Monday, October 31, 2016

New Treatment Leaves Liver Cancer Cells in Limbo


Stuck in senescence, this cell can no longer grow or divide. The Arid1b protein (green) induces this state by regulating the expression of specific genes. In contrast other regions of the DNA (blue) contain genes that are not bound by Arid1b and are not expressed (red).

New treatment leaves liver cancer cells in limbo
By Deborah Oakley

Newswise — Scientists have shown that a mutation in a gene called Arid1b can cause liver cancer. The gene normally protects against cancer by limiting cell growth, but when mutated it allows cells to grow uncontrollably. The researchers have shown that two existing drugs can halt this growth in human cells. This points to a new approach to treating liver cancer.

These early results could be translated into a treatment relatively quickly, says Jesus Gil of the MRC Clinical Sciences Centre (CSC), based at Imperial College London, and who led the study. This is because the drugs are already used to treat other types of cancer. Gemcitabine is used on bladder, pancreas and ovary cancer, whilst DON has been tested in clinical trials. Both are known to be safe in people so will not require the usual toxicity testing.

According to MacMillian Cancer Support, 4200 people in the UK are diagnosed with liver cancer annually. “Liver cancer is a deadly disease,” says Luca Tordella, a postdoctoral researcher at the CSC who played a key role in the study. He says the new treatment will be most effective in people who have a mutation in the Arid1b gene. “It’s important to better classify patients into groups, according to their genes. One advance of personalised medicine is to understand which drug will work best on you, and which on me.”

The CSC team began by looking for mutations in the DNA of 100 people with liver cancer. They focused in on genes known to regulate a cellular state called senescence. This is a built-in safety mechanism that helps to protect the cell against cancer. Senescence is triggered when a cell grows abnormally fast and, once induced, it acts to keep the cell in limbo, such that it is alive but can no longer grow or divide. Bypassing senescence is a hallmark of many types of cancer.

It has previously been suggested that the Arid1b gene plays a role in liver cancer. The CSC team are the first to show that it does so by disrupting senescence. Working with researchers at the University of Tübingen, Germany, they mutated Arid1b in mice and human cells, and this stopped the cells from entering senescence. When Arid1b was mutated in mice that also had a mutation in the gene Ras, the mice developed liver cancer.

The researchers also identified exactly how Arid1b stimulates senescence. In healthy cells, Arid1b is part of a bigger complex (called SWI/SNF) that regulates the activity of hundreds of genes. One of these genes produces an enzyme that breaks down the building blocks of DNA. Without these blocks, the cell cannot continue to grow and divide so enters senescence. But if Arid1b is mutated, the blocks cannot be degraded and the cell continues to grow, bypassing senescence and potentially growing out of control.

Gil and Tordella have shown that it’s possible to induce senescence by treating human cells, which have an Arid1b mutation, with either gemcitabine or DON. Both drugs inhibit the synthesis of these blocks, called nucleotides, and thereby induce senescence and stop cancer in its tracks.

“Around 20% of patients with liver cancer have mutations on the genes encoding for components of the SWI/SNF complex. What we suggest is if we treat these people with drugs that target the degradation of nucleotides, they will respond,” says Gil. “We plan to continue to research this in the lab to develop treatments to target liver cancer.”

Find out more here and read the full paper here.
SEE ORIGINAL STUDY

Two genes linked to postpartum immunity revival in women with persistent hepatitis C

Two genes linked to postpartum immunity revival in women with persistent hepatitis C
Research may provide a model for identifying immune factors needed to control chronic infections

Nationwide Children's Hospital

Alternative forms of two genes are associated with a boost in immunity to hepatitis C after childbirth, a study led by a Nationwide Children's Hospital physician-researcher shows.

At three months postpartum, the number of viruses circulating in the blood declined sharply in most women who carried particular versions of IFNL3 and HLA-DPB1 genes. Mothers lacking these gene variants experienced little change in viral levels after delivery.

