of telaprevir, anorectal symptoms consisted primarily of hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning.^[1] Some patients experience diarrhea while taking telaprevir, which can exacerbate these symptoms. Overall, 29% of patients treated with telaprevir experienced anorectal symptoms. Most events were mild, and it was rare that they were treatment limiting. The median time to onset was 9 days, and the median duration was 57 days.^[3] My colleagues and I have found in our practice that these symptoms are troubling or annoying to patients, but tolerable. Moreover, it is very rare that patients need to discontinue treatment due to these events.
Management of anorectal adverse events should target the symptoms through use of topical lubricants (eg, petroleum jelly, aloe vera), topical hydrocortisone cream, and in some cases, topical anesthetics (eg, lidocaine). The underlying approach is to get patients through treatment and to remind them that these symptoms will resolve when the course of telaprevir is complete.

Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:

Free registration is required to view the below links

To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.

1. Incivek [package insert]. Cambridge, Mass: Vertex Pharmaceuticals Inc.; 2011.
2. Cacoub P, Bourlière M, Lübbe J, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol. 2011;[Epub ahead of print].
3. US Food and Drug Administration, Center for Drug Evaluation and Research. Drug approval package, Incivek (telaprevir) film-coated tablets. Application number: 201917Orig1s000, medical review(s). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201917Orig1s000MedR.pdf. Accessed December 12, 2011.

Coffee consumption reduces the risk of advanced fibrosis in NAFLD-nonalcoholic fatty liver disease

2012-02-02T15:21:00.000-05:00

Coffee Consumption Reduces Fibrosis Risk in those with Fatty Liver Disease

February 2, 2012
Caffeine consumption has long been associated with decreased risk of liver disease and reduced fibrosis in patients with chronic liver disease. Now, newly published research confirms that coffee caffeine consumption reduces the risk of advanced fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Findings published in the February issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, show that increased coffee intake, specifically among patients with nonalcoholic steatohepatitis (NASH), decreases risk of hepatic fibrosis.

The steady increase in rates of diabetes, obesity, and metabolic syndrome over the past 20 years has given rise to greater prevalence of NAFLD. In fact, experts now believe NAFLD is the leading cause of chronic liver disease in the U.S., surpassing both hepatitis B and C. The majority of patients will have isolated fatty liver which has a very low likelihood of developing progressive liver disease. However, a subset of patients will have NASH, which is characterized by inflammation of the liver, destruction of liver cells, and possibly scarring of the liver. Progression to cirrhosis (advanced scarring of the liver) may occur in about 10-11% of NASH patients over a 15 year period, although this is highly variable.

To enhance understanding of the correlation between coffee consumption and the prevalence and severity of NAFLD, a team led by Dr. Stephen Harrison, Lieutenant Colonel, U.S. Army at Brooke Army Medical Center in Fort Sam Houston, Texas surveyed participants from a previous NAFLD study as well as NASH patients treated at the center's hepatology clinic. The 306 participants were asked about caffeine coffee consumption and categorized into four groups: patients with no sign of fibrosis on ultrasound (control), steatosis, NASH stage 0-1, and NASH stage 2-4.

Researchers found that the average milligrams in total caffeine consumption per day in the control, steatosis, Nash 0-1, and Nash 2-4 groups was 307, 229, 351 and 252; average milligrams of coffee intake per day was 228, 160, 255, and 152, respectively. There was a significant difference in caffeine consumption between patients in the steatosis group compared to those with NASH stage 0-1. Coffee consumption was significantly greater for patients with NASH stage 0-1, with 58% of caffeine intake from regular coffee, than with NASH stage 2-4 patients at only 36% of caffeine consumption from regular coffee.

Multiple analyses showed a negative correlation between coffee consumption and risk of hepatic fibrosis. "Our study is the first to demonstrate a histopatholgic relationship between fatty liver disease and estimated coffee intake," concludes Dr. Harrison. "Patients with NASH may benefit from moderate coffee consumption that decreases risk of advanced fibrosis. Further prospective research should examine the amount of coffee intake on clinical outcomes."

More information: "Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholic Steatohepatitis, and Degree of Hepatic Fibrosis." Jeffrey W Molloy, Christopher J Calcagno, Christopher D Williams, Frances J Jones, Dawn M Torres, Stephen A Harrison. Hepatology; December 22, 2011(DOI: 10.1002/hep.24731);; Print Issue Date: February 2012.

Roundwood Doctor Nicola leads Hepatitis C reseach

2012-02-02T07:42:00.001-05:00

Roundwood Doctor Nicola leads Hepatitis C reseach

By MYLES BUCHANAN

Wednesday February 01 2012

A DOCTOR FROM Roundwood is leading pioneering research into Hepatitis C.
Dr. Nicola Fletcher is the head of a team of virologists from the University of Birmingham who found that the endothelial cells in the brain possess the four main protein receptors necessary for the blood-brain barrier to be targeted by HCV.

The findings, which are published in Research Highlights in the journal Nature Reviews Gastroenterology and Hepatology, show that cells other than liver hepatocytes can be vulnerable to HCV infection.

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that poses a global health problem. Infection leads to progressive liver disease and has been associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities.

Working with the Manhattan Brain Bank in New York, USA, the researchers, led by Dr. Fletcher, of the University's School of Immunity and Infection, detected HCV genomic material in the brains of four out of ten infected patients who posthumously donated brain and liver tissue.
The team went on to demonstrate in laboratory tests that brain cells isolated from the blood-brain barrier could be infected with HCV.

' This is the first report that cells of the central nervous system support HCV replication,' says corresponding author Professor Jane Mckeating, chair of molecular virology at the University of Birmingham. ' These observations could have clinical implications providing a reservoir for the virus to persist during antiviral treatment'

Dr. Fletcher was educated in St David' Secondary School in Greystones, University of Limerick, and UCD where she completed her PHD before moving to the University of Birmingham to progress her research into the Hepatitis C virus.

Speaking about the findings, she says, ' The endothelial cells make up the security system of the brain, a kind of bouncer at the door that keeps out undesirable elements. If this barrier is compromised all kinds of substances can gain access to the brain, which may explain the fatigue and other symptoms reported by Hcv-infected patients.'

The current standard of care for treating Hcv-infected patients is only partially effective, she says, so there is a considerable drive to develop agents that target viral specific enzymes as alternative therapies. 'We anticipate that such agents will be less able to cross the bloodbrain barrier compared to existing drugs. We believe our data provides a detailed mechanistic view of how an infectious agent can target the brain.' Dr. Fletcher's other passion in life in the UK is her award-winning flock of pedigree Jacob Sheep appropriately called the 'Sugarloaf Jacob Flock' which she keeps at her home in Roundwood.

- MYLES BUCHANAN

Hepatitis C-What A Pain-Liver Pain!

2012-02-01T19:55:00.005-05:00

Liver pain is a common symptom for people living with hepatitis C. Although, we as patients feel somewhat humored when describing the pain to our physicians, we know its there, but do they hear us?

Being a patient isn't easy, so why not be the doctor?
Maybe if we used the medical term for "liver pain" while describing our discomfort, we may just raise a few eyebrows.

Enter you.

Excuse me, Dr. Frances Liver M.D., if I could bring to your attention this ongoing "Hepatalgia" I've had for the last six months.

On second thought, skip the medical jargon. I'm easily confused by Google.

Here's the deal folks, during routine check ups most physicians wait for patients to raise any issues they might be having, right? We're the chosen one to bring up symptoms or treatment side effects. Wouldn't it be refreshing if after treating with incivek for about a month, Dr. William Rectum M.D., asked you straight up if you still have full use of your anus?

Hey, that side effect is a whole other story, if you're suffering with it-check it out here. Other side effects like dry mouth-its here, fever- here, rash you say? Yep, that's here and here.

SVR-priceless!!

Liver pain, side effects, are all part of equation, but when you reach the end of the race and hear you're SVR, the journey was worth the ride. For the brave people who continue to fight this disease, may the drugs you need be available soon.

While searching for information related to liver pain and hepatitis C, I found a few interesting facts from an online survey held by Hepatitis C Trust. The survey ran from April 2006 to September 2007 and asked people about their experience during hepatitis C treatment. Also how they felt after treatment ended.

Liver Pain Before, During And After HCV Therapy

Before treatment 33% participants experienced liver pain, that's 165 out of the 500 people who took part in the survey. During therapy 28% of respondents continued to have liver pain. However, six to twelve months after therapy the percentage dropped to 21%. One year after treatment, liver pain was reported by only 15% of people surveyed.

Of the 500 respondents who took part in the survey 90 (18%) reported they had been diagnosed with cirrhosis before starting treatment. To check out the complete survey download the PDF here.

Although HCV infection is not usually a cause of chronic pain, people with hepatitis C can have pain in the liver area as a direct result of the infection.

According to an article at Better Medicine, the liver’s pain receptors lie primarily on its surface, especially in the capsule covering a portion of the liver, meaning that pressure on the capsule is most often the source of pain. This pain is usually felt in the upper right part of the abdomen, often under the rib cage, and is almost always associated with a swelling or enlargement of the liver, acute inflammation or distention of the liver’s surface, or any other sort of injury that puts pressure on the capsule.

Liver pain may be confused with a more general abdominal pain, unless it occurs specifically in the upper right abdomen. Even then, right upper quadrant pain can be due to gallstones, intestinal pain, pancreatitis, or other abdominal disorders. Because pain in the liver area can be caused by many different conditions, some of which are serious, it is important for you to contact your health care provider to determine the underlying cause.

Additionally, there are diseases that have an association with hepatitis C infection, such as HCV-associated arthritis or cryoglobinemia, and "Conditions Outside The Liver" which may cause other chronic pain.

A Few Sources Of Pain In Liver Disease

Liver pain.
Pain in the right upper quadrant of the abdomen, the area over the liver, is due to the distention, or stretching, of the fibrous capsule that encloses the liver.
Changes in liver size due to inflammation are the most common causes of liver pain.
If the liver disease progresses towards cirrhosis, the incidence of liver-related right upper quadrant pain tends to decrease.

The Biliary System.
The gallbladder is a hollow organ located under the lower surface of the liver.
The liver enfolds the gallbladder and the ducts that transport bile from the gallbladder to the small intestine.
Swelling or inflammation of the liver capsule can cause the gallbladder and bile ducts to become irritated.
Spasms of the gallbladder and biliary tract can cause pain that radiates to the right shoulder and subscapular area (the area beneath the shoulder blade).
Inflammation of the gallbladder can also cause pain beneath the lower right margin of the ribcage.

Intestinal pain.
Intestinal problems can cause extreme pain that can be both acute and chronic.
Stretching of the large bowel by gas or constipation can cause pain in the upper right quadrant, which can be mistaken for liver pain.
Spasms and cramping can also result from an obstruction, or ileus, of the small bowel.
Pain in the left upper quadrant can be caused by stretching of the large bowel at the point where it bends sharply down on the way to the sigmoid and rectum (the splenic flexure).

Pancreatic pain.
The pancreas is a small, elongated organ that lies just beneath the stomach, mostly on the left side of the body.
Its job is to secrete insulin and various digestive enzymes.
In viral or alcohol-related hepatitis, the pancreas may become inflamed, causing severe pain that spreads to both upper abdominal quadrants, the back and the shoulder.
Lying down tends to make the pain worse. Sitting with the knees to the chest, or bending forward tends to decrease the pain.

Splenic pain.
The spleen is a small organ located on the left side of the body, wedged between the stomach, diaphragm and left kidney.
It is responsible for removing damaged red blood cells from circulation, and controlling the responses of certain cells in the immune system.
In liver disease, the spleen may become swollen, or may be deprived of blood flow (infarcted). Pain from the spleen is felt in the right upper quadrantof the abdomen.

Fatty Liver
Most people with simple fatty liver or NASH have no symptoms. However, some people with simple fatty liver or NASH have a nagging persistent pain in the upper right part of the abdomen, over an enlarged liver.

Pain Defined

Somatic pain originates from either the supporting structures or cavities of the body, or from the body surface.

The somatic nerve pathways report sensations from the abdominal cavity wall, parietal peritoneum (a lining of the abdominal cavity), and parts of the diaphragm.

The somatic nerves are sensitive to pressure, squeezing, pulling, chemical and bacterial toxins, enzymes, and the accumulation of fluids, like edema.

Also, the central parts of the diaphragm and biliary tract have nerves that can cause abdominal sensations to be felt in the shoulder - this is called "referred pain."
Somatic pain is sometimes described as sharp, cutting, or stabbing. It is usually well-localized, meaning the patient can usually point to the source of the pain.

Visceral pain originates in the organs of the body.

Most solid organs (such as the liver) do not have pain receptors, but are enclosed by a membrane or capsule that generates pain when the organ swells or stretches, exerting pressure on the enclosing membrane.

Hollow organs, such has the gallbladder, bile tract or intestine, have nerve receptors in the muscular wall of the organ, which can cause pain during stretching or spasm.
Visceral pain is usually described as deep or dull, and is difficult to localize.

Neuropathic pain is "nerve pain." With neuropathic pain, the nerve fibers are damaged or injured, and send incorrect signals to other pain centers.

The nerves send pain messages even though there is no apparent cause for the pain.

Neuropathic pain may be caused by diseases like diabetes and shingles, or from trauma, surgery, or amputation, or there may be no known cause.
Neuropathic pain may be described as sharp, stinging, like a tooth-ache, or shock-like. It can be very sudden, very intense and very brief, or it may persist.

Of Interest
Functional Dyspepsia; Chronic and persistent upper abdominal pain that's often related to eating

We often put the care of our families above our own needs, if you have chronic hepatitis C, or currently receiving HCV therapy, don’t forget to take care of yourself! Wishing you all a healthy and safe journey.

Always Tina

Hepatitis News Ticker: Anemia During HCV Therapy - INCIVEK and VICTRELIS

2012-02-01T12:04:00.005-05:00

“Systems,” by Dan Beckemeyer

HCV Abstract Corner

CAP Hepatitis C Literature Review

Monthly Pubmed Review of the most relevant research on hepatitis C.

Jan 2012

Open publication - Free publishing

Tylenol And The Liver

Featured Fact Sheet From HCV Advocate:
Acetaminophen and You Liver
Learn about how the liver processes Tylenol (acetaminophen) and what the dangers are of accidental overdose.
Click Here

Anemia During HCV Therapy

Anemia and Hepatitis C Treatment

January 24, 2012

In opposition to what seems logical, research demonstrates that becoming anemic while on Hepatitis C therapy is not such a bad thing.

Continue reading "Anemia and Hepatitis C Treatment"

The Outcomes and Management of Anemia in the Phase III Trials of Boceprevir and Telaprevir

Source CCO

Brian L. Pearlman, MD, FACP

Posting Date: December 13, 2011

Medical Director, Center for Hepatitis C
Atlanta Medical Center
Atlanta, Georgia
Professor of Medicine
Medical College of Georgia
Augusta, Georgia
Associate Professor of Medicine
Emory School of Medicine
Atlanta, Georgia

Dec 2011

In the pivotal phase III studies of the protease inhibitors boceprevir or telaprevir, which led to their approval for treatment of genotype 1 hepatitis C virus (HCV), anemia was an important adverse event observed in both treatment-naive and treatment-experienced patients for both medications.^[1-4] In the telaprevir ADVANCE trial of treatment-naive patients, an additional 18% to 20% of the study population experienced anemia on a telaprevir-containing regimen compared with the control arm of peginterferon/ribavirin (37% to 39% vs 19%, respectively).^[1] The same comparison in the SPRINT-2 trial showed that anemia occurred in an additional 20% of treatment-naive patients receiving a boceprevir-containing regimen compared with control (49% vs 29%, respectively).^[2] Likewise, in the treatment-experienced trials, anemia rates with either protease inhibitor exceeded those observed in the peginterferon/ribavirin control arm by at least 15%. In the REALIZE trial, anemia rates were 30% to 36% in the telaprevir-containing arms vs 15% in the control arm,^[3] and RESPOND-2 reported anemia among 45% in the boceprevir-containing arms vs 20% in the control arm.^[4] Of note, the seemingly higher rates of anemia in boceprevir vs telaprevir trials are possibly due to the extended exposure of the drug rather than a true greater impact of the drug on anemia development.