The research is published in the Proceedings of the National Academy of Sciences. The study focused on hepatitis C, but it may serve as a model for identifying factors that restore immunity to other chronic infections, the researchers suggest.

"Immunity is normally exhausted in people who have chronic hepatitis C. The liver produces about a trillion viruses per day, and the T-cells that should attack the virus don't work," says Jonathan R. Honegger, MD, principal investigator at the Center for Vaccines and Immunity in The Research Institute at Nationwide Children's, and lead study author.

While studying hepatitis C transmission from mother to baby, he noticed that some mothers experienced unusual sharp declines (10-1000 fold) in blood viral levels after childbirth. Women with these viral load declines also had improved T-cell activity against hepatitis C after delivery.

"These initial observations really piqued our interest. There's a lot of effort underway to find ways to turn on exhausted T-cells, and the months following pregnancy appeared to provide a unique opportunity to study this," says Dr. Honegger, who is also assistant professor of clinical pediatrics at The Ohio State University College of Medicine.

Among 34 women in this study, five had consecutive pregnancies. "The postpartum viral load decline was very similar with each consecutive pregnancy, which made you think it wasn't just a random event--that some stable factor was controlling how viremia fell after delivery," Dr. Honegger says.

The team focused on genes.

Interferon lambda 3, a signaling protein that induces antiviral activity, is known to affect control hepatitis C in non-pregnant people. The researchers found that a common variant in the IFNL3 gene also increases the likelihood of controlling hepatitis C after pregnancy.

Human leukocyte antigen (HLA) molecules present small pieces of proteins to T-cells, enabling T-cells to recognize the presence of foreign pathogens such as viruses. The team found that women who possessed particular variants of HLA-DBP1 genes demonstrated greater T-cell recovery and virus control than women lacking these variants. HLA-DPB1 molecules present peptides to a type of T-cell called CD4+ "helper" T-cells. "This finding was important because helper T-cells are thought to be particularly dysfunctional in chronic hepatitis C. These findings suggest that HCV-specific helper T-cells may regain function after delivery. This is now an active line of investigation for us."

Reversal of T-cell exhaustion may also be relevant for controlling other persistent infections such as hepatitis B or HIV, the researchers say.

In another study to be published, the researchers examined effects of the IFNL3 genotype on immune gene signaling after childbirth in un-infected women.

Reference:

Honegger JR, Tedesco D, Kohout JA, Prasad MR, Price AA, Lindquist T, Ohmer S, Moore-Clingenpeel M, Grakoui A, Walker CM. Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery. Proceedings of the National Academy of Sciences.

Tampa Bay woman with Hepatitis C reduces co-pay for treatments with coupon

Tampa Bay woman with Hepatitis C reduces co-pay for treatments with coupon
Published:

Wendy Latorre, of Pasadena, says when she heard about the drugs she was extremely hopeful. “And then I found out what the cost was, most people do about 12 weeks and it’s about $120,000,” she said.

Even with insurance coverage, Latorre’ s co-pay of $6,000 a month, made the drug out of reach, until Latorre found a hidden link for a coupon on Harvoni’s official website.

She entered her first and last name, date of birth, and zip code and then came surprise call from her insurance company.

“Five dollars for all eight weeks of treatment. It’s like my lucky day, it’s like I hit the lottery,” said LaTorre.

Continue reading....

Dating after Hepatitis C: Hope on the horizon for the 1 in 30 boomers estimated to be infected

Dating after Hepatitis C: Hope on the horizon for the 1 in 30 boomers estimated to be infected

Baby boomers are 6 times more likely to be infected than other adults. We need to talk about testing and treatment

Recently I went on a first date — a stroll in a city park — that went rather well. We had so much in common, from a love of reading to a history of youthful troublemaking. If I wasn’t convinced already he was someone I could relate to, my new friend shared that he’d been cured of Hepatitis C.