In the registration trials for boceprevir, anemia was managed with ribavirin dose reduction and/or with off-label use of erythropoietin.^[2,4] In clinical trials, 43% of anemic patients received erythropoietin (vs 24% in the control arms). Similar to the association between the development of anemia and improved sustained virologic response (SVR) rates with peginterferon/ribavirin observed in the era prior to the introduction of direct-acting antivirals,^[5] patients who became anemic on triple therapy in the SPRINT-2 trial attained superior SVR rates compared with those who did not become anemic.^[2] Among patients who did not develop anemia, the SVR rate was 58%, whereas SVR rates ranged from 71% to 78% in those who did become anemic. SVR rates were similar whether the investigator chose to manage anemia with ribavirin dose reduction (78% [29/37]), erythropoietin (74% [95/129]), or both (71% [109/153]), as shown in Figure 1.^[6] A similar pattern was seen in the RESPOND-2 trial. Apparently, patients who become anemic during peginterferon/ribavirin therapy have higher ribavirin plasma concentrations. Even when ribavirin doses are reduced, plasma levels are sufficient to maintain the medication’s efficacy.^[7]

Figure 1. SVR rates according to management strategy in patients receiving boceprevir.[6]

In contrast with the boceprevir trials, only ribavirin dose reduction was used in the telaprevir trials to manage anemia, as growth factors were strictly prohibited in the protocols.^[1,3] Also in contrast with boceprevir, no overall relationship was identified between anemia development and SVR rates in a pooled analysis of treatment-naive patients from ADVANCE and ILLUMINATE who were treated with telaprevir for 12 weeks.^[8] SVR rates were 74% for patients with a hemoglobin level that fell to < 10 g/dL and 73% for patients whose hemoglobin remained at ≥ 10 g/dL.^[8] However, in the control arms without the protease inhibitor, anemia development corresponded with an improved SVR rate compared with patients who did not become anemic (50% vs 41%, respectively). Of note, however, when analyzed according to degree of hemoglobin change from baseline, patients with a < 3 g/dL reduction in hemoglobin achieved an SVR rate of 55% (61/111), whereas the SVR rate was 76% (590/774) among individuals who experienced a reduction of ≥ 3 g/dL from baseline. Finally, this pooled analysis showed that ribavirin dose reduction had no apparent effect on SVR in the telaprevir-containing arms (12 weeks) but seemed to have a deleterious effect on SVR in the arms without the protease inhibitor (Figure 2).

Figure 2. ADVANCE/ILLUMINATE: impact of ribavirin dose reduction on SVR.[8]

The prescribing information for both boceprevir and telaprevir advise that anemia should be managed through ribavirin dose reductions. Although it would appear that ribavirin dose reduction is a reasonable management strategy for patients who develop anemia while receiving boceprevir- or telaprevir-containing triple therapy, the reader should note that the aforementioned data were garnered from retrospective analyses. An ongoing manufacturer-sponsored prospective trial may further clarify the decision to either dose reduce ribavirin or to use off-label erythropoietin when a prescriber is confronted with therapy-induced anemia.^[9] Of note, protease inhibitors cannot be dose reduced and must be discontinued if ribavirin (or peginterferon) is discontinued for any reason.

Anemia can develop rapidly and may be severe. In my practice, and in discussions with other high-volume treaters, we are finding that anemia can occur very rapidly—within 2 weeks of protease inhibitor introduction. The rapid development seen in clinical practice is likely due to the different patient characteristics of individuals within a practice when compared with those eligible for inclusion within clinical trials. Because of this potential for rapid and severe anemia development, I have selected a more aggressive monitoring strategy in my practice and begin evaluation of hemoglobin levels within 2 weeks of treatment initiation and continue to monitor levels every 4 weeks.

Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:

Free registration is required to view the below links

To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.

Cirrhosis-Varices

Less Terlipressin Effective in Variceal Bleeding

By David Douglas

NEW YORK (Reuters Health) Jan 30 - The usual three days of terlipressin treatment after ligation of bleeding esophageal varices could possibly be cut down to a single day, according to Pakistani researchers.

Overall, a 24-hour course of terlipressin was not inferior to 72 hours of treatment after endoscopic variceal band ligation (EVBL).

On the basis of this trial and a previous one, the researchers say they "may recommend shortening the duration of therapy in future guidelines."

However, Dr. Saeed S. Hamid added in an email to Reuters Health, until "others have had a chance to comment on it," he and his colleagues are not yet ready to suggest that the shorter course be the standard of care.

In a report online December 16th in the Journal of Hepatology, Dr. Hamid and colleagues note three to five days of vasoactive drugs are usually advised in addition to EVBL when varices bleed. However, the optimal duration in any given patient has not been established. Moreover, the team has found that particularly when the risk of rebleeding is low, 24 hours appears effective.

To investigate further, the researchers randomized 130 patients to receive terlipressin for 24 or 72 hours. Most patients were men and had hepatitis C virus infection. All had open-label terlipressin for the first 24 hours and then switched to active or dummy treatment.

Bleeding was controlled in everyone in the short-course group but there was one failure in the standard course group within 5 days. At 30 days, there was no difference in rebleeding rates, although the number in the control group was numerically lower: 3.1% and 1.5%.

At 30 days, there were 12 deaths from any cause (six in each group), and seven patients in each group reached the composite outcome of re-bleeding and/or death.

Overall, the short course was not inferior to longer term use.

If indeed the treatment could be safely shortened, Dr. Hamid said, there would be "significant cost implications, as well as perhaps implications on the safety of the drug without losing efficacy."

SOURCE: http://bit.ly/yYxQrf

J Hepatol 2011.

Source-Medscape

Ribavirin Rather than PEG-interferon Pharmacodynamics Predict Nonresponse to Antiviral Therapy in Naive Chronic Hepatitis C Patients

Discussion Only

Click Here For Full Text

In this study, we explored the potential influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse to PEG-interferon alfa-2b and ribavirin in treatment-naive CHC patients. Our main finding is that lower week-24 serum ribavirin concentrations are an independent risk factor for nonresponse.

This finding indicates the importance of adequate exposure to ribavirin, especially in HCV genotype 1–4 patients. Only 3% of patients with HCV genotype 2–3 were nonresponders, but all had a serum ribavirin concentration below 2 mg/L. Although one could speculate that a certain threshold in serum ribavirin concentrations has to been reached to exclude an unfavourable outcome in patients with HCV genotype 2–3, the low numbers of genotype 2–3 patients with nonresponse preclude any conclusion in this respect.

Inter-patient variability in serum ribavirin concentrations is known to be high.^[5,6] Body weight, renal function, gender and age are associated with ribavirin clearance at various time points but can only explain a small part of the variability.^[5,15,16] In our study, only higher average ribavirin doses (in mg/kg per day) were an independent predictor of higher serum ribavirin concentrations (r ² = 0.029). Determinants not studied in the current analysis such as nonadherence^[17] and factors influencing absorption, transport and intracellular metabolism of ribavirin could contribute to the high variability.

Ribavirin has a narrow therapeutic index: while low ribavirin concentrations increase the risk of nonresponse, high ribavirin concentrations increase the risk of toxicity, especially haemolytic anaemia.^{[5,7,8,18,19]} In line with these data, week-24 haemoglobin decreases in the current study were significantly correlated with week-24 ribavirin concentrations (r = 0.42, P < 0.001).

A potential bias in our analysis is that only patients who completed 24 weeks of treatment were included. However, only two patients stopped therapy before week 24 because of anaemia. We were interested in week-24 serum ribavirin concentrations, because we aimed at identifying factors determining risk of nonresponse rather than to adapt ribavirin dose at an early point during antiviral therapy. However, according to previous literature, steady state concentrations are already reached after 4–8 weeks.^[20] Another possible limitation of this study is that we did not measure serum PEG-interferon concentrations. It should also be noted that some aspects of the study protocol differ from current practice, because the design of the CIRA study dated from 1999–2000.^[12] Patients received high-dose induction therapy with interferon, which is currently not advised. PEG-interferon alfa-2b dose was decreased in the second half of the treatment period from 1.5 to 1.0 μg/kg per week.

However, PEG-interferon doses 1.0 μg/kg per week appear not to compromise SVR rates.^[21,22] Also, in our series of 236 patients with ribavirin determinations, there was one outlier, with ribavirin concentration of 7.4 mg/L. Although we cannot exclude some haemolysis associated with antiviral therapy in this patient, all available clinical data would suggest that ribavirin exposure was considerable: the patient received a high ribavirin dose (17.5 mg/kg per day), with corresponding drop in haemoglobin (3.6 mm at week 24 compared to basal). Finally, patients were not checked after 12 weeks of treatment for early viral response,^[23] and patients with HCV genotype 2–3 were treated for 1 year.

Apart from lower serum ribavirin concentrations, infection with HCV genotype 1–4 and higher baseline γ-GT levels were identified as independent risk factors for nonresponse. HCV genotype 1 has extensively been described as the predominant risk factor for nonresponse to combination therapy for CHC. In our study, HCV genotype 1–4 was the predominant predictor for nonresponse. In contrast, elevated γ-GT levels have not been described as an independent predictive factor for nonresponse in patients with hepatitis C before. However, low or normal γ-GT levels have been associated with SVR,^[24–26] and our findings suggest that lower nonresponse rates under these circumstances could be the explanation of this finding. Elevated γ-GT levels are associated with more severe hepatic fibrosis or cirrhosis.^[27,28] In the current analysis, 54% of patients exhibited elevated γ-GT levels, similar to other reports,^{[25,26,29,30]} and γ-GT levels were significantly correlated with severe fibrosis or cirrhosis (median of γ-GT level 70 (range 16–700) in case of severe fibrosis or cirrhosis vs 48 (5–575) in case of less severe fibrosis scores, P = 0.004). Severe fibrosis or cirrhosis could not be identified as a predictive factor for nonresponse, and one may speculate that γ-GT is a more sensitive marker for fibrosis than classification according to the METAVIR scoring system.

We also compared various on-treatment factors suggested to be different on re-treatment between patients with partial response and null response in the HALT-C trial^[11] to evaluate whether similar differences could be found in treatment-naive patients. The predictive value of less reduction in body weight, leucocytes and platelets for nonresponse was not confirmed in our treatment-naive patients. Nevertheless, when comparing partial responders with null responders, a trend towards less reduction in body weight, leucocytes, granulocytes and platelets was observed, suggesting type II error. Alternatively, interferon-related factors may predict null response, especially during re-treatment of previous nonresponder patients and/or patients with severe fibrosis/cirrhosis. No other relevant studies on this topic have been published.

In conclusion, our results indicate that ribavirin rather than PEG-interferon pharmacodynamics determine in part the chance of nonresponse in treatment-naive CHC patients. This is especially the case in patients with HCV genotype 1–4, although HCV genotype 2–3 patients with serum ribavirin concentrations below a threshold of 2.0 mg/L may also experience nonresponse.

Generic Drugs ?

Source Pharmalot

Docs Are Surrendering To Generics: Survey

A group of physicians - mostly, family medicine docs and internists - were asked about their views on prescribing lower-cost copycat meds, in general.

65 percent reported that they have experienced a failure with a generic equivalent where the brand-name drug was successful. And 94 percent reported that their own patients had indicated a generic did not work as well as the branded drug they were taking previously, according to DoctorDirectory, a firm that specializes in brand-name marketing....continue reading

Just Because

Valentine's Day Is The Worst Time To Kiss, Says Loyola Infectious Disease Specialist

Released: 2/1/2012 10:30 AM EST
Source: Loyola University Health System

Newswise — Say “I love you” with flowers, chocolates or a greeting card, but be careful when you kiss this Valentine’s Day.

“Mid-February is usually the peak season for infectious diseases, such as the seasonal and H1N1 flu, mononucleosis, colds and coughs,” says Jorge Parada, MD, medical director, infectious disease at Loyola University Health System. “And don’t rely on obvious signs of illness - such as sneezing or fever as a tip off. People with infectious diseases start shedding the virus before they experience the full effect of the illness.”

Changing weather or temperatures are often blamed for winter’s coughs and sniffles. But in reality, colds, coughs and the flu are infectious diseases “caught” through transmission from one human to another.

“Becoming too hot or too cold can cause stress to the body, weaken the defense in fighting off infections and thus make us more vulnerable,” said Parada, who is also a professor of preventive medicine at Stritch School of Medicine. “But a person has to be exposed to a virus or bacteria to catch it.” Dr. Parada feels that winter trends such as staying indoors in crowded arenas such as shopping malls or movie theatres may promote winter colds and flu.

Drink to Me Only with Thine Eyes
Drinking from the same wine glass or sharing dessert with the same fork may seem romantic, but also may lead to infections.

And keep your chopstick to yourself.

“Someone can have a cold sore that hasn’t erupted yet and use lip balm which is then shared, and the cold sore virus – otherwise known as herpes - is transmitted,” said Parada. Albeit less frequently, shared linens also are transmitters of infections. “A shared pillowcase, napkin or towel can also actually be a conduit for disease, especially if someone has a sore or cut,” says Parada.

Do’s and Don’ts For Safe Displays of Affection

Do Give and Get a Flu Shot – “It’s the gift that keeps on giving – you protect yourself, your loved one and you stop the virus from spreading to others,” said Parada. “If that isn’t sexy, and say ‘I love you’ I don’t know what does.”

Don’t Share Utensils – “Humans can transmitsome infections through saliva. A glass, fork or napkin can act as a bridge and pass the bug along to another person when that shared object is used by one infected person and then used by another.”

Don’t Kiss or Have Close Body Contact if You Feel Unwell – “Throwing up and blowing your nose is not fun; no one wants to be ill so being upfront and honest when you feel under the weather will be appreciated.”

Give The Flu The Kiss-Off
Parada says that it takes 10 – 14 days after injection for the flu shot to have full preventive effect. “Get that flu shot now to increase your odds for romance on Valentine’s Day,” says Parada. “Having a flu shot is definitely sexy. It beats the flu every time!”

Off The Cuff

Source Medgadget

Magic Mirror for Seeing Your Insides Gets an Upgrade

A year ago we reported on a nifty use of augmented reality technology to display tomography images virtually right on the body of the patient who was scanned.

The project, called “mirracle,” is spearheaded by researchers from Technical University of Munich who have been improving the interactivity of the system over the last year to make it more intuitive and easy to use. Here’s the latest demo video of the latest iteration of the magic mirror:
Read More

FYI

Dr. Paul Kwo on Hepatitis C Screening During Routine Colonoscopy

Uploaded by HCPLiveTV on Jan 12, 2012

Paul Kwo, MD, FACG, professor of medicine in the division of gastroenterology and hepatology at the Indiana University School of Medicine, discusses a program in which hepatitis C screening was offered to patients aged 50 to 65 during routine colonoscopy. He explains that these patients are prime candidates for undiagnosed hepatitis C infection due to high-risk behavior they may have engaged in several decades ago and that screening during colonoscopy offers gastroenterologists an opportunity to reduce morbidity and mortality due to hepatitis C. This video was shot during the annual scientific meeting of the American College of Gastroenterology in Washington, DC.

IOM publishes call to action on chronic disease

Posted by Rebecca Hersher

Source Spoonful Of Medicine-Nature

A report published today by the US Institute of Medicine (IOM) calls for an overhaul of the way public health departments conduct surveillance and treatment of chronic diseases ranging from arthritis to depression. The report, co-sponsored by the US Centers for Disease Control and Prevention (CDC) and the Arthritis Foundation, both based in Atlanta, warns that chronic disease, which accounts for three quarters of healthcare spending in the United States, is an overlooked crisis. The authors argue that the CDC can use funds more efficiently by expanding surveillance systems, integrating community health systems in schools and workplaces and prioritizing patient education.

The report, Living Well with Chronic Illness, focuses on nine chronic conditions. In addition to cancer and type 2 diabetes, diseases for which substantial public health initiatives already exist, it names mental illnesses such as dementia, post-traumatic stress disorder, schizophrenia and depression.

Such diseases decrease the productivity and quality of life of millions of Americans, but public health departments do not adequately address such illnesses, the report argues, in part because surveillance systems fail to assess the needs of patients with chronic disease. For example, little information exists about how people with chronic illnesses such as arthritis access healthcare and what interventions are most effective at increasing their productivity and decreasing the cost of managing the disease.

“Historically, when infectious diseases were the dominant thing, that was what surveillance systems counted,” says Robert Wallace, a physician at the University of Iowa and the chairman of the committee that produced the report. “But now there are enormous numbers of people with chronic illnesses and not enough information about what is and is not working in the public health sphere.”
At the core of the report’s recommendations is a call for the CDC to enact policies that empower people to seek care for chronic diseases. Such policies could include integrating health services in schools and workplaces to encourage healthy lifestyle choices that can prevent or mitigate chronic illness. The report also stresses the importance of getting individuals into the healthcare system early and helping them navigate care options to avoid confusion and alienation.

John Klippel, president of the Arthritis Foundation, says the IOM’s decision to issue a report on chronic illness is timely, and he hopes the public pays attention. “I don’t know that the public quite recognizes the importance and magnitude of chronic illness,” he says. “The effects of these illnesses on lifestyle and quality of life are profound. We need to use resources better, but we also need to empower people to take control of their own care.”

Video-New and experimental oral drugs to treat hepatitis C

2012-01-31T21:22:00.004-05:00

Hepatitis C New Drug Research And Liver Health

Multimedia;Videos and Podcasts-Updated

Video-New and experimental oral drugs to treat hepatitis C.

Transcript included, also from CCO the "Current Recommendations for Using Telaprevir and Boceprevir in Patients With Advanced Fibrosis or Cirrhosis."

Hepatitis C Drug Victrelis-Boceprevir released for public use in Australia.

2012-01-31T08:43:00.000-05:00

A RECENTLY developed treatment for the most common form of hepatitis C has been approved for use in Australia by the Therapeutic Goods Administration (TGA).

Victrelis, also known as boceprevir, comes from a group of drugs known as a protease inhibitors.
Scientists say it is an effective way to fight hepatitis C, genotype 1.
The director of the AW Morrow Gastroenterology and Liver Centre in Sydney, Professor Geoff McCaughan, says people who suffer from this strand of hepatitis C now have their first new treatment option in a decade.

"In the last ten years there has been little development in the availability of treatments for hepatitis C and a significant proportion of patients fail to respond to current standard of care." Professor McCaughan said in a statement.

"Victrelis is an approved treatment that works directly on the hepatitis C virus and prevents it from replicating and therefore reproducing."
He said this was a big step forward in the battle against hepatitis C, genotype 1.
"Unfortunately, hepatitis C is a silent disease where there is very little awareness of the condition and patients often present late with severe complications.

"Hepatitis C is a huge burden for individuals and is still very heavily stigmatised, and having another new treatment option marks progress in the management of patients with the disease."
Hepatitis C affects more than 200,000 Australians, with 20,000 new cases reported each year.
A spokeswoman for the TGA said now that Victrelis had been approved it had been released for public use.

The Pharmaceutical Benefits Scheme Committee is to consider listing the drug at its March meeting.

Stem cells may shed light on hepatitis C, MIT researchers find

2012-01-30T16:07:00.000-05:00

Stem cells may shed light on hepatitis, MIT researchers find
By Lori Valigra

Researchers at MIT and their colleagues said they have devised a way to produce liver-like cells from stem cells, a key step in studying why people respond differently to Hepatitis C.

An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.

The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.

The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.

The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.

The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.

The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.

The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.

Hepatitis C News Ticker: The ELF test-Blood Test Instead of Liver Biopsy?

2012-01-30T10:31:00.003-05:00

New On The Blog

Hepatitis C-Clinical evidence for the regression of liver fibrosis

The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis

Fatigue in Cirrhosis: Is Transplant the Answer?

The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis

Why Boomers Should Be Aware of Hepatitis

Video-Muscle and Mortality in Cirrhosis

In The News

Stem cells may shed light on hepatitis C, MIT researchers find

Researchers at MIT and their colleagues said they have devised a way to produce liver-like cells from stem cells, a key step in studying why people respond differently to Hepatitis C.

An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.

The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.

The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.

The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.

The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.

The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.

The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.

Blood Test Instead of Biopsy Identifies Liver Damage

Siemens is marketing the first rapid, automated biomarker test for diagnosing and assessing liver fibrosis. The ELF test (Enhanced Liver Fibrosis test) takes approximately one hour to complete and requires only a blood sample

The ELF test (Enhanced Liver Fibrosis test) takes approximately one hour to complete and requires only a blood sample. The process is therefore less invasive but just as reliable as the previously required biopsy, and it usually takes about a week to deliver a biopsy result.

The new test was developed by Siemens Healthcare in collaboration with University College London and can be used as a routine test on the Siemens ADVIA Centaur Immunoassay System.
Liver fibrosis is the result of chronic liver damage caused by vi-ral hepatitis, alcoholic cirrhosis, or fatty liver disease. It is characterized by scarring of the liver tissue, which can lead to cirrhosis or cancer of the liver over the long term — a frequent cause of death worldwide.

At present, the “gold standard” for assessing the severity of a liver fibrosis is a liver biopsy, which involves the removal of a small amount of liver tissue. This biopsy has drawbacks, however: It is painful; it entails some risk for the patient; and it tests only a small sample of the liver.

With the automated ADVIA Centaur ELF Test, a fast and mini-mally invasive technique is now available for determining both the severity of a liver fibrosis and the risk that it will worsen. The test examines three direct blood serum biomarkers: hyaluronic acid (HA), procollagen III N-terminal propeptide (PIIINP), and the tissue inhibitor of metalloproteinase 1 (TIMP-1). These direct biomarkers are molecules that are involved in the formation of fibrosis. In the test, special reagents react with the biomarkers and generate light in the process. The greater the intensity of this chemiluminescence, the greater the presence of the biomarker.

A special algorithm is used to convert the results of the three biomarkers into the ELF score, which indicates the degree of fibrosis. The combination of three biomarkers increases the accuracy of the test. As an international clinical trial has shown, the ELF test can precisely differentiate between slight, moderate, and serious cases of fibrosis. In the event of slight or moderate fibrosis, patients normally have no symptoms. Doctors can thus intervene before significant damage to the liver and monitor the progress of therapy.

To complement the ELF test, Siemens is also offering imaging and laboratory diagnostic technologies like hepatitis blood tests and ultrasound systems that help physicians identify liver fibrosis at an early stage and monitor its development.

Dr. Norbert Aschenbrenner | Source: Siemens Innovation News
Further information: www.siemens.com/innovationnews

Researchers Show How Cholesterol Receptor Promotes HCV Cell Entry

A molecule in liver cell membranes that plays a role in cholesterol uptake also enables hepatitis C virus (HCV) to enter cells, according to research reported in the January 8, 2012, advance online edition of Nature Medicine.

Big Pharma

Vertex Falls as Analyst Cuts Sales Estimates on Hepatitis C Pill

Vertex Pharmaceuticals Inc. (VRTX) fell the most in two months after an analyst with Leerink Swann & Co. cut sales predictions for the company’s hepatitis C pill that was approved by U.S. regulators last year.

Vertex’s Incivek, among the first new hepatitis C drugs to reach the market in nearly a decade, could be eclipsed by new pill-only treatments with fewer side effects and shorter courses of treatment. Incivek is given with interferon, an injected medicine. Merck & Co.’s similar pill, Victrelis, was also approved last year.

Shares of Cambridge, Massachusetts-based Vertex fell 4.2 percent to $34.48 at 10:18 a.m., after declining 5.2 percent in the biggest intraday drop since Nov. 14.
Howard Liang, an analyst with Leerink Swann in Boston, cut his sales forecast for Incivek by 35 percent from $2.3 billion this year to $1.5 billion. Liang also cut his target price for Vertex shares from $66 to $48.

“In light of recent development of interferon-free regimens and likely more aggressive development as a result of recent transactions in the space, we are further curtailing the Incivek tail,” Liang said in a note to clients today.

Vertex had $420 million in revenue from Incivek in the third quarter of 2011. Revenue from the drug accounts for 64 percent of the company’s sales.
To contact the reporter on this story: Drew Armstrong in Washington at darmstrong17@bloomberg.net;

Liver Cancer

Hepatitis C Virus Studied as Risk Factor in Liver Cancer

by George Ochoa

Two Mayo Clinic studies have clarified the importance of chronic hepatitis C virus (HCV) in the rising trend of liver cancer, or hepatocellular carcinoma (HCC).

One study (Yang et al. Mayo Clin Proc. 2012;87:9-16) analyzed longitudinal trends in the incidence, etiology, treatment of HCC and survival in community residents in Olmsted County, Minn. The researchers found that in earlier periods (1976-1990, 1991-2000), alcohol use was the most common risk factor, but, in 2001 to 2008, HCV filled that role. At the same time, HCC incidence rose dramatically, from 3.5 per 100,000 person-years for the 1976 to 1990 time period, to 3.8 for the period from 1991 to 2000, to 6.9 for the 2001 to 2008 period.

Study author W. Ray Kim, MD, associate professor of medicine, Mayo Clinic College of Medicine, Rochester, Minn., wrote in an email: “The biggest and unique risk factor of HCC is underlying liver disease. Our data showed that previously alcohol, more recently HCV has become the underlying cause.”

The second study (Shire et al. Mayo Clin Proc. 2012;87:17-24) investigated a sample of Somali immigrants seen at Mayo Clinic from July 1, 1996, to Oct. 31, 2009. Non-Somali Olmsted County residents served as controls. The frequencies of chronic hepatitis B virus (HBV) and HCV, and their associations with HCC, were studied. Both HBV and HCV occurred frequently in the sample of Somalis, but HCV was the major risk factor for HCC. There were significant differences in the HCV genotype distributions between Somalis and non-Somalis.
The high prevalence of HCV in the Somali sample came as a surprise to the researchers. “We didn’t expect it,” Abdirashid M. Shire, PhD, assistant professor of medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, said in an interview. The study, Dr. Shire added, “supports the value of early detection” of HCV. “It’s very important to screen for HCV.” Dr. Kim reported that his study also “indirectly” supports the value of early detection and treatment to improve outcomes.

—Drs. Kim and Shire had no relevant financial disclosures

Researchers Discover New Therapeutic Target To Combat Liver Cancer

28 January 2012

Researchers at CIC Biogune, the Cooperative Centre for Research into Biosciences and led by Dr. Maria Luz Martinez Chantar, have found a strong relationship between high levels of Hu antigen R (HuR) protein and the...

Statins May Stave Off Liver Cancer in People With Hepatitis B

By Denise Mann
HealthDay Reporter

THURSDAY, Jan. 26 (HealthDay News) -- Popular cholesterol-lowering statins may also lower risk for liver cancer among people with hepatitis B, a new study shows. Hepatitis B, an inflammation of the liver due to the hepatitis B virus, is one of the main causes of liver cancer.

This is not the first time that statins have shown promise in reducing risk for cancer. Other studies have hinted that these drugs may play a role in preventing certain types of cancer, including breast cancer.

In the new study of more than 33,000 individuals with hepatitis B followed from 1997 to 2008, those who took a statin were less likely to develop liver cancer, when compared to participants who were not prescribed statins. What's more, the longer a person took statins, the greater the liver-cancer risk reduction. Study participants were prescribed the statins to treat high cholesterol levels. Overall, 1,021 people developed liver cancer during the study period.

More research is needed to see how statins may lower liver cancer risk among people with hepatitis B, the researchers said.

"Statins have potential protective effects against cancers [and] carriers of hepatitis B virus infection have a substantial risk of [liver] carcinoma," said Dr. Pau-Chung Chen, a professor of environmental medicine and epidemiology at National Taiwan University, in Taipei. "Statin use is not only a benefit to preventing cardiovascular diseases, but also an additional, convenient and acceptable strategy for preventing hepatocellular carcinoma," or liver cancer, Chen said.

However, statins can cause a potentially dangerous rise in liver enzymes and liver damage. Regular liver function tests are required for all people who take statins.

The study appeared online Jan. 23 in the Journal of Clinical Oncology.

"This is exciting and unequivocally solid research," said Dr. Eugene Schiff, a professor of medicine and director of the Center for Liver Diseases at the University of Miami Miller School of Medicine.

"One of the issues is that statins are relatively contraindicated in people with liver disease," Schiff said. But "the take-home message for people with hepatitis B or anybody with liver disease is that statins are safe. This re-emphasizes the point that if someone has chronic hepatitis B and there is an indication for statins, they should get them and they may be beneficial far beyond lowering cholesterol: They may also reduce their risk for liver cancer."

Dr. David Bernstein, chief of hepatology at North Shore University Hospital and Long Island Jewish Medical Center in Manhasset, N.Y., is more cautious. "In almost all other liver conditions, cirrhosis must be present before [liver cancer] develops," he said. During cirrhosis, scar tissue replaces healthy liver tissue. "Statins must be used with caution in patients with cirrhosis, which can limit their use in patients with liver disease at risk of developing liver cancer," he said. "Further studies are needed in this patient population to confirm these findings."

More information

For information on hepatitis B, visit the U.S. National Digestive Diseases Information Clearinghouse.

Transplant

Live Liver Donations Confirmed As Safe

27 January 2012

According to Johns Hopkins researchers, individuals who donate a portion of their liver for live transplantation usually recover safely from the procedure and can expect to live long, healthy lives...

Risk of death among live liver donors

A study in February's issue of Gastroenterology estimates early death, acute liver failure, and long-term mortality among live liver donors.

Dr Abimereki Muzaale and colleagues from Maryland, USA estimated the risk of perioperative mortality or acute liver failure for live liver donors in the United States, and avoid selection or ascertainment biases and sample size limitations.

The research team followed up 4111 live liver donors in the United States between 1994 and 2011 for a mean of 8 years.

Deaths were determined from the Social Security Death Master File. Survival data were compared with those from live kidney donors and healthy participants of the National Health and Nutrition Examination Survey (NHANES) III.

The team observed that 7 donors had early deaths.

Risk of early death among live liver donors is almost 2 per 1000 donors

Gastroenterology

The research team found that risk of death did not vary with age of the liver recipient or portion of liver donated.

There were 11 catastrophic events.

The team found that risk did not vary with recipient age, or portion of liver donated.

The researchers noted that long-term mortality of live liver donors was comparable to that of live kidney donors and NHANES participants.

Dr Muzaale's team concluded, "The risk of early death among live liver donors in the United States is almost 2 per 1000 donors."

"Mortality of live liver donors does not differ from that of healthy, matched individuals over a mean of 8 years."

Gastroenterol 2012: 142(2): 273-280

30 January 2012

Transmission of HCV Through Transplanted Organs and Tissue

How common is transmission of hepatitis C through organ donation, and what types of preventive practices can be put into place to prevent this from happening?

Immunosuppression, Liver Injury and Post-transplant HCV

Even after a liver transplant, patients can often experience a recurrence of hepatitis C. How should it be treated in this setting?

HCV Brain Function

Hepatitis: Brain endothelial cells support HCV entry and replication

Chronic HCV infection causes progressive liver disease and can also be associated with various CNS abnormalities. To date, however, few studies have investigated the mechanisms by which these abnormalities arise, that is, whether they are a result of impaired hepatic function or virus replication in the CNS. Thus, the researchers quantified HCV RNA levels in the brain and liver of 10 individuals infected with HCV. They also investigated the expression of HCV entry receptors in the brain, and conducted in vitro studies to ascertain whether two brain-derived endothelial cell lines could support HCV infection.

HCV SVR Improves Quality of Life & Brain Function

The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration ("brain fog") are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established this study provides a substantial link between HCV and cerebral dysfunction by demonstrating a reduction in spectroscopic markers of cerebral inflammation and an improvement in cognition, following HCV eradication

Research

HCV Management for Individuals on Methadone Maintenance

This article takes an in-depth look at hepatitis C treatment options in a specialized community of people on methadone maintenance.

FDA

FDA Makes Way for Wider Access to OraQuick HCV Rapid Test

The FDA recently granted a waiver under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to OraSure Technologies for its OraQuick HCV Rapid Antibody Test for use with fingerstick whole blood and venous whole blood specimens. With this waiver, the OraQuick HCV test now can be used by more than 180,000 sites in the United States to test individuals who are at risk for hepatitis C virus (HCV) infection.

The CLIA, passed by Congress in 1988, establishes quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results, regardless of where a test is performed. As defined by the CLIA, waived tests are categorized as “simple laboratory examinations and procedures that have an insignificant risk of an erroneous result.” The FDA determines the criteria for tests being simple with a low risk for error, and approves manufacturers’ applications for waivers.