I could hardly believe it. Instead of having to awkwardly explain my medical history, I’d met someone who shares it. It was a first. The only other time I’d met people who’d been cured of Hepatitis C, I was at an event at Johns Hopkins celebrating the first 1,000 successes of the new drugs. Some of my fellow drug program participants had gotten it from blood transfusions, some from vaccinations in the military. Some had no idea how.

Continue reading..

Sunday, October 30, 2016

Side Effects - HCV current DAA therapies

Weekend Reading:
Side Effects - HCV direct-acting antiviral therapy

Welcome to Weekend Reading, today we offer a short review of recent warnings issued for hepatitis C direct-acting antivirals.

Maybe you missed important warnings, here we lay them out for you with links and other important information spanning from April to October.  We end with an article discussing side effects, medical contraindications, viral resistance and cost for patients using current DAAs.

Recent Warning
As you may have read the FDA is now requiring a “black box warning” on certain hepatitis C direct-acting antiviral (DAA) medicines because of the risk of hepatitis B reactivation. Why wasn't this reported during clinical trials? Because people with HBV were excluded from the trials, in case you missed it read all about the warning, here.

Around seven months ago we started learning about the safety issue in both Europe and Japan. In May FiercePharma reported about; Japan's PMDA review - hep B risk link to hep C therapies.

Risk Of Liver Cancer
When meeting highlights were released from Pharmacovigilance Risk Assessment Committee (PRAC) in April, in addition to the hepatitis B re-activation safety review,  the EMA expanded an ongoing review about the risk of liver cancer (hepatocellular carcinoma) coming back in patients who were treated with direct-acting antivirals.

Here is Google's cache, the site was down today, should be back up Monday.

The PRAC also extended the scope of its ongoing safety review of medicines known as direct-acting antivirals (Daklinza, Exviera, Harvoni, Olysio, Sovaldi, Viekirax) used for treating chronic (long-term) hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus).

At its previous meeting in March, the Committee had initiated a review following cases of hepatitis B re-activation in patients who have been infected with hepatitis B and C viruses, and who were treated with direct-acting antivirals for hepatitis C.

In April 2016, data from a study became available regarding the risk of liver cancer (hepatocellular carcinoma) coming back in patients who were treated with these medicines. The study suggested that these patients were at risk of their cancer coming back earlier than patients with hepatitis C who were not treated with direct-acting antivirals. The scope of the ongoing review has therefore been extended to also assess the risk of liver cancer with these medicines.

Here is a more in-depth article published in May over at Medscape; EMA Expands Review of New HCV Drugs for Liver Cancer Recurrence
The European Medicines Agency (EMA) has extended the scope of its review of the six direct-acting antivirals approved for use in the European Union for treating chronic hepatitis C virus (HCV) infection to include the risk for early liver cancer recurrence, the agency said today. They are daclatasvir (Daklinza, Bristol-Myers Squibb), dasabuvir (Exviera, AbbVie), sofosbuvir/ledipasvir (Harvoni, Gilead Sciences), simeprevir (Olysio, Janssen), sofosbuvir (Sovaldi, Gilead Sciences), and ombitasvir/paritaprevir/ritonavir (Viekirax, AbbVie).
Continue reading...

Liver Cancer - The International Liver Congress 2016
April 13-17 in Barcelona, Spain
Two studies presented during the International Liver Congress suggest that patients with a history of hepatocellular carcinoma have the highest risk of developing a tumor after direct-acting antiviral therapy, but new diagnoses were also reported.

"I do not think that direct-acting antivirals are directly responsible," said lead investigator Stefano Brillanti, MD, from the University of Bologna, Italy.

"The hypothesis is that immune surveillance may be reduced too rapidly," he told Medscape Medical News. "You have an immediate drop in viremia, but also attenuation of inflammation. I think inflammation is a bad thing in terms of hepatitis progression, but it may be a good thing in terms of controlling cancer."
Read the article, also reported by Medscape.