The CLIA waiver granted for OraSure’s OraQuick HCV Rapid Antibody Test, extends the use of the assay to more than 180,000 facilities, such as outreach clinics, community-based organizations and physician offices, according to a press release from OraSure.
“A CLIA waiver for our OraQuick HCV test represents a critical milestone in our quest to make the test available to the widest possible range of at-risk individuals in the United States,” said Douglas A. Michels, president and CEO of OraSure Technologies. “The CLIA waiver will enable health care providers, those on the front lines of fighting this devastating disease, to use this simple and accurate test in physician offices and outreach settings so more individuals infected with hepatitis C can be diagnosed and treated.”

The OraQuick HCV Rapid Antibody Test is the first and only FDA-approved rapid test for the detection of antibodies to HCV. The test is approved for fingerstick whole blood specimens and venipuncture whole blood specimens in individuals aged 15 years or older, and provides results in 20 minutes. The assay has not been approved for use in patient populations without signs or symptoms of HCV, and its use has not been established for testing patients younger than 15 years of age or for pregnant women.

—Based on a press release from OraSure Technologies

Healthy You

Can yoga help women suffering from fibromyalgia?

A study recently published in the Journal of Pain Research shows that practicing yoga boosts levels of the stress hormone cortisol and could help ease some symptoms of fibromyalgia such as pain, fatigue, muscle stiffness and depression.

That Which Does Not Kill Yeast Makes It Stronger

Under stressful conditions yeast genomes become unstable, readily acquiring or losing whole chromosomes to enable rapid adaption. The musical spectrum was derived from the copy number data of the aneuploid yeast genomes selected under different stress conditions, where the gain and loss of chromosomes are represented as red and green bars, respectively.

Released: 1/25/2012 12:00 PM EST
Embargo expired: 1/29/2012 1:00 PM EST
Source: Stowers Institute for Medical Research

Newswise — KANSAS CITY, MO— Cells trying to keep pace with constantly changing environmental conditions need to strike a fine balance between maintaining their genomic integrity and allowing enough genetic flexibility to adapt to inhospitable conditions. In their latest study, researchers at the Stowers Institute for Medical Research were able to show that under stressful conditions yeast genomes become unstable, readily acquiring or losing whole chromosomes to enable rapid adaption.

The research, published in the January 29, 2012, advance online issue of Nature, demonstrates that stress itself can increase the pace of evolution by increasing the rate of chromosomal instability or aneuploidy. The observation of stress-induced chromosome instability casts the molecular mechanisms driving cellular evolution into a new perspective and may help explain how cancer cells elude the body’s natural defense mechanisms or the toxic effects of chemotherapy drugs.

“Cells employ intricate control mechanisms to maintain genomic stability and prevent abnormal chromosome numbers,” says the study’s leader, Stowers investigator Rong Li, Ph.D. “We found that under stress cellular mechanisms ensuring chromosome transmission fidelity are relaxed to allow the emergence of progeny cells with diverse aneuploid chromosome numbers, producing a population with large genetic variation.”

Known as adaptive genetic change, the concept of stress-induced genetic variation first emerged in bacteria and departs from a long-held basic tenet of evolutionary theory, which holds that genetic diversity—evolution’s raw material from which natural selection picks the best choice under any given circumstance—arises independently of hostile environmental conditions.

“From an evolutionary standpoint it is a very interesting finding,” says graduate student and first author Guangbo Chen. “It shows how stress itself can help cells adapt to stress by inducing chromosomal instability.”

Aneuploidy is most often associated with cancer and developmental defects and has recently been shown to reduce cellular fitness. Yet, an abnormal number of chromosomes is not necessarily a bad thing. Many wild yeast strains and their commercial cousins used to make bread or brew beer have adapted to their living environs by rejiggering the number of chromosomes they carry. “Euploid cells are optimized to thrive under ‘normal’ conditions,” says Li. “In stressful environments aneuploid cells can quickly gain the upper hand when it comes to finding creative solutions to roadblocks they encounter in their environment.”

After Li and her team had shown in an earlier Nature study that aneuploidy can confer a growth advantage on cells when they are exposed to many different types of stress conditions, the Stowers researchers wondered whether stress itself could increase the chromosome segregation error rate.

To find out, Chen exposed yeast cells to different chemicals that induce various types of general stress and assessed the loss of an artificial chromosome. This initial screen revealed that many stress conditions, including oxidative stress, increased the rate of chromosome loss ten to 20-fold, a rate typically observed when cells are treated with benomyl, a microtubule inhibitor that directly affects chromosome segregation.

The real surprise was radicicol, a drug that induces proteotoxic stress by inhibiting a chaperone protein, recalls Chen. “Even at a concentration that barely slows down growth, radicicol induced extremely high levels of chromosome instability within a very short period of time,” he says.

Continued growth of yeast cells in the presence of radicicol led to the emergence of drug-resistant colonies that had acquired an additional copy of chromosome XV. Yeast cells pretreated briefly with radicicol to induce genomic instability also adapted more efficiently to the presence of other drugs including fluconazole, tunicamycin, or benomyl, when compared to euploid cells.

Interestingly, certain chromosome combinations dominated in colonies that were resistant to a specific drug. Fluconazole-resistant colonies typically gained an extra copy of chromosome VIII, tunicamycin-resistant colonies tended to lose chromosome XVI, while a majority of benomyl-resistant colonies got rid of chromosome XII. “This suggested to us that specific karyotypes are associated with resistance to certain drugs,” says Chen.

Digging deeper, Chen grew tunicamycin-resistant yeast cells, which had adapted to the presence of the antibiotic by losing one copy of chromosome XVI, under drug-free conditions. Before long, colonies of two distinct sizes emerged. He quickly discovered that the faster growing colonies had regained the missing chromosome. By returning to a normal chromosome XVI number, these newly arisen euploid cells had acquired a distinctive growth advantage over their aneuploid neighbors. But most importantly, the fast growing yeast cells were no longer resistant to tunicamycin and thus clearly linking tunicamycin resistance to the loss of chromosome XVI.

Researchers who also contributed to the work include William D. Bradford and Chris W. Seidel both at the Stowers Institute for Medical Research.

The study was funded in part by the National Institute of General Medical Sciences.

About the Stowers Institute for Medical Research

The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife Virginia opened the Institute in 2000. Since then, the Institute has spent over 800 million dollars in pursuit of its mission.

Currently the Institute is home to over 500 researchers and support personnel; over 20 independent research programs; and more than a dozen technology development and core facilities. Learn more about the Institute at www.stowers.org.

A glass of milk a day could benefit your brain

New research finds milk drinkers scored better on memory and brain function tests

Pouring at least one glass of milk each day could not only boost your intake of much-needed key nutrients, but it could also positively impact your brain and mental performance, according to a recent study in the International Dairy Journal.1 Researchers found that adults with higher intakes of milk and milk products scored significantly higher on memory and other brain function tests than those who drank little to no milk. Milk drinkers were five times less likely to "fail" the test, compared to non milk drinkers.

Researchers at the University of Maine put more than 900 men and women ages 23 to 98 through a series of brain tests – including visual-spatial, verbal and working memory tests – and tracked the milk consumption habits of the participants. In the series of eight different measures of mental performance, regardless of age and through all tests, those who drank at least one glass of milk each day had an advantage. The highest scores for all eight outcomes were observed for those with the highest intakes of milk and milk products compared to those with low and infrequent milk intakes. The benefits persisted even after controlling for other factors that can affect brain health, including cardiovascular health and other lifestyle and diet factors. In fact, milk drinkers tended to have healthier diets overall, but there was something about milk intake specifically that offered the brain health advantage, according to the researchers.

In addition to the many established health benefits of milk from bone health to cardiovascular health, the potential to stave off mental decline may represent a novel benefit with great potential to impact the aging population. While more research is needed, the scientists suggest some of milk's nutrients may have a direct effect on brain function and that "easily implemented lifestyle changes that individuals can make present an opportunity to slow or prevent neuropsychological dysfunction."

New and emerging brain health benefits are just one more reason to start each day with lowfat or fat free milk. Whether in a latte, in a smoothie, on your favorite cereal, or straight from the glass, milk at breakfast can be a key part of a healthy breakfast that help sets you up for a successful day. The 2010 Dietary Guidelines for Americans recommend three glasses of lowfat or fat free milk daily for adults and each 8-ounce glass contains nine essential nutrients Americans need, including calcium and vitamin D.

About the National Milk Mustache "got milk?"® Campaign

The Milk Processor Education Program (MilkPEP), Washington, D.C., is funded by the nation's milk processors, who are committed to increasing fluid milk consumption. The National Fluid Milk Processor Promotion Board, through MilkPEP, runs the National Milk Mustache "got milk?"® Campaign, a multi-faceted campaign designed to educate consumers about the health benefits of milk. For more information, go to www.whymilk.com. Deutsch, A Lowe and Partners Company, is the creative agency for the National Milk Mustache "got milk?"® Campaign.

1Crichton GE, Elias MF, Dore GA, Robbins MA. Relation between dairy food intake and cognitive function: The Maine-Syracuse Longitudinal Study. International Dairy Journal. 2012; 22:15-23.

For Your Reading Pleasure

Chuck Garcia is launching the January 2012 collection of daily blog entries for the “31 Days of Wellness”, our annual celebration of the New Year, and the opportunity to start anew as we ring in the New Year. Enjoy, visit us daily, and send us your feedback.
Dr. Joe Galati

Frozen Vegetables and Frozen Fruit: What You Need to Remember-A Video Blog

by Dr. Joe Galati on 01/28/2012

OH My Aches And Pains
As I am getting ready to start Hepatitis C (HCV) treatment, I've been running across some pretty interesting pieces of information that I think will make my treatment experience more successful.

Behind The Headlines

Behind the Headlines provides an unbiased and evidence-based analysis of health stories that make the news.

How our system works

Each day the NHS Choices team selects health stories that are making headlines.
These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information.
Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.

Fried food study does not reflect UK diet

The idea that regularly eating fried foods causes heart attacks is a ‘myth’, The Daily Telegraph has today reported.

The newspaper has panned conventional wisdom based on a large Spanish study investigating how people’s fried food consumption was linked to their risk of events such as heart attacks and episodes of heart pain. To study the relationship researchers surveyed over 40,000 people on how much fried food they ate during the previous year, looking at any episodes related to coronary heart disease over an average period of 11 years.

In this particular setting the researchers found no link between consuming food fried in olive or sunflower oils and the risk of heart disease (the UK’s biggest killer) or death from any cause. However, while such a phenomenon could exist in the context of this specific group of people eating a specific type of diet, the research does not support the idea that fried food is generally harmless, or that it represents diets among the UK population. For example, most participants reported eating a relatively small amount of fried food each day, much less than might be typically found in a fry-up or a fast food meal. In short, it is not clear whether the same study conducted in the UK would have the same results.

Many news sources have reported the results in an accurate, measured way. However, The Daily Telegraph’s account has been somewhat overcooked, as the study did not look at the impact of factors such as frying with other types of fats, reusing oils several times (as is the case in most fast food outlets), or consuming fried snacks high in salt, sugar or calories.

Where did the story come from?

The study was carried out by a collaboration of researchers from Spanish universities and other health organisations based in Spain. It was funded by Spain’s FIS Fund for Health Research and published in the peer-reviewed British Medical Journal.

Media reports were generally balanced, with many making the point that the study was primarily concerned with a Mediterranean diet containing olive oil, which is typically very different from the dietary patterns in the UK. This limits how relevant this study is to the UK population. Many news sources also rightly warn against assuming that the study results suggested that consuming large amounts of fried foods is not harmful. The Telegraph included a picture of a full English breakfast, which is not a recognised part of a Mediterranean dietary pattern.

What kind of research was this?

This prospective cohort study investigated the association between people’s consumption of fried foods and their risk of experiencing coronary heart disease events such as heart attacks and heart pain (angina) which require surgery. It was conducted in a Spanish population.

Previous research has shown fried foods have been associated with high blood pressure, obesity and low levels of ‘good’ cholesterol (high-density lipoproteins or HDL cholesterol). However, existing studies into the association of fried food and coronary heart disease provided mixed results, the authors report.

When food is fried the nutritional content changes; water is lost and fat is absorbed, increasing the calorie content of the food. During frying, the oils also deteriorate and change into other forms, especially when reused, as is often the case in fried fast food outlets. This process leads to a loss of unsaturated fats and an increase in harmful trans fats.

A prospective cohort study is a good way of investigating whether fried foods are linked to heart disease because you can be sure the consumption of the food occurred before the development of the disease. However, the limitation is that you cannot be certain that fried foods caused a disease because its development may be influenced by numerous other factors, some measured in the research and some not.

The best type of study to definitively assess this link would be a large randomised controlled trial, providing it could be performed ethically. However, given the cost and complexity of such a task, this approach may ultimately be impractical.

What did the research involve?

The participants were Spaniards enrolled in a research project called the European Prospective Investigation into Cancer and Nutrition (the EPIC-Spain cohort). The analysed cohort consisted of 40,757 adults aged between 29 and 69 who were recruited between 1992 and 1996. They were followed up for an average of 11 years to see what diseases they developed and what they died of.

When enrolled, participants were asked by trained interviewers to complete a questionnaire about the food they consumed over a typical week during the previous 12 months. Only foods consumed at least twice a month were recorded.

The study’s authors report that this method had previously been shown to be accurate (validated) at assessing the diet of Spanish people. The type of oil used for frying (olive oil versus sunflower oil or other vegetable oils) was recorded and then checked again after two years. No further information on diet was collected at a later date.

At enrolment, the researchers also recorded non-dietary variables. These included demographic variables such as age and sex as well as educational level, body mass index (BMI), smoking and physical activity levels. Participants were also asked if they had coronary heart disease, diabetes, high blood pressure, cancer or angina or had experienced a heart attack or stroke in the past.

For the analysis, people were divided into four groups depending on their level of fried food consumption. The researchers specifically analysed how consuming fried food was linked to the chance of having a coronary heart disease event and dying from any cause (known as all-cause mortality) and how these varied for the four groups.

The analysis was adjusted for a large number of factors, including energy intake, educational level, smoking and physical activity. This statistical technique aims to minimise the effect these external factors have on the association of interest, in this case between fried food and heart disease.

What were the basic results?

An average of 138g of fried food was consumed daily, including 14g of oil used for frying. About 7% of the total amount of food consumed was fried. Of the total amount of fried food consumed, 24% (34g/day) was fish, 22% (31g/day) meat, 21% (30g/day) potatoes, and 11% (15g/day) eggs. Almost two thirds (62%) of participants used olive oil for frying, the rest used sunflower oil or other vegetable oils.

During the 11-year follow up, 606 definite cases of heart disease were recorded (466 heart attacks and 140 episodes of angina requiring surgery) and 1,135 deaths from all causes.

Fried food consumption was not associated with the risk of coronary heart disease after adjusting for possible confounders. There was also no association between fried fat consumption and death from all causes. These findings were no different in those who fried using olive oil compared to sunflower oil or other vegetable oils.

In the study, coronary heart disease events were defined as definite, probable and possible depending how they were assessed. The researchers first analysed their data using only the definite cases of coronary heart disease and found no association between fried food and these cases. The same result was found when they combined the definite coronary heart disease cases with those that were less certain (probable and possible groups).

How did the researchers interpret the results?

The researchers concluded that within the EPIC-Spanish cohort they found ‘no association between consumption of fried food and risk of coronary heart disease or all-cause mortality’.

They point out that their results are ‘directly applicable only to Mediterranean countries with frying methods similar to those in Spain’ and state that oil (mainly olive and sunflower) rather than solid fat is used for frying in Spain. They also point out that the majority of fried food eaten in Spain is not necessarily fast food.

They also make the important point that ‘frying with other types of fats, reusing oils several times, or consuming fried snacks high in salt may still be harmful’.

Conclusion

This study found no association between how often people ate fried food and their risk of coronary heart disease or death from any cause in a large Spanish cohort.