Additional Reading
Liver Cancer After Treatment For Hepatitis C

Side effects, medical contraindications, viral resistance and cost for patients using current DAAs
October 23, 2016
Emerging complexities with HCV DAA regimens: Less is still way more. 
The arrival of interferon-free direct acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infection have been transformative. Treatment approaches which were once marred by frequent and potentially severe side effects, lack of patient and provider acceptance and marginal efficacy have been replaced by DAA regimens which can cure the vast majority of patients in 12 weeks with minimal to no side effects. Despite these tremendous advances in HCV therapy providers must recognize, as with any medication, that severe side effects and medical contraindications still exist for certain populations when using current DAA therapies. ​

The Changing HCV Landscape: Update on Treatment
Review Article
OCTOBER 26, 2016
DAAs for HCV infection have all but replaced IFN as the foundation of treatment for HCV across all genotypes. Among the major advantages of these oral regimens, beyond their remarkable efficacy, has been their relatively clean safety profile. Adverse effects are common but generally mild, including headache, fatigue, and insomnia—and are trivial relative to the effects of earlier regimens, reflected by a low rate of discontinuation for adverse events. Clinicians must be aware of potential drug–drug interactions, and should prescribe these medications with a commitment toward mastering these and/or consulting the numerous published and online references, including package inserts, containing this information...
Continue to article....

My Journey
In 1999 I began my own HCV journey, it ended with eradicating the virus, today I am still cured. With that said, the side effects were many, still I do not regret my decision.

We have come a long way in developing cures for hepatitis C, today HCV can be cured in most patients, some in 8-12 weeks. Yes, even with fewer side effects.

For people with cirrhosis, or waiting on a transplant list these new drugs are nothing short of a miracle. For the rest of us, its still pretty much a miracle.

Wishing you all a safe and successful journey.

Tina

Friday, October 28, 2016

Liver fibrosis: Which mechanisms matter?

Of Interest - Is There A Natural Way To Improve Liver Fibrosis?

The latest issue of Clinical Liver Disease is available on Wiley Online Library

Clinical Liver Disease is an official digital educational learning resource from the American Association for the Study of Liver Diseases.

Visitors are able to view videos, access full text articles, and download files in either HTML or PDF formats.

Reviews
Implications of Translational Research
Guest Edited by Frank Tacke, MD

New pharmacological approaches to a functional cure of hepatitis B (pages 83–88)
Wai-Kay Seto and Man-Fung Yuen
Version of Record online: 27 OCT 2016 | DOI: 10.1002/cld.577


The transition from inflammation to cancer in the liver (pages 89–93)
Augusto Villanueva and Tom Luedde
Version of Record online: 27 OCT 2016 | DOI: 10.1002/cld.578


Liver fibrosis: Which mechanisms matter? (pages 94–99)
Ralf Weiskirchen and Frank Tacke
Version of Record online: 27 OCT 2016 | DOI: 10.1002/cld.581


Hepatocellular Carcinoma and Nonalcoholic Steatohepatitis (NASH)
Guest Edited by Gregory Gores, MD



Natural history of nonalcoholic steatohepatitis–associated hepatocellular carcinoma (pages 105–107)
Stefano Bellentani, Gianluca Svegliati Baroni, Fabio Piscaglia and Claudio Tiribelli
Version of Record online: 27 OCT 2016 | DOI: 10.1002/cld.582


In My Opinion
Guest Edited by Jay Talwalkar, MD
New organ allocation policy in liver transplantation in the United States (pages 108–112)
David A. Goldberg, Richard Gilroy and Michael Charlton
Version of Record online: 27 OCT 2016 | DOI: 10.1002/cld.580




The latest issue of Clinical Liver Disease is available on Wiley Online Library

WEBINAR Nov 1st: An Introduction to Accessing Generic Hepatitis C Medicines

UPCOMING WEBINAR: An Introduction to Accessing Generic Hepatitis C Medicines
DATE: Tuesday 1 November, 14:00 GMT
Following the success of the first two webinars in this series the upcoming webinar on generic hepatitis C medicines will continue to explore the issue of access.

With presentations on, and discussions around, the legalities, quality and performance of generic hepatitis C medicines and the ways in which people are accessing them this webinar will provide an introduction to the topic. It will also give viewers the opportunity to ask questions to experts working in this field.

Panellists:
  • Raquel Peck, CEO, World Hepatitis Alliance
  • Esteban Burrone, Head of Policy, Medicines Patent Pool
  • Andrew Hill, Senior Visiting Research Fellow, Department of Pharmacology, University of Liverpool
  • Giten Khwairakpam, Project Manager for Community and Policy, TREAT Asia
Register your attendance here. https://attendee.gotowebinar.com/register/5550764983655340801
If you are unable to attend the webinar but wish to submit a question please email it to jessica.hicks@worldhepatitisalliance.org

Can Direct-acting Antivirals Treatment of HCV Reactivate Herpesvirus Infection?

Download Full Text Article​:
Reactivation of Herpesvirus in Patients With Hepatitis C Treated With Direct-Acting Antiviral Agents
Patients with herpesvirus reactivation were receiving the DAA agents sofosbuvir with ledipasvir (with or without ribavirin, 7/10), ombitasvir with paritaprevir and ritonavir plus dasabuvir (with or without ribavirin, 2/10), or sofosbuvir with simeprevir plus ribavirin (1/10). Two of the 10 patients developed postherpetic neuralgia and 1 patient developed kerato-uveitis. All 10 patients with herpesvirus reactivation achieved a sustained virologic response.

Article Summary - AGA Journals Blog

Can Direct-acting Antivirals Treatment of HCV Reactivate Herpesvirus Infection?

Researchers report reactivation of herpesvirus in 10 patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents in the November issue of Clincial Gastroenterology and Hepatology.

They found herpesvirus to be reactivated in 10 patients who received DAA therapy (7 patients had cirrhosis and 3 patients had received liver transplants), a median of 8 weeks after the therapy was initiated. None of the controls had herpesvirus reactivation.
Begin here....


Fatty liver: Turning off TAZ reverses disease

Fatty liver: Turning off TAZ reverses disease

In mice, turning off the liver's TAZ protein reverses fibrosis, the primary feature of nonalcoholic fatty liver disease that turns it into a deadly disease

Columbia University Medical Center

NEW YORK, NY (Oct. 27, 2016) -- Scientists at Columbia University Medical Center (CUMC) have identified a factor in liver cells that is responsible for turning a relatively benign liver condition, present in 30 percent of U.S. adults, into a serious disease that can lead to liver failure.

The study was published online today in Cell Metabolism.

With the rise of obesity in the U.S., the incidence of nonalcoholic fatty liver disease (NAFLD) -- in which excess fat fills the liver -- has risen to epidemic levels. The extra liver fat is generally benign, but in one in five people, NAFLD evolves into a more serious condition, nonalcoholic steatohepatitis (NASH).

In NASH, the liver becomes inflamed and criss-crossed by fibrous scar tissue, and liver cells start dying. Patients with NASH are at risk of liver failure and liver cancer, but there are no drugs on the market that can slow or stop the disease.

Because the amount of fibrosis in the liver is associated with a greater risk of death from NASH, Xiaobo Wang, PhD, associate research scientist in the Department of Medicine at CUMC, looked for ways to stop fibrosis in a mouse model of NASH.

He found that in liver cells, TAZ, a previously unknown factor in NASH, plays a critical role in initiating fibrosis, and that fibrosis stops in mice with NASH when TAZ is inactivated in liver cells. With TAZ shut down, existing fibers in the liver also dissolved, essentially reversing the disease. Two other critical features of NASH, inflammation and cell death, were also reduced when TAZ was turned off. Fat accumulation in the liver was unaffected.