This study has strengths, including using a valid method of assessing diet, a large sample size and long follow-up time, but also has significant limitations. The following limitations should be considered when interpreting the findings of this study:

The study looked at frying using olive oil or sunflower oil in the context of a Mediterranean diet. The authors make the important point that frying with other types of fats or reusing oils several times may still be harmful. Reusing oils is common in fast food preparation in the UK, and so this study does not show that consuming this type of food is not linked to heart disease.
Diet was measured only when the participants were first enrolled. Any changes in diet after this will be missed and could lead to an association being masked because of error in the classification of fried food consumption.
Fried food consumption was self-reported using a computerised questionnaire and so there may have been under-reporting given that many people perceive it to be unhealthy and may want to partially conceal the amount they eat. This could potentially hide an association.
The study did not assess the extent to which the oils were reused, assuming that this was not common in foods consumed in the home. Hence, the effects of foods fried in reused oils are still unknown and may warrant further research as reusing oils is known to make them more harmful, the authors report.
This study cannot separate the effect of the food from the cooking method. For example, the beneficial effect of omega 3 fatty acids from fish compared with the effect of frying this fish in oil that may be harmful. Therefore, the food itself blurs the link between the cooking method and disease. It is not clear whether the same results would be found if the study was conducted on the UK diet, which is generally considered less healthy than the Mediterranean diet.
This study cannot say that consuming fried foods at a higher level than their highest consumption group (249.6g/day) does not increase risk of heart disease.

Bearing in mind the limitations, this study showed that there may not be a link between consuming foods fried in olive oil or vegetable oil and coronary heart disease in Spanish adults consuming a typical Mediterranean diet. The relevance of this to the UK is limited due to differences in diet and the type of fried foods consumed in the two countries.

It is important to note that frying foods with other types of fats, particularly saturated fats such as lard or butter, reusing oils several times, or consuming fried snacks high in salt may still be harmful.

Links to the headlines

Fried food 'fine for heart' if cooked with olive oil. BBC News, January 25 2012

Fried food heart risk 'a myth'. The Daily Telegraph, January 25 2012

You'll be oil right. The Sun, January 25 2012

The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis

2012-01-29T12:33:00.003-05:00

From Liver International

The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis

A Study of 1045 Asian Hepatitis B Patients Using Transient Elastography

Arlinking Ong; Vincent Wai-SunWong; Grace Lai-Hung Wong; Henry Lik-Yuen Chan
Posted: 01/25/2012; Liver International. 2011;31(7):1047-1053. © 2011 Blackwell Publishing

Abstract and Introduction

Background:
Role of caffeine consumption in chronic hepatitis B virus (HBV)-infected patients and the interaction with alcohol consumption is unclear.

Aim:
This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV-infected patients.

Methods:
Chronic HBV-infected patients who underwent transient elastography examination in 2006–2008 were studied. Advanced fibrosis was defined as liver stiffness >9 kPa for patients with normal alanine aminotransferase (ALT) or >12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women.

Results:
The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety-five (19.0%) patients who drank ≥1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank <1 cup (P=0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (r_s=0.167, P<0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non-drinkers (190, 21.0%) (P=0.57).

Conclusion: Caffeine intake does not affect liver stiffness in chronic HBV-infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV-infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.

Introduction
Chronic hepatitis B virus (HBV) infection is a global health problem affecting over 350 million people. Persistent hepatic inflammation because of chronic HBV infection will result in progressive liver fibrosis, which will eventually result in cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC).^[1]

Alcoholism^[2] is a primary chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations. Heavy alcohol consumption commonly causes alcoholic liver disease, cirrhosis and even HCC.^[3] However, it is unclear whether consumption of a smaller amount of alcohol is safe in chronic hepatitis B patients.

On the other hand, consumption of coffee or caffeine may reduce liver injury. Greater coffee, and especially caffeine, intake was associated with a lower prevalence of abnormal alanine aminotransferase (ALT) activity in USA^[4] and Japan.^[5] Plasma glutathione was increased by 16% on coffee consumption in an Italian population.^[6] In a prospective study among advanced Hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.^[7] In human hepatoma cell lines, coffee and its major components (caffeine, cafestol and kahweol) alter expression and activity of enzymes involved in xenobiotic mechanisms.^[8] Mice pretreated with cafestol and kahweol were protected from carbon tetrachloride toxicity by inhibiting cytochrome CYP 2E1,^[9] an enzyme responsible for carbon tetrachloride bioactivation while caffeine specifically inhibited expression of connective tissue growth factor by interfering with transforming growth factor-β signaling through the SMAD pathway and upregulate peroxisome proliferator activated receptor γ levels. These in vitro and in vivo data suggested that caffeine has antifibrotic effects.^[10]

A recent case control study among chronic hepatitis B carriers showed that coffee consumption reduced the risk of HCC by half with a significant dose-response effect.^[11] It is uncertain if the beneficial effect is mediated through prevention of liver fibrosis and cirrhosis. In the past, large-scaled studies on risk factors of liver fibrosis and cirrhosis were difficult to conduct because the assessment required liver biopsy, which was invasive and not acceptable by all patients. In this study, we aimed to determine the effect of alcohol and caffeine consumption on the prevalence of advanced liver fibrosis among chronic HBV-infected patients using transient elastography.

Methods
Study Population We prospectively recruited chronic HBV-infected patients regardless of the disease activity for transient elastography. We received referrals from all primary care and hospital clinics in Hong Kong from July 2006 to February 2008.^[12] Chronic HBV infection was diagnosed by positive serology tests for serum HBsAg for at least 6 months. We excluded patients with evidence of other chronic liver disease by screening with antibody against hepatitis C virus, antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, serum ceruloplasmin, transferrin saturation and ferritin.
From April to May 2008, patients from the original cohort were phone-interviewed with a verbal consent for this study. Questions concerning their alcohol and caffeine consumption (days per week of consumption and amount per day) in the previous year were asked from a standardized questionnaire. Patients who refused to give verbal consent for the phone-interview were not included in this study.

Clinical Evaluation
All patients received comprehensive clinical and laboratory assessment at the time of transient elastography. Serum HBV DNA levels were measured by the TaqMan real-time polymerase chain reaction assay with a range of detection from 100 to 10⁹ copies/ml.^[13] Anthropometric parameters including body weight, body height, hip circumference and waist circumference were measured. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Overweight was defined as BMI≥23 kg/m², and obesity as BMI≥25 kg/m² according to the Asian and Chinese criteria.^[14] We defined moderate and severe obesity as BMI≥28 kg/m² M and ≥30 kg/m² respectively. Excessive alcohol intake was defined as >30 g/day in men and >20 g/day in women.^[15]

Liver Stiffness Measurement by Transient Elastography
Transient elastography (FibroScan®, Echosens, Paris, France) is one of the new noninvasive modality to evaluate liver fibrosis by measuring liver stiffness. It uses an ultrasound-based technique to measure the speed of propagation of the shear wave through the liver. It can assess approximately 1/500 of the liver's total mass thus reducing the sampling error. Transient elastography has been shown to accurately predict histological advanced fibrosis in different liver diseases.^[16–21]
Liver stiffness measurement (LSM) was performed using transient elastography according to the instructions of the manufacturer. Details of the technical background and examination procedure was described previously.^[22] Officially trained operators who had performed at least 50 measurements prior this study were responsible to perform the LSM for the patients who had kept fast for at least 8 h. The LSM was considered reliable only if 10 successful acquisitions were obtained, an interquartile range (IQR)/LSM of ≤30% and the success rate was ≥60%. Liver stiffness was expressed in kPa. We defined advanced fibrosis as liver stiffness >9 kPa for those with normal ALT or >12 kPa for those with elevated ALT (F3 fibrosis on histology).^[23,24]

Hui's Index
Hui's index was a non-invasive model comprising of BMI, platelet count, serum albumin and total bilirubin [predictive probabilities=exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [10⁹/L])/(1+exp(3.148+0.167 × BMI+0.088 × bilirubin [μM]−0.151 × albumin [g/L]−0.019 × platelet [10⁹/L]))] to predict significant fibrosis (F2 fibrosis on histology).^[25] Among 235 chronic hepatitis B patients with liver biopsy, at a cutoff value of 0.15, the sensitivity, specificity, positive and negative predictive values for significant fibrosis were 93, 49, 41 and 95% respectively.

Phone-interview and Questionnaire
A structured questionnaire interview was conducted over the phone to collect data on alcohol and caffeine intake. Participants were specifically asked about the average quantity and frequency of beer, wine, or liquor consumption to estimate the amount of alcohol consumption. The average quantity and frequency of consumption of coffee (regular, instant, ground and decaffeinated), tea (any kind), cola-type soda (regular or decaffeinated) and chocolate (including chocolate milk) was also enquired to estimate the amount of caffeine consumption. Effect of alcohol and caffeine consumption was analyzed with respect to the severity of liver fibrosis as assessed by transient elastography, Hui's Index and other clinical and biochemical parameters

Statistical Analyses
Total caffeine consumption (mg/day) was estimated by summing caffeine from regular coffee (137 mg per cup), regular tea (47 mg per cup), regular and diet cola-type soda (46 mg per bottle or can) and chocolate (7 mg per serving).^[26] As for the coffee cup equivalent, the total caffeine consumption per day was divided by 137 (Table 1).

Table 1. Caffeine content in beverages or food

Beverage or food	Caffeine content (mg per standard unit of consumption)	Units consumed per day (mean ± SD)	Proportion of caffeine consumed in the cohort (%)
Coffee (8 oz)	137	0.30 ± 0.62	20.7
Decaffeinated coffee (8 oz)	3	0.01 ± 0.12	0
Black tea (8 oz)	47	3.21 ± 5.35	75
Cola (12 oz)	46	0.12 ± 0.24	2.8
Caffeine free cola (12 oz)	0	0.00 ± 0.06	0
Chocolate bar (1 oz)	7	0.38 ± 0.71	1.3
Cocoa (8 oz)	6	0.05 ± 0.16	0.2

Continuous variables were expressed in mean ± standard deviation or median (IQR) as appropriate. Qualitative and quantitative differences between subgroups were analyzed using χ² or Fisher's exact test for categorical parameters as appropriate, and Student's t-test or Mann–Whitney test for continuous parameters as appropriate. Logistic regression analyses were performed to determine if caffeine and alcohol consumption was associated with liver fibrosis. The multivariate adjusted logistic regression model included covariates that were included in univariate analysis. Spearman's rank correlation was used to correlate caffeine and alcohol intake. All statistical tests were two-sided. Statistical significance was taken as P<0.05. Statistical analysis was performed by Statistical Package for Social Science (SPSS version 17.0, Chicago, IL, USA).

Results
Patient CharacteristicsOverall, 22.7% of 1532 patients in this study came from primary care clinics and 77.3% were from hospital clinics. Six patients were excluded because of anti-HCV positivity, 60 patients because of unreliable LSM results and 421 as we failed to contact for phone-interview because of various reasons (e.g. changed telephone numbers or no answer despite multiple attempts). For patients we able to contact via phone, none of them refused to give verbal consent for the phone interview. A total of 1045 chronic hepatitis B patients were thus included in this study. Majority of patients were males (652, 62.4%), of which 175 (26.8%) were overweight and 210 (32.2%) were obese. Two hundred forty seven (37.9%) male patients had elevated ALT with 71% having HBV DNA of more than 4 logs copies/ml. Four hundred and ninety-nine (47.8%) patients consumed one cup of coffee or more per day, while 231 (22.1%) patients drank alcohol. Only 26 (2.5%) patients reported no intake of both coffee and alcohol. The median (IQR) daily consumption of caffeine from food and beverages was 124 (51.6–275.6) mg/day or 1 (0.4–2.0) cup of coffee/day while alcohol consumption of >20 g/day was 1.9% (Table 2). Two hundred and sixteen (20.7%) patients had LSM suggestive of advanced fibrosis.

Table 2. Baseline characteristics of patients (n=1045)

Characteristics
Age (years, mean ± SD)	46.5 ± 12.2
BMI (kg/m², mean ± SD)	23.1 ± 3.3
Waist circumference (cm, mean ± SD)	84.5 ± 10
Platelet [ × 10⁹/L, median (IQR)]	206 (167–250)
ALT [IU/L, median (IQR)]	41 (26–68)
HBeAg positive (%)	224 (21.4%)
HBV DNA (log copies/ml, mean ± SD)	7.82 ± 8.51
LSM [kPa, median (IQR)]	6.4 (4.9–9.1)
Caffeine per day
Overall [mg, median (IQR)]	124.0 (51.6–275.6)
Coffee-cup equivalent [median (IQR)]	1 (0.4–2.0)
Black-tea-cup equivalent [median (IQR)]	3 (1.2–5.8)
Alcohol consumption per day [g, median (IQR)]	0 (0–0)
0 g (%)	810 (77.5%)
>0–20 g (%)	215 (20.6%)
>20 g(%)	20 (1.9%)

ALT, alanine aminotransferase; BMI, body mass index; IQR, interquartile range; kPa, kilopascal; LSM, liver stiffness measurement; SD, standard deviation.

Caffeine Intake and Liver Fibrosis
Table 3 shows the median total caffeine consumption in mg/day and the coffee cup equivalent according to different patient characteristics where there was no significant difference in caffeine consumption among those with no fibrosis and advanced fibrosis.

Table 3. Daily caffeine consumption according to patient characteristics (n=1045)

Characteristics	N	Median caffeine intake (mg/day)	Coffee-cup equivalent (caffeine in mg divided by 137)	Black-tea-cup equivalent (caffeine in mg divided by 47)	P-value*
Sex
Male	652	131.5 (53.7–281.7)	1.0 (0.4–2.1)	2.9 (1.2–6.1)	0.129
Female	393	111.9 (48.0–259.4)	0.8 (0.4–1.9)	2.3 (1.2–5.5)
Age
≤45	483	113.9 (47.0–263.1)	0.8 (0.3–1.9)	2.3 (0.9–5.5)	0.163
>45	562	128.9 (56.9–282.0)	0.9 (0.4–2.1)	2.6 (1.2–6.1)
Body mass index
Normal	515	123.0 (48.9–247.7)	0.9 (0.4–1.8)	2.6 (1.2–5.2)	0.315
Overweight	253	141.9 (53.6–284.4)	1.0 (0.4–2.1)	2.9 (1.2–6.1)
Obese	277	116.7 (53.1–282.0)	0.9 (0.4–2.1)	2.6 (1.2–6.1)
Alanine aminotransferase
≤58 IU/L	715	113.7 (47.4–262.1)	0.8 (0.3–1.9)	2.3 (0.9–5.5)	0.074
>58 IU/L	330	144.1 (59.7–282.0)	1.1 (0.4–2.1)	3.2 (1.2–6.1)
HBeAg status
Positive	224	137.3 (48.9–280.8)	1.0 (0.4–2.0)	2.9 (1.2–5.8)	0.709
Negative	821	121.2 (53.1–274.7)	0.9 (0.4–2.0)	2.6 (1.2–5.8)
Alcohol consumption
No	814	113.0 (46.7–243.8)	0.8 (0.3–1.8)	2.3 (0.9–5.2)	<0.001
Yes	231	180.1 (83.0–313.1)	1.3 (0.6–2.3)	3.8 (1.7–6.7)
Liver stiffness measurement
No fibrosis	829	127.6 (48.1–282.0)	0.9 (0.4–2.1)	2.6 (1.2–6.1)	0.355
Advanced fibrosis and cirrhosis	216	111.3 (54.1–239.0)	0.8 (0.4–1.7)	2.3 (1.2–4.9)

All caffeine intakes were presented as median (interquartile range).
*P-values refer to the comparison of caffeine intake by Kruskal–Wallis's test between groups under the same characteristic (e.g. male vs. female).

There was no significant difference in LSM (Table 4). In addition, caffeine intake had no significant correlation with liver stiffness (r_s=0.011, P=0.722) or the Hui's index (r_s=−0.002, P=0.948).

Table 4. Characteristics of patients by category of caffeine consumption

	Coffee-cup equivalent of caffeine intake				P-value*
	Non-drinker	>0–1/day	>1–2/day	>2/day	P-value*
Number in cohort	27	519	237	262
Age (years, mean ± SD)	49 ± 13	46 ± 12	46 ± 13	47 ± 12	0.55
Age (years)
≤45	11 (40.7%)	246 (47.4%)	110 (46.4%)	116 (44.3%)	0.80
>45	16 (59.3%)	273 (52.6%)	127 (53.6%)	146 (55.7%)
Sex
Female	13 (3.3%)	204 (51.9%)	85 (21.6%)	91 (23.2%)	0.37
Male	14 (2.2%)	315 (48.3%)	152 (23.3%)	171 (26.2%)
Body mass index (kg/m², mean ± SD)	23.9 ± 3.3	23.1 ± 3.2	22.3 ± 8.7	24.6 ± 21.4	0.16
Body mass index
Normal	12 (44.4%)	262 (50.5%)	124 (52.3%)	117 (44.7%)	0.36
Overweight	5 (18.5%)	117 (22.5%)	60 (25.3%)	71 (27.1%)
Obese	10 (37.1%)	140 (27.0%)	53 (22.4%)	74 (28.2%)
Waist circumference (cm, mean ± SD)	86.9 ± 11.1	84.5 ± 10.1	82.8 ± 15.2	84.9 ± 9.8	0.09
Alanine aminotransferase (IU/L)	38 (21–64)	41 (26–64)	42 (25–72.5)	41 (27–72)	0.37
Alanine aminotransferase
≤58 IU/L	19 (2.7%)	371 (51.9%)	154 (21.5%)	171 (23.9%)	0.19
>58 IU/L	8 (2.4%)	148 (44.8%)	83 (25.2%)	91 (27.6%)
Albumin (g/L, mean ± SD)	44 ± 4	44 ± 4	44 ± 3	44 ± 3	0.68
Total bilirubin [μmol/L, median (IQR)]	13 (10–19)	13 (9–17)	13 (9–18)	13 (9–18)	0.58
HBeAg status
Positive	4 (1.8%)	108 (48.2%)	55 (24.6%)	57 (25.4%)	0.73
Negative	23 (2.8%)	411 (50.1%)	182 (22.2%)	205 (24.9%)
HBV DNA (log copies/ml, mean ± SD)	7.28 ± 7.98	7.91 ± 8.57	7.81 ± 8.51	7.62 ± 8.23	0.34
Liver stiffness measurement (kPa, mean ± SD)	8.0 ± 6.5	8.4 ± 6.6	8.4 ± 6.1	8.2 ± 5.5	0.95
Liver stiffness measurement
No fibrosis	24 (88.9%)	401 (77.3%)	189 (79.7%)	215 (82.1%)	0.25
Advanced fibrosis and cirrhosis	3 (11.1%)	118 (22.7%)	48 (20.3%)	47 (17.9%)
Hui's index
Unlikely to have fibrosis	20 (74.1%)	351 (67.6%)	164 (69.2%)	179 (68.3%)	0.89
With fibrosis	7 (25.9%)	168 (32.4%)	73 (30.8%)	83 (31.7%)
Alcohol consumption
No	26 (96.3%)	422 (81.3%)	181 (76.4%)	185 (70.6%)	0.001
Yes	1 (3.7%)	97 (18.7%)	56 (23.6%)	77 (29.4%)
Daily alcohol intake [g, median (IQR)]	0 (0–0)	0 (0–0)	0 (0–0)	0 (0–1.1)	0.001

*Categorical variables were compared by χ²-test, while continuous variables were compared by Kruskal–Wallis test.
HBV, hepatitis B virus; IQR, interquartile range; SD, standard deviation.

Based on LSM and the Hui's index, caffeine intake by univariate and multivariate analysis was not associated with the risk of advanced liver fibrosis (Table 5).

Table 5. Relationship of caffeine intake, advanced fibrosis and alcohol consumption

Click On Table 5 To Enlarge

Alcohol Intake and Liver Fibrosis
Majority of patients (77.9%) did not consume alcohol while only 11 out of 231 patients with alcohol consumption had excessive alcohol drinking. The highest alcohol consumption per day was 88 g. Advanced fibrosis was only prevalent in 26 (18.8%) of those with mild to moderate alcohol consumption compared with 190 (21.0%) of those non-alcoholic drinkers (P=0.57).
Those who drink alcohol have significantly higher caffeine consumption than those who do not drink alcohol (Table 3). Caffeine intake had positive correlation with alcohol intake (r_s=0.167, P<0.001).

DiscussionIn this large territory-wide observational study with prospective recruitment, we assessed the relationship between caffeine and alcohol consumption and the risk of advanced liver fibrosis in chronic hepatitis B patients with different disease severity. Caffeine intake was not associated with advanced fibrosis. Patients who drank coffee regularly were more likely to consume alcohol. On the other hand, few chronic hepatitis B patients in Hong Kong had excessive alcohol consumption. Mild to moderate alcohol consumption did not increase the risk of advanced fibrosis.
Coffee is a rich source of a number of phenol compounds with antioxidant effects in vitro, with main polyphenols are phenolic acids such as chlorogenic and caffeic acid.^[27] Caffeine and its metabolites, 1-methylxanthine and 1-methyluric acid, have also been shown to have antioxidant properties.^[28] Caffeine has also been reported to inhibit chemical carcinogenesis and ultraviolet B light induced carcinogenesis in mice.^[29,30] Coffee is also found to decrease the progression of liver disease among those with advanced hepatic fibrosis^[7] and even reduce the risk of HCC^[31,32] One study^[33] concluded that approximately 2 coffee cup equivalents/day was associated with less severe hepatic fibrosis, but the beneficial effect was only shown in patients with chronic hepatitis C rather than patients with other liver diseases. A case control study in Italy showed that the protective effect of coffee on HCC was mainly in people who are not chronically infected with HBV.^[31] Overall, previous studies included mostly chronic hepatitis C patients and HBV patients were underrepresented. Based on our results, it appears that liver fibrosis in chronic hepatitis B patients is determined mainly by virological and genetic factors and less affected by caffeine intake.
In previous reports, men who have daily alcohol intake of 30–39 g and women who consumed 20–29 g of alcohol daily would have an increased risk of all cause mortality among the general population.^[34] Seventy-eight percent of our cohort did not drink alcohol at all while only 1% of patient had history of excessive alcohol consumption. Nonetheless, we could not find any deleterious effect of mild to moderate alcohol consumption to liver fibrosis. As alcohol drinkers were mostly coffee drinkers as well, the concomitant caffeine intake might but one of the confounders leading to the absence of increased risk of advanced fibrosis in alcohol drinkers. Nonetheless only a minority (1% of the study population has excessive alcohol intake, we believe that the major reason of the absence of increased risk of advanced fibrosis in alcohol drinkers was the modest instead of excess amount of alcohol use. Because most of our patients had no advanced liver disease as compared with other studies (33, 35–38), our results could not be extrapolated to cirrhotic patients. Less than 20 g of alcohol intake tends not to increase risk of advanced fibrosis in our present study. Controlled prospective studies may be done in the future to verify this.

One of the limitations of our study was the lack of liver biopsy. As liver biopsy is an invasive procedure, studies using histological fibrosis as an endpoint might suffer from the problem of small sample size and selection bias towards patients with active or advanced liver disease.^[39] On the other hand, a non-invasive test such as transient elastography could be applied to a large number of patients with different disease severity. In fact, transient elastography has been shown to be highly accurate in detecting histological advanced fibrosis and cirrhosis in chronic hepatitis B patients,^[16,23] though the accuracy might be limited in settings of grossly elevated transaminase levels,^[16] but not in the presence of steatosis.^[18] Secondly, recall bias might occur during the questionnaire survey and affect the accuracy of the measurement of the caffeine intake measured. We have tried to minimize this bias by using a quantity-frequency questionnaire, which has been previously adapted in a study demonstrating the protective effect of coffee consumption from HCC.^[11] There were 159 (15.2%) participants drinking >2–3 coffee-cup equivalents/day and 103 (9.9%) drinking >3 coffee-cup equivalents/day. Because the above numbers for these groups were low and previous finding showing 2 coffee-cup equivalents/day was associated to less severe liver fibrosis, we combined these groups for analysis. Because this is a cross sectional study, possible unmeasured as well as poorly measured confounding factors that may affect the interpretation of our data such as changes in the drinking habit of the patients, variability of caffeine intake over time, socioeconomic status, educational level were not considered in our analysis.

In conclusion, cross-sectional caffeine intake does not affect liver stiffness in chronic HBV-infected patients. The protective effect of caffeine on HCC demonstrated in previous studies is probably via the pathway other than reducing liver fibrosis. The prevalence of advanced liver fibrosis is low (20%) in chronic hepatitis B patients with daily alcohol consumption below 20 g.

References

Fatigue in Cirrhosis: Is Transplant the Answer?

2012-01-29T11:12:00.000-05:00

Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 103-105, February 2012

Editorial
Fatigue in Cirrhosis: Is Transplant the Answer?
Fatigue is a complex symptom that encompasses a range of complaints including malaise, exhaustion, lethargy, and loss of motivation and social interest. Chronic fatigue is common in the general population, affecting up to 20%.¹ Many chronic diseases are associated with fatigue including rheumatoid arthritis, systemic lupus erythematosus,² and multiple sclerosis.³ Fatigue is often a major factor in the reduction of quality of life associated with chronic disease. Furthermore, the symptom of fatigue does not typically correlate with traditional markers of disease activity, severity, disability, or clinical disease subtype.⁴, ⁵ The exact frequency of fatigue in patients with chronic liver disease is variable; however it does constitute the most common complaint.⁶, ⁷, ⁸ Any physician who manages patients with chronic liver disease will acknowledge the presence of fatigue in this patient population. However, because of difficulties in measuring and treating fatigue, it is often minimized.
The study by Kalaitzakis and colleagues⁹ in this issue of Clinical Gastroenterology and Hepatology follows cirrhotic patients longitudinally pre- and post liver transplantation. As expected, fatigue was greater in patients with cirrhosis as compared with the general population. Additionally, the degree of fatigue was related to the severity of cirrhosis; specifically, patients with higher Child–Pugh classification scores had more severe fatigue.

When discussing fatigue, it is important to differentiate between central and peripheral fatigue.⁴, ⁵ Peripheral fatigue, classically manifested by neuromuscular dysfunction and muscle weakness, does not appear to be the main factor in patients with liver disease in the absence of decompensated cirrhosis or liver failure. In comparison, central fatigue is characterized by difficulty performing physical and mental activities: a lack of self-motivation.¹⁰ Central fatigue is often associated with an increased perceived effort for tasks.

The prevalence of fatigue varies depending on the specific form of liver disease. Fatigue is well characterized in chronic cholestatic liver diseases including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis.¹¹ In fact, fatigue is present in 50% to 80% of patients with PBC and can often be the presenting symptom.¹², ¹³, ¹⁴ Fatigue in PBC has been shown to be a poor prognostic factor, as patients with higher fatigue scores had reduced survival.¹³ The predominance of fatigue in hepatitic liver pathology is less clearly defined, with chronic hepatitis C,⁷, ¹⁵, ¹⁶ autoimmune hepatitis,¹⁷ and nonalcoholic fatty liver disease⁵ the most commonly reported. Additionally, the discussion of fatigue in patients with chronic liver disease must be placed in the context of a diagnosis with an uncertain prognosis and associated social stigma. This patient population also frequently has coexisting psychological issues, including depression and anxiety.¹⁸ The presence of hepatic encephalopathy compounds this further. Therefore, the clinical expression of fatigue encompasses complex interactions with biological, psychosocial, and behavioral processes.¹¹ This is supported in the current study where fatigue was highest amongst cirrhotic patients that were unemployed or disabled; again showing the complexity of the clinical picture in this group of patients. Patients with the highest level of fatigue had the lowest described quality of life. Additionally, a significant proportion of patients in the study had anxiety or depression, which dramatically improved post liver transplant.

The pathophysiology of fatigue is complex. Animal models and clinical studies have documented that chronic liver inflammation is associated with changes in the central nervous system (CNS) that manifest as behavioral modifications.¹⁹ The inflamed liver communicates with the brain and results in altered brain function. Abnormal central neurotransmission gives rise to behavioral changes in the absence of pathologic CNS tissue damage.²⁰, ²¹, ²² The neurotransmitters that have been implicated in central fatigue include coricotropin-releasing hormone (CRH),²³ serotonin,²⁴ and noradrenaline.²⁵ In fact, pharmacologic targeting of serotonin has proven to be advantageous in managing fatigue in some patients with liver disease.²⁶, ²⁷ In addition to altered neurotransmission, the liver can communicate with the brain via neural, immune cell, or cytokine-driven routes. The liver is innervated by vagal nerve afferents that respond to immune mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interleukin-6.²⁸, ²⁹ Activated vagal nerves project to different regions of the brain, potentially driving subsequent behavior changes. However, it is likely that this neural pathway plays only a minor role in mediating fatigue in the setting of chronic liver disease because post liver transplant patients (in which the liver is deinnervated) often report little change in their fatigue³⁰; a finding also supported by this current study. Inflammatory mediators and cytokines within the circulation can also interact with their cognate receptors, expressed on the surface of cerebral endothelial cells, to activate their corresponding signaling pathways and subsequently stimulate cells within the brain parenchyma through the release of secondary messengers, including prostaglandins and nitric oxide.³¹, ³² The CNS is protected by a blood-brain barrier which is impermeable to large, hydrophilic cytokine molecules. However, the circumventricular organs are regions of the brain that lack an intact blood-brain barrier. The fenestrated capillaries allow the passage of inflammatory molecules that can then activate microglia, resident immune cells of the brain.³³, ³⁴ Finally, glial cells and neurons within the brain are capable of producing de novo cytokines that can mediate behavior effects, including fatigue.³², ³⁵

The basal ganglia is comprised of 6 nuclei that project to the limbic system and frontal cortex. Fatigue has been linked to alterations in neural activity within the basal ganglia.¹⁰ Magnetic resonance imaging (MRI) studies in PBC patients have demonstrated increased signal intensity in the basal ganglia in patients with high fatigue levels.³⁶ A recent study using MRI and voxel-based morphometry, which measures brain tissue density and concentration, found a decrease in brain density in certain areas in patients with cirrhosis.³⁷ The brain areas found to have scores most indicative of decreased brain density were the frontal and parietal regions and putamen for gray matter, and the cingulate gyrus and temporal and frontal regions for white matter. Interestingly, many of these brain areas overlap structurally and/or functionally with the basal ganglia. Intriguingly, post liver transplant patients in this study also had areas of decreased brain density, even several months after transplantation. Cirrhosis had not recurred in these patients, suggesting that neurological injury may be persistent, or at least very slow to improve. The study by Kalaitzakis and colleagues⁹ is unique as it longitudinally documents fatigue in patients before and after liver transplantation. In concordance with the above-mentioned MRI study, Kalaitzakis et al⁹ found that fatigue improved post liver transplantation, but only in a minority of patients. The degree of fatigue was still significantly higher than the control population. No specific etiologies of posttransplant fatigue were identified in this study and further work is warranted in this area.

Fatigue in the advanced stages of chronic liver disease is challenging to study due to potential overlap with symptoms associated with hepatic encephalopathy (HE). HE ranges from subtle neuropsychiatric disturbances, only apparent by performing psychometric testing (minimal HE), to varying degrees of confusion, stupor, and coma.³⁸ However, HE is not a requirement for the development of changes within the CNS in patients with chronic inflammatory liver disease. Traditionally, HE was attributed to the toxic effects of ammonia on astroglial cells,³⁹ with hyperammonemia leading to the accumulation of glutamine within astrocytes, causing brain edema due to osmotic stress.⁴⁰ However, recent attention has focused on the role of systemic inflammation in the development of HE, possibly acting synergistically with ammonia toxicity, including blood-brain cytokine transfer and receptor-mediated cytokine signal transduction.⁴¹, ⁴² These proinflammatory mechanisms are similar in many ways to the pathophysiology underlying behavioral changes and fatigue in the setting of liver inflammation and/or cirrhosis.

Fatigue is a complex and prevalent symptom in patients with chronic liver disease. Several pathophysiological mechanisms for explaining the development of fatigue have been generated; however, our understanding of fatigue in patients with liver disease is still incomplete. Moreover, the issue of fatigue in these patients is even more problematic given the recent findings that liver transplantation often does not completely alleviate this debilitating symptom. Future studies will be imperative to further examine factors predictive of fatigue in post liver transplant patients, and should help to inform us as to potential therapeutic interventions which could be instituted in order to improve fatigue in this clinical setting. Importantly, studies such as that reported by Kalaitzakis et al⁹ will help us to counsel patients more effectively with regards to expectations post liver transplantation; including that their fatigue potentially may not be significantly improved.
References

Factors Related to Fatigue in Patients With Cirrhosis Before and After Liver Transplantation

Evangelos Kalaitzakis, Axel Josefsson, Maria Castedal, Pia Henfridsson, Maria Bengtsson, Irene Hugosson, Bengt Andersson, Einar Björnsson et al.