Based on their examination of liver biopsies from NAFLD and NASH patients, Drs. Wang and Tabas believe that TAZ works in the same way in people.

"We think that by stopping fibrosis through TAZ and its partners, we may be able to prevent the serious consequences of NASH, including liver failure and liver cancer," said Ira Tabas, MD, PhD, Richard J. Stock Professor and vice-chair of research in the Department of Medicine and professor of pathology & cell biology (in physiology and cellular biophysics) at CUMC.

The study is titled, "TAZ/WWTR1 Promotes Hepatic Inflammation and Fibrosis in Nonalcoholic Steatohepatitis." Authors include Xiaobo Wang (CUMC), Ze Zheng (CUMC), Jorge Matias Caviglia (CUMC), Kathleen E. Corey (Massachusetts General Hospital and Harvard Medical School), Tina M. Herfel (Teklad Diets, Envigo, Madison, WI), Ricard Masia (Massachusetts General Hospital and Harvard Medical School), Raymond Chung (Massachusetts General Hospital and Harvard Medical School), Jay H. Lefkowitch (CUMC), Robert F. Schwabe (CUMC), and Ira Tabas (CUMC).

The research was supported by grants from the National Institutes of Health (HL087123, HL075662, DK078772, DK099422, R03 DK101863, and UL1 TR000040) and a Russell Berrie Foundation Scholarship in Diabetes Research.

Drs. Wang and Tabas and Columbia University have filed a patent for the use of TAZ pathway inhibitors in treating NASH.

The authors report no additional conflicts of interest.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.


Thursday, October 27, 2016

GLOBAL REPORT ON ACCESS  TO HEPATITIS C TREATMENT

GLOBAL REPORT ON ACCESS TO HEPATITIS C TREATMENT
World Health Organization (WHO) released its global report on access to hepatitis C treatment in low and middle-income countries. Here is the report and press release.​

Publication details

Number of pages: 68
Publication date: October 2016
Languages: English
WHO reference number: WHO/HIV/2016.20

Downloads

News release

Over 1 million treated with highly effective hepatitis C medicines
High prices–a major barrier to access

27 October 2016 | GENEVA - Over one million people in low- and middle-income countries have been treated with a revolutionary new cure for hepatitis C since its introduction two years ago.

When Direct Acting Antivirals (DAAs) were first approved for hepatitis C treatment in 2013, there were widespread fears that their high price would put them out of reach for the more than 80 million people with chronic hepatitis C infections worldwide.

The new medicines have a cure rate of over 95%, fewer side effects than previously available therapies, and can completely cure the disease within three months. But at an initial estimated price of some US$85 000 they were unaffordable even in high-income countries.
Countries show hepatitis C treatment is achievable

Thanks to a series of access strategies supported by the World Health Organization (WHO) and other partners, a range of low- and middle-income countries, including Argentina, Brazil, Egypt, Georgia, Indonesia, Morocco, Nigeria, Pakistan, Philippines, Romania, Rwanda, Thailand and Ukraine – are beginning to succeed in getting drugs to people who need them. Strategies include competition from generic medicines through licensing agreements, local production and price negotiations.

"Maximizing access to lifesaving hepatitis C treatment is a priority for WHO," says Dr Gottfried Hirnschall, Director of WHO's Department of HIV and Global Hepatitis Programme. "It is encouraging to see countries starting to make important progress. However, access still remains beyond the reach for most people."

A new WHO report, Global Report on Access to Hepatitis C Treatment: Focus on Overcoming Barriers, released today shows how political will, civil society advocacy and pricing negotiations are helping address hepatitis C, a disease which kills almost 700 000 people annually and places a heavy burden on health systems’ capacities and resources.

"Licensing agreements and local production in some countries have gone a long way to make these treatments more affordable," says Dr Suzanne Hill, WHO Director for Essential Medicines and Health Products. For example, the price of a three-month treatment in Egypt dropped from US$900 in 2014 to less than US$200 in 2016.

"But there are still huge differences between what countries are paying. Some middle-income countries, which bear the largest burden of hepatitis C, are still paying very high prices. WHO is working on new pricing models for these, and other expensive medicines, in order to increase access to all essential medicines in all countries," says Dr Hill.

80% of people in need still face challenges

Among middle-income countries, the price for a three-month treatment of sofosbuvir and daclatasvir varies greatly. Costs range from US$9 400 in Brazil to US$79 900 in Romania.

High costs have led to treatment rationing in some countries, including in the European Union, where price agreements have not accounted for the full cost of treating the whole affected population.

"Today's report on access, prices, patents and registration of hepatitis C medicines will help create the much needed market transparency which should support country efforts to increase access to DAAs," said Dr Hirnschall. "We hope countries will update their hepatitis treatment guidelines, work to remove barriers to access, and make these medicines available promptly for everyone in need."

In May 2016, at the World Health Assembly, 194 countries adopted the first-ever Global Health Sector Strategy on Viral Hepatitis, agreeing to eliminate hepatitis as a public health threat by 2030. The strategy includes a target to treat 80% of people in need by this date.

WHO issued guidelines recommending the use of DAAs in 2014 and 2016 and included DAAs on its Essential Medicines List – which is compiled to address the priority healthcare needs of populations; to make needed essential medicines available at all times in adequate amounts, at a price the health system and community can afford.


Buyers’ Clubs: Generic versions of HCV drugs resulted in very high cure rates

Generic hepatitis C
Keith Alcorn
Published: 27 October 2016

Use of generic versions of direct-acting antivirals resulted in very high cure rates for people who obtained the products through three buyers’ clubs, indicating that the generics products are effective, according to three presentations at the International Congress on Drug Therapy in HIV Infection in Glasgow this week.

People who purchased the drugs were cured of hepatitis C at a cost of around $700-$900, Dr Andrew Hill of St Stephen’s AIDS Trust, London, reported in three poster presentations at the conference.

Continue reading ....

Wednesday, October 26, 2016

The Changing HCV Landscape: Update on Treatment

Gastroenterology & Endoscopy News

The Changing HCV Landscape: Update on Treatment
Review Article
OCTOBER 26, 2016
DAAs for HCV infection have all but replaced IFN as the foundation of treatment for HCV across all genotypes. Among the major advantages of these oral regimens, beyond their remarkable efficacy, has been their relatively clean safety profile. Adverse effects are common but generally mild, including headache, fatigue, and insomnia—and are trivial relative to the effects of earlier regimens, reflected by a low rate of discontinuation for adverse events. Clinicians must be aware of potential drug–drug interactions, and should prescribe these medications with a commitment toward mastering these and/or consulting the numerous published and online references, including package inserts, containing this information...

Continue to article....

Review - Laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy

Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C

Full Text Article
Download PDF

Citation Wilson EM, Rosenthal ES, Kattakuzhy S, Tang L, Kottilil S. 2017. Clinical laboratory testing in the era of directly acting antiviral therapies for hepatitis C. Clin Microbiol Rev 30:23–42. https://doi.org/10.1128/CMR.00037-16.

SUMMARY
Directly acting antiviral (DAA) combination therapies for chronic hepatitis C virus (HCV) infection are highly effective, but treatment decisions remain complex. Laboratory testing is important to evaluate a range of viral, host, and pharmacological factors when considering HCV treatment, and patients must be monitored during and after therapy for safety and to assess the viral response. In this review, we discuss the laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy, grouped according to viral and host factors.


Continue Reading - Download PDF

Full Text Articles
I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C. A link to the above mentioned article (PDF) was tweeted by Mr. Chang this morning.

Tuesday, October 25, 2016

Liver Awareness Month: What pain medication can Liver Disease patients take? Is milk thistle good for my liver?