Clinical Gastroenterology and Hepatology

Volume 10, Issue 2 , Pages 174-181.e1, February 2012

Abstract

Background & Aims We performed a prospective study to evaluate fatigue and identify potential determinants among patients with cirrhosis. We also studied the effects of liver transplantation on fatigue in these patients.

Methods
A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T₃ and T₄, cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year.

Results
Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = −0.44 to −0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05).

Conclusions
Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.

Discussion Only

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In the current study, we observed high fatigue levels in patients with cirrhosis undergoing pretransplant evaluation. Fatigue was related to impaired HRQL and to being unemployed or having disability pension. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of fatigue in these patients, whereas anemia and impaired renal function are of further importance in physical fatigue. Physical fatigue also appears to be of concern at 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant. Our findings are in line with previously published data showing increased fatigue levels in patients with decompensated cirrhosis compared with those with compensated cirrhosis or liver transplant recipients.³⁹ Fatigue has also been shown to be common in patients with chronic liver disease, but only a fraction of the patients included in these studies had cirrhosis.¹, ², ⁴, ⁵, ⁶ Our study is a systematic evaluation of fatigue in cirrhosis, simultaneously assessing potential associations with psychological distress, hormone abnormalities, and HRQL, as well as the effect of transplantation.
Hypothalamic-pituitary-adrenal dysfunction resulting in hypocortisolism can be accompanied by weakness and fatigue. Hypocortisolism has been reported in patients with chronic fatigue syndrome and fatigued patients with other chronic conditions.¹², ¹³, ²⁵ In cirrhosis, dysfunction of the hypothalamic-pituitary-adrenal axis resulting in hypocortisolism has been previously described,²¹, ⁴⁰, ⁴¹ and it has been shown to contribute to increased mortality in cirrhotic patients with sepsis.⁴⁰, ⁴¹ Our findings suggest that hypocortisolism might also contribute to fatigue and thus impaired HRQL in cirrhosis.

Psychological distress was found to be a major determinant of fatigue in cirrhosis. It was more closely related to fatigue domains than cirrhosis severity or peripheral factors, such as cirrhosis complications with an impact on patient survival, were. This is in accordance with studies in chronic (liver and nonliver) disease reporting that fatigue correlates strongly with anxiety and depression.¹, ⁵, ⁶, ¹², ¹³ In our cohort, 23% of patients had significant anxiety or depression as assessed by the HAD, and a dramatic improvement in both fatigue and psychological distress was seen after transplant. Previous studies have questioned the role of depression in the development of fatigue in cholestatic liver disease,³, ⁴² and antidepressants do not improve cancer-related fatigue.⁴³ Our findings, however, indicate that patients with cirrhosis and significant anxiety or depression confirmed by a psychiatrist might benefit from specific treatment for these disorders, which could lead to improvement in fatigue and HRQL. However, this would need to be formally tested in interventional trials.
Anemia, present in 60% of patients in our cohort, was a predictor of pretransplant physical fatigue. Previous studies have shown that anemia is common in cirrhotic patients and that hemoglobin levels are inversely related to the hepatic venous pressure gradient.⁴⁴ Interestingly, 35% of patients were found to be anemic after transplant, but this did not affect fatigue. Although anemia in cirrhosis is probably multifactorial, it is conceivable that rigorous measures to treat known anemia causes, especially those related to portal hypertension, could potentially improve fatigue and HRQL.
Fatigue scores were found to be more closely related to Child–Pugh scores compared with the Model for End-Stage Liver Disease (MELD) score. This is in line with previously published data on the closer relationship of the Child–Pugh score with HRQL indexes compared with the MELD score.⁴⁵ Ascites and hepatic encephalopathy are known to be important factors influencing HRQL in patients with cirrhosis⁴⁶ and were also found to be associated with fatigue levels in the current study. The fact that the Child–Pugh score but not the MELD score includes ascites and encephalopathy might explain, at least in part, the better correlation with fatigue.

Renal function is often impaired in cirrhosis.¹⁶, ¹⁸ Although fatigue is common in patients with renal failure and hemodialysis,⁴⁷ the potential association of renal function impairment with fatigue in patients with cirrhosis has not been previously reported to our knowledge. Renal function has been tested as a potential determinant of HRQL in different cohorts of patients with cirrhosis, but no statistically significant results were obtained.⁸, ¹⁹ However, serum creatinine was used as a measure of renal function in these studies, whereas the GFR assessed by 51 Cr-EDTA clearance was used in the current study.

Although fatigue domain scores improved after transplant, 37% of transplant recipients were physically fatigued 1 year after transplant. Previous studies have shown that physical fatigue is a major problem after liver transplantation,⁷, ⁹, ¹⁰, ¹¹ but our study specifically assessed fatigue in patients with cirrhosis before and after transplantation in a longitudinal fashion. A discussion about the expected benefit of transplantation on survival is part of the normal pretransplantation consent. Equally, with improving long-term transplantation results, being able to discuss the effect of transplantation on HRQL is central to an informed process. In the current study, almost half of fatigued patients before transplant remained fatigued at 1 year after transplant. However, no distinct potential cause of post-transplant fatigue could be identified. Further studies are clearly warranted on fatigue in transplant recipients.

The main strength of our study is its design, ie, it was a prospective longitudinal study in which validated HRQL instruments were used. Potential determinants of fatigue were carefully characterized, such as 51 Cr-EDTA clearance for GFR assessment, psychometric tests and serum ammonium ion measurements for hepatic encephalopathy, and anthropometry and DEXA measurements for nutritional status. One of the limitations of our study is potential selection bias because patients were recruited from a transplant program. Similarly, patients unable to fill in questionnaires were excluded, which might have underestimated the impact of more severe grades of hepatic encephalopathy on fatigue. Also, serum total cortisol measurements, used in the current study, are thought to overstate adrenal insufficiency in cirrhosis.²¹ However, hypoalbuminemia (<25 g/L) is the only reported risk factor for misdiagnosis of adrenal insufficiency by serum total cortisol assays.²¹ In the present study, only 1 patient with low serum cortisol had albumin <25 g/L, and exclusion of this patient from the analysis did not alter our results. Ideally, however, future studies investigating the role of glucocorticoids on fatigue in cirrhosis should use salivary cortisol measurements (not affected by hypoalbuminemia²¹) and synachten testing to identify patients with altered cortisol response.⁴⁰, ⁴¹ Finally, controls were only asked to complete the FIS and not the questionnaire related to psychological distress (HAD), and they did not undergo any blood tests. In an attempt to improve the response rate of controls, published data on HAD results from the general Swedish population³⁴ and established cutoff values of the laboratory of our institution³⁸ were used.
In conclusion, patients with cirrhosis show increased fatigue, which impairs HRQL. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of most fatigue domains, whereas anemia and impaired renal function are of further importance in physical fatigue. Liver transplantation was associated with improvement in fatigue, but physical fatigue appeared to be of concern 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant.

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The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis

2012-01-28T13:40:00.001-05:00

Journal of Hepatology

Article in Press

The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis

Tatiana Kisseleva
Affiliations
Corresponding author. Address: 9500 Gilman Drive # 0702, La Jolla, CA 92093, USA. Tel.: +1 858 822 5339., David A. Brenner Dept. of Medicine, University of California, San Diego, CA, USA

Received 5 April 2011; received in revised form 12 August 2011; accepted 4 September 2011. published online 14 December 2011.

Corrected Proof

Summary
Liver fibrosis is an outcome of chronic liver injury of any etiology. It is manifested by extensive deposition of extracellular matrix (ECM) proteins that produce a fibrous scar in the injured liver. Bone marrow (BM) cells may play an important role in pathogenesis and resolution of liver fibrosis. BM cells contribute to the inflammatory response by TGF-β1 secretion and activation of liver resident myofibroblasts. Moreover, BM itself can serve as a source of collagen expressing cells, e.g. BM-derived fibrocytes and mesenchymal progenitors, which in turn, have a potential to in situ differentiate into fibrogenic myofibroblasts and facilitate fibrosis. Finally, BM cells play an active part in resolution of liver fibrosis after cessation of fibrogenic stimuli. While natural killer (NK) cells are implicated in apoptosis of activated hepatic stellate cells/myofibroblasts, cells of myelo-monocitic lineage secrete matrix metalloproteinases to actively degrade the fibrous scar. The focus of this review is on the current understanding of the role of different subsets of BM cells in the onset, development and resolution of liver fibrosis.

Introduction
Liver fibrosis is caused by chronic injury which triggers apoptosis of hepatocytes, damage of the endothelial barrier, recruitment of inflammatory cells, increased secretion of TGF-β1, and activation of myofibroblasts responsible for scar formation [10], [50]. However, the contribution of bone marrow (BM) cells to liver fibrosis remains controversial [44], [51]. At the onset of fibrosis, BM cells are recruited to the site of injury to facilitate inflammation. It is believed that monocytes and macrophages are the primary source of TGF-β1, the major fibrogenic cytokine that plays a critical role in activation of fibrogenic myofibroblasts.

Myofibroblasts express type I collagen and other extracellular matrix proteins that constitute the fibrous scar in liver fibrosis. Three sources of myofibroblasts have been identified: hepatic stellate cells (HSCs) in hepatotoxic liver injury [27], portal fibroblasts in cholestatic liver injury [18], and fibrocytes in any inflamed liver (Fig. 1). Most myofibroblasts retain the markers of being originally derived from either fibroblasts (such as Thy1 and elastin), HSCs (such as vitamin A droplets, GFAP, and desmin), or fibrocytes (CD45). Theoretically, myofibroblasts may also be derived directly from a precursor cell, unrelated to stellate cells, fibroblasts, or fibrocytes. Cell fate mapping studies in reporter mice have demonstrated that both hepatic stellate cells and fibroblasts are septum transversum mesenchymal cells that migrate from the mesothelium and submesothelium C [5].

Figure 1

Possible origins of fibrogenic myofibroblasts.
Hepatic myofibroblasts may originate from liver resident mesenchymal cells. These include hepatic stellate cells, which under physiological conditions reside in the space of Disse in a quiescent state, and in response to injury undergo activation into myofibroblasts. Portal fibroblasts may also be a source of myofibroblasts in the fibrotic liver. In addition, BM-derived hematopoietic and mesenchymal cells may contribute to the myofibroblast population. While the role of mesenchymal stem cells in liver fibrosis is not well characterized due to the lack of specific markers and difficulties with their isolation, hematopoietic stem cells contribute to hepatic fibrocytes in response to liver injury.

Cessation of the injury often causes resolution of liver fibrosis with resorption of the fibrous scar [40], [41]. Under these circumstances, activated myofibroblasts undergo senescence [53], [77], [80], apoptosis and disappear [42], [73]. It has been shown that NK (and NKT) cells facilitate aHSCs apoptosis during regression of fibrosis [72], while newly recruited monocytes actively degrade extracellular matrix proteins (ECM) [20] via upregulation and secretion of matrix metalloproteinases (e.g. MMP13) [95] and collagenases [43].

Stem cell biology has become one of the most intensely studied areas of biomedical research and there is great optimism among scientists and the lay public that stem cells will be used as novel therapies for many incurable chronic diseases. Many institutions, including the State of California, have committed billions of dollars specifically to promote stem cell research with the goal of developing new therapies within a few years. As a result of new insights into stem cells, there is a renewed interest in the role of the bone marrow and its stem cells in liver fibrosis. The information to date is very conflicted, with different studies showing either a contributing effect or a therapeutic effect of bone marrow-derived cells to liver fibrosis.

Many studies have raised the issue of whether liver myofibroblasts may be derived from bone marrow stem cells, either hematopoietic or mesenchymal stem cells. Due to their well defined cell lineage markers and methodology for hematopoietic stem cell transfer, the contribution of hematopoietic stem cells to the population of liver myofibroblasts may be readily assessed in experimental murine liver fibrosis.

This review will address three issues: (1) the role of BM-derived macrophage to liver fibrogenesis, (2) the contribution of BM cells to myofibroblasts in the fibrotic liver, and (3) the role of BM stem cells in the resolution of liver fibrosis.

Inflammation
Expression of collagen type I marks fibrogenic/hematopoietic cells

While the fibrogenic properties of fibrocytes will be discussed below, it is important to note that expression of collagen type I by hematopoietic cells has a critical role in the development and maturation of hematopoietic BM cells required to mediate injury-triggered immune responses [22], [78], [89]. First, activated macrophages upregulate collagen type I upon maturation and migration to the site of injury [67]. Surprisingly, the level of collagen expression in activated macrophages is similar to activated cultured fibrocytes or fibrocyte-like cells [67]. Second, upregulation of collagen type I is associated with maturation of hematopoietic stem cells [22], [78], [89]. It is unknown why collagen expression is required for the function of hematopoietic stem cells. A recent study suggested that collagen I regulates the self-renewal of mouse embryonic stem cells through α2β1 integrin- and DDR1-dependent Bmi-1 [89]. However, the level of collagen expression in activated macrophages and fibrocytes is relatively low compared to activated myofibroblasts [67], [79], so that these cells are not major sources of collagen, but most likely mediate cellular interaction [78] with extracellular matrix causing cytoskeletal rearrangement [17], [31], [86].

Increased intestinal permeability has a critical role in the pathogenesis of liver fibrosis [81], [104]. Recent studies have demonstrated that in addition to phagocytosis, neutrophils, macrophages, and fibrocytes may utilize an alternative pathway to combat bacteria, by releasing extracellular DNA-based traps enriched in histones and major antimicrobial enzymes, cathelescidin and myeoloperoxidase [12], [16], [97], [106]. It remains unclear why terminally differentiated cells with phagocytic capacity decide to intake or exterminate bacteria [16]. This mechanism is activated in Vegenar granulomatosus [46] and Lupus nephritis [34]. Although the significance of such phenomenon for liver fibrosis still has to be investigated, fibrocyte-like cells from the spleen (CD45⁺Collagen-α1(I)⁺ BM-derived cells) may form DNA traps following LPS- or CCl₄-induced liver injury [52]. Thus, identification and classification of fibrocytes and fibrocyte-like cells recruited to the injured liver may provide new insights into the pathogenesis of liver fibrosis.

Recruited BM macrophages induce fibrosis
BM macrophages and Kupffer cells (liver resident macrophages) are the major source of TGF-β1 in liver fibrosis [81]. T and B lymphocytes are also recruited to the site of injury and further facilitate secretion of fibrogenic cytokines. Ablation of myolo-monocytic CD11b⁺ cells in mice at the onset of liver fibrosis attenuated activation of fibrogenic myofibroblasts and collagen deposition in liver and kidney fibrosis [20], [21], [45].

Bacterial flora and toll-like receptor (TLRs) signaling are critical in the activation of Kupffer cells/macrophages and TGF-β1 release [81]. For example, TLR4 mutant and knockout mice are resistant to fibrosis of different etiologies [38]. Moreover, genome wide analysis studies have demonstrated that individuals carrying a low efficiency polymorphism in TLR4 gene are less susceptible to HCV-induced liver fibrosis [56]. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMP) such as lipopolysaccharide (LPS), bacterial cell wall component, peptideglycan, and bacteria-derived unmethylated CpG-DNA [38]. In addition, endogenous ligands (alarmins, e.g. HMGB-1, hyaluronan) can bind TLR4 in the presence of CD14 and LPS-binding protein [LBP) and transduce similar signals [105]. Upon activation of TLRs, recruited BM cells produce inflammatory cytokines, such as TNF-a, IL-6, IL-1, MCP-1, and RANTES [82]. Moreover, microbial products have a significant impact on fibrogenic progression [104], and LPS synergistically facilitates other fibrogenic factors such as TGFβ-1, oxidative stress, and mechanical injury [2]. TLR4 on BM cells is important in experimental alcoholic liver disease [39], and TL9 on BM cells is important in experimental non-alcoholic steatohepatitis [61].