Liver Awareness Month, Nana and Zombies
October has been busy around here folks, fall is one of our favorite times of the year. Nana and the little people finally completed our little Halloween horror movie, a family tradition since 2013. I am hoping this isn't the last year, but it could be.

People are saying (mostly my daughter) that I went a bit too far this year. Note to self; during lunch never film a bloody zombie attack - especially at Taco Bell.

Who knew our blood curdling screams would offend so many people. I ask you; how scary can a four and eight year old be? After the manager explained the situation, I somewhat understood.

In any event we named our movie "Zombies Eat Tacos - Not People." The kids were excited "Manager Frank" made a special appearance in the movie, he also gave us a tour around the kitchen before showing us the door.

Liver Awareness Month
Moving on to something more important, as most of you know October is both Liver and Liver Cancer Awareness Month. Yep, I almost missed it. Not to worry, the wonderful website of the American Liver Foundation (ALF) just published their E-Newsletter "LIVERLOWDOWN" chock–full of great information about the causes, symptoms and risk factors associated with liver disease.
Begin here....

ALF Mayo Nutrition and Wellness Liver Chat
In addition, last month ALF along with experts from the Mayo Clinic and University of Florida Health hosted a Q&A on Twitter about liver wellness and nutrition. Below I condensed the chat highlighting the questions and answers, or view the Liver Chat on Twitter here. Enjoy.

Panelists Weigh in on Liver Nutrition
Is milk thistle good for my liver? How about the Paleo diet? Leading experts from the Mayo Clinic and University of Florida Health answered these questions and more at ALF’s September Nutrition Tweet Chat. Three transplant hepatologists and a dietician weighed in on wellness and nutrition.

Highlights
American Liver Foundation (ALF) - The first topic we will be covering is liver disease and diet

Q1. Why do people who have never consumed alcohol get Liver Disease?
A1. Many causes besides alcohol. Your doctor will check to see if you have a condition requiring specific treatment.

Q2. What kinds of processed or salty foods should patients with ascites/edema limit?
A2. Patients should read nutrition labels. Common culprits include frozen meals, deli meats, chips, fast food

Q3. Is it healthy to skip meals or try to drastically decrease calorie intake to lose weight?
A3. Patients with cirrhosis can often suffer from malnutrition. The key to losing weight: healthy diet and exercise.

Q4. For patients with issues such as nausea or lack of appetite, are smaller meals better than 3 meals/day?
A4. Smaller, frequent meals can be beneficial. Especially to those with slow gastric emptying and decreased appetite.

Q5. Next, what are some smart snacks to pack or have on hand, instead of reaching for candy or chocolate?
A5. High protein stacks are always favorable: nuts, seeds, yogurt, protein bars, or high protein shakes.

Q6. Patients often ask, you recommend the DASH diet to all patients?
A6. Despite limited data showing the benefits of DASH for Fatty Liver Disease, I recommend discussing with your dr.

Q7. What foods should I be eating if I have liver disease and low platelets? Or what if I'm anemic?
A7. Drink 1.5-2 L water per day, but avoid all fruit juice. Make sure you eat 3-4 servings vegetables, 2 servings fruit. Fruit juice contains significant amounts of fructose sugar- metabolized like fat. Also eat 4 servings whole grains/day, 3 servings low fat dairy. Try eating 1-2 servings ocean fish weekly, 2 egg yolk. Finally, avoid meats/sausages/butter/vegetable oil. And limit sodium (<2g daily), as well as processed and restaurant foods!

Q8. If I have fatty liver disease- are there good fats I should consume or should all be eliminated for your diet?
A8. Avoid fried foods, pizza, and sausage. Choose ocean fish, which are good sources of Omega-3 fatty acids.

Q9. The Paleo diet is popular- but is it a good choice for overall wellness?
A9. No, too much saturated fat and minimal whole grains. It's easy to develop Vitamin B deficiencies

Q10. If I have too much iron in blood- are there foods I should avoid or limit consumption