Antifibrotic effects of macrophages
Original experiments by Duffield et al. [20] and subsequent studies [60], [102] have demonstrated that, over a period of time, two functionally distinct types of macrophages are recruited to the injured liver. During the injury phase, pro-fibrogenic macrophages mediate recruitment of injury-associated macrophages that promote myofibroblast proliferation and apoptosis [32]. In contrast, during recovery from injury, a population of macrophages predominates that resembles classical macrophages and does not promote HSC survival but mediates matrix degradation. This macrophage population is present during resolution of injury and at a time when pro-fibrogenic and inflammatory mediator levels are decreasing [20]. These two functional phenotypes are separated chronologically in experimental liver fibrosis by several days, suggesting that they may represent different populations.
How do monocytes/macrophages promote matrix degradation? First of all, during the resolution phase, myelo-monocytic cells serve as a source of collagen degrading enzymes, such as collagenase and other matrix metalloproteinases (MMPs) [24], [36], [99]. Thus, increased secretion of MMP13 by hepatic macrophages is critical for dissolution of the fibrous scar in the recovering liver [24]. In addition, macrophages are responsible for clearance of apoptotic cells [10], [58], [69].

Fibrogenic myofibroblasts
Definition of myofibroblasts Myofibroblasts are characterized phenotypically by a stellate shape and expression of stress fibers, abundant pericellular matrix and fibrotic proteins (α-smooth muscle actin (α-SMA), non-muscle myosin, fibronectin, vimentin, and collagen type I) [23]. Ultrastructurally, myofibroblasts are defined by prominent rough endoplasmic reticulum (rER), a Golgi apparatus producing collagen, peripheral myofilaments, fibronexus (no lamina) and gap junctions [23]. Myofibroblasts are implicated in wound healing and fibroproliferative disorders [28], [57]. Myofibroblasts are produced in response to fibrogenic stimuli, such as TGF-β1 [65]. Classic myofibroblasts differentiate from a mesenchymal lineage and, therefore, lack expression of lymphoid markers such as CD45 or CD34. However, subsets of myofibroblasts can express Thy1.1 (CD90) or CD34. It remains unclear whether expression of these genes links (myo)fibroblasts to hematopoietic stem cells, or these antigens have a broader distribution than previously appreciated. Sustained injury may trigger (trans)differentiation of myofibroblasts from other cellular sources, including HSCs [10].
The question remains whether BM-derived cells are capable of giving rise to the functional myofibroblasts in liver fibrosis. Several BM cells have been implicated in fibrogenesis, such as fibrocytes and circulating mesenchymal cells, which could contribute to liver fibrosis.

The origin of fibrogenic myofibroblasts
Although initial reports have suggested that BM may be a source of fibrogenic myofibroblasts [26], [75], most recent studies have reported that the majority of myofibroblasts activated in response to injury are from liver resident cells [37], [48], [49], [51], [81]. These findings are based on BM transplantation techniques in mice, in which the collagen-α1(I) or collagen-α2(I) promoters drive expression of the GFP reporter only in BM cells [37], [51]. Since collagen-α1(I) or collagen-α2(I) fibers are expressed in the same cells to form a triple helix [85], these reporter genes are expected to exhibit identical localization. Indeed, similar results were obtained in both mice in response to two models of liver fibrosis [37], [51], bile duct ligation and toxic liver injury induced by CCl₄, demonstrating that activated myofibroblasts do not originate in the BM but emerge from the liver resident cells, e.g. HSCs and portal fibroblasts. Meanwhile, a small population of collagen type I expressing BM-derived cells, scattered in the liver and spleen of these mice, is composed of fibrocytes [37], [51]. Despite differences in experimental approaches and duration of injury, there was no evidence that BM contributes to replenishment of HSCs and portal fibroblasts or liver stem cells.

Fibrocytes are implicated in fibrogenesis of parenchymal organs
Fibrocytes are defined as spindle shaped “CD45 and collagen type I (Col⁺) expressing leukocytes that mediate tissue repair and are capable of antigen presentation to naive T cells” [13]. Due to their ability to differentiate into myofibroblasts, fibrocytes are implicated in the fibrogenesis of skin, lungs, kidneys, and the liver [1], [48], [87]. In addition to collagen type I, fibronectin and vimentin, fibrocytes express CD45, CD34, MHCII, MHCI, CD11b, Gr-1, and secrete growth factors (TGF-β1, MCP-1) that promote deposition of ECM [11], [70]. Upon injury or stress, fibrocytes proliferate in the BM and migrate to the injured organ [13], [70]. The reported number of recruited fibrocytes varies from 25% (lung fibrosis) [48], [88] to ∼3–5% (liver fibrosis, e.g. BDL and CCl₄) [49] of the collagen expressing cells, suggesting that the magnitude of fibrocyte differentiation into myofibroblasts depends on the organ and the type of injury. Fibrocytes originate from hematopoietic cells and differentiate in the liver into typical myofibroblasts [79]. Mice treated with human serum amyloid protein (hSAP) [66], a natural inhibitor of fibrocyte differentiation and maturation, develop less fibrosis in response to injury. Our data and studies in other parenchymal organs [14], [63], [68] clearly demonstrate that fibrocytes play an important role in pathogenesis of many fibrogenic disorders, including lungs. Elevated levels of circulating fibrocytes in peripheral blood in patients with lung fibrosis have a poor prognostic value [62]. Moreover, hSAP has been successfully tested in limited clinical trials in patients with skin, kidney and lung fibrosis [14], [59], [63], [68].

BM mesenchymal stem cells (MSCs)
MSCs are defined as self-renewable, multipotent progenitor cells with the capacity to differentiate into lineage specific cells that form bone, cartilage, fat, tendon and muscle tissue [44], [84]. Unlike hematopoietic stem cells, MSCs are radio- and chemoresistant [9] and do not express progenitor markers (CD45, CD34, 133 [44]) or myelo-monocytic markers (CD11b, MHCII, and F4/80). Hepatic myofibroblasts may arise from BM-derived mesenchymal progenitors [26], [75]. BM-derived mesenchymal progenitors can give rise to myofibroblasts in the injured liver [6], [19], [55]. BM-derived cells may populate fibrotic lungs [35] and the liver [75] and contribute to fibrosis by differentiating into tissue myofibroblasts [40], [48], [75]. By subfractionating the BM stem cell compartment, the hepatic BM-derived myofibroblast-like cells were reported to be of mesenchymal stem cell origin [44], [75]. Cultured mesenchymal stem cells have the potential to become myofibroblast-like cells when transplanted into mouse livers [6], [19].

Whether circulating mesenchymal progenitors significantly contribute to ECM deposition in the course of experimental liver fibrosis remains to be determined, but they most likely represent a population, distinct from hematopoietic-derived fibrocytes [51]. Unlike hematopoietic stem cells, the definitive markers for mesenchymal stem cells have not been identified, and ablative radiation protocols to establish donor cell transfer have not been standardized. Therefore, a definitive murine liver fibrosis experiment with documented transfer of all bone marrow constituents expressing a myofibroblast specific marker has not been reported. Although initial enthusiasm about the BM origin of myofibroblasts declined in the recent years, further studies are required to re-evaluate this phenomenon.

Liver fibrosis precedes development of hepatocellular carcinoma [10], [38]. Recruitment of BM-derived fibroblasts (including fibrocytes) has been implicated in the pathogenesis of liver cancer, and cancer of other organs [8]. Thus, using collagen-α1(I)-GFP and α-smooth muscle actin (SMA)-RFP mice, BM-derived myofibroblasts were shown to contribute to neoplasia in gut and intestine [71]. Since most liver injury models in mice develop within a short period of time, it is possible that these experimental conditions are too short for the recruitment of BM myofibroblasts, as seen in cancer during 8–9months of development.

Contribution of BM cells in genetically altered mice
BM cells may have different roles in different mouse models of genetically-induced liver injury. Since these phenomena are usually not observed in the wild type mice, contribution of BM-derived cells to hepatic cells is discussed separately.

The classical example is FAH^−/− mice, in which a mutation in fumaryl-aceto-acetate hydrolase (FAH) gene causes a metabolic disorder equivalent to hereditary tyrosinemia type 1. Withdrawal of the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) from drinking water causes extensive apoptosis of FAH^−/− hepatocytes in these mice. Transplantation of wild type BM into these mice results in rescue from fatal liver failure by FAH-deficient hepatocytes. Wild type BM myelo-monocytes cells fuse with damaged hepatocytes to give rise to colonies of functional hepatocytes [54], [98]. Moreover, infusion of myeloid cells alone is sufficient to give rise to functional hepatocytes [3], [92], [101]. However, fusion of hepatocytes with macrophages was only rarely observed in wild type mice in response to other types of liver injury (CCl₄, BDL), suggesting that hematopoietic cells have a limited contribution to hepatocyte population under physiological conditions or in response to injury [3], [92].

Recruitment of fibrocytes into the injured liver representing a high percentage of myofibroblasts has been observed in Abcb4-deficient mice (Abcb4^−/− mice), and has been shown to substantially ameliorate development of liver fibrosis [74]. However, only a modest contribution of fibrocytes to liver fibrosis (3–5% of fibrogenic myofibroblasts) has been observed in wild type mice in response to CCl₄ and BDL [51], [79]. Although Abcb4-deficient mice provide a unique opportunity to study recruitment of fibrocytes in great detail, they do not reflect the fibrocyte contribution to the population of myofibroblasts in hepatotoxic or cholestatic injury.

Resolution of liver fibrosis
Disappearance of myofibroblasts Reversal of fibrosis is associated with increased collagenase activity, activation of macrophages/Kupffer cells that secrete matrix metalloproteinases, e.g. MMP-13, and matrix degradation [24], [95]. Senescence and apoptosis of activated HSCs play a significant role in resolution of liver fibrosis by eliminating the cell type responsible for producing the fibrotic scar [41], [53]. Several mechanisms are implicated in the apoptosis of activated HSC: (1) activation of death receptor-mediated pathways (Fas or TNFR-1 receptors) and caspases 8 and 3; (2) upregulation of pro-apoptotic proteins (e.g., p53, Bax, caspase 9); and (3) decrease of pro-survival genes (e.g., Bcl-2) [50]. A population of liver-associated natural killer (NK) cells and NKT cells mediate apoptosis of activated HSCs [72]. Kupffer cells and BM macrophages actively participate in clearance of apoptotic cells and degradation of extracellular matrix proteins.

Studies in culture suggest that aHSCs, at least in part, can revert to a quiescent phenotype. Therefore, the disappearance of activated α-SMA⁺ Col⁺ HSCs in the course of fibrosis reversal may indicate that activated HSCs return to their quiescent state, which is associated with expression of lipogenic genes (Adfp, Adipor1, CREBP, PPAR-γ) [83] and storage of vitamin A in lipid droplets. Depletion of peroxisome proliferator-activated receptor gamma (PPAR-γ) constitutes a key molecular event for HSC activation, and ectopic over-expression of this nuclear receptor results in the phenotypic reversal of activated HSC to quiescent cells in culture [83]. The treatment of activated HSCs with an adipocyte differentiation cocktail, over-expression of SREBP-1c, or culturing on basement membrane-like ECM [29], [100] result in up-regulation of adipogenic transcription factors and cause morphologic and biochemical reversal of activated HSCs to quiescent cells [93], [94]. Although these results suggest that activated HSCs can revert to a quiescent state, these findings have only been documented in cultured cells.

Therapy
Many studies have demonstrated that transplantation of bone marrow cells reduces experimental liver fibrosis ([76], [90] and others). The mechanism is not trans-differentiation of bone marrow cells into hepatocytes. More likely, hematological stem cells may contribute to the reversal of liver fibrosis via macrophages that produce collagenases [91] and phagocytose dead parenchymal cells [69]. More unexpectedly, mesenchymal stem cells, even though they have the potential to become myofibroblasts, also have functions that may contribute to the reversal of fibrosis. Cultured mesenchymal stem cells secrete agonists that inhibit hepatocyte apoptosis, induce hepatocyte proliferation, and increase hepatocyte specific gene expression [96]. Also, mesenchymal stem cells may be induced in culture to become endothelial progenitor cells (EPCs). Transplantation of EPCs reverses hepatic fibrosis and improves survival in CCl₄-induced cirrhosis in rats [64].

BM cells for anti-fibrotic therapy
The improvement of liver function following transplantation of hematopoietic progenitors in mice and rats with injured livers provided the basis for clinical trials [25]. Clinical studies with adoptive transfer of autologous CD133⁺ BM cells in patients have been reported to stimulate liver regeneration [4]. Similar to that, autologous infusion of CD34⁺ blood cells, or even monocytes, improved biochemical parameters and stimulated liver regeneration [33]. Within the limits of these small, uncontrolled clinical trials, evidence is starting to accumulate that transplantation of hematopoietic progenitors may be beneficial in patients. However, the mechanism of their action remains to be defined. Such improvement may result from release of cytokines and growth factors by transplanted hematopoietic cells, or occur due to infusion of scar-resorbing monocytes. In concordance with these observations, treatment with granulocyte-colony stimulating factor (G-CSF) was used to mobilize the BM cells and demonstrated a positive histological effect in patients with alcoholic steatohepatitis [30].
Mesenchymal stem cells serve as another potential target for the liver stem cell therapy. In addition, mesenchymal cells are readily available (for example, from fat tissue) and relatively easy to expand in vitro. A recent study investigated the ability of purified hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and mononuclear cells to engraft and contribute to liver regeneration in response to injury in mice [15]. However, only a low level of engraftment with the MSCs and reconstitution of the liver mass has been reported [7].

In concordance with this notion, injection of MSC-derived conditioning media into a liver-assist device decreased hepatocyte apoptosis and increased their proliferation [96], [103]. However, recent studies have raised a safety question on MSCs transplantation, demonstrating that MSCs can give rise to myofibroblasts in mice in response to liver injury. For example, BM-derived MSCs contributed to the development of liver fibrosis in chimeric mice that received bone marrow transplantation with an enriched BM mesenchymal fraction, and subjected to the CCl₄-liver injury [75]. Taken together, both hematopoietic and mesenchymal stem cells demonstrate a limited, if any, contribution to hepatocyte replenishment, but may stimulate liver function by providing soluble growth factors or cytokines [3], [49], [92].
A few clinical trials have been performed in patients with end-stage liver disease caused by hepatitis B, hepatitis C, alcoholic liver disease, and cryptogenic fibrosis. These patients were transplanted with autologous MSCs harvested from the iliac crest. The tested parameters (albumin, creatinine) demonstrated a modest but significant improvement without severe adverse effects, suggesting that MSCs might be useful for the treatment of end-stage liver disease with satisfactory tolerability [47].

Conclusions
The literature provides evidence that bone marrow cells might contribute to increase or to inhibit experimental liver fibrosis Figure 2. Although there is clearly a need for additional, better defined studies, some conclusions can be made from our current information. Hematological stem cells are the source of monocytes, Kupffer cells and recruited macrophage. Overall, these cells contribute to the initial inflammation in the injured liver that progresses to liver fibrosis. However, recruited macrophages may also secrete agonists such as IL-10 that inhibit stellate cell activation as well as collagenases that cause regression of fibrosis. Hematological stem cells are also the source of fibrocytes, which are recruited to the injured liver and function in the innate immune response as well as differentiate into myofibroblasts. Mesenchymal stem cells have the capacity to become myofibroblasts, but studies to follow their cell fate in vivo are limited by the lack of specific markers.

Figure 2
Potential roles of BM-derived progenitor populations in liver injury. BM is the source of hematopoietic and mesenchymal stem cells, which may participate in the response to liver injury.

Most, but not all, studies using BM transplantation have demonstrated a beneficial effect on experimental liver fibrosis. The mechanism for this benefit is unclear, and in particular BM-derived cells do not constitute a significant source of hepatocytes in the injured liver. However, both mesenchymal stem cells and hematopoietic stem cells are reported to contribute to the regression of liver fibrosis. On the basis of these studies, small, mostly uncontrolled clinical studies have treated cirrhotic patients with autologous transplantation of BM derived cells. Although these studies have established the feasibility of this approach, the mechanism and long term benefit of transplantation of BM-derived cells in cirrhosis is unknown.

Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The underlying research reported in the study was funded by the NIH Institutes of Health.

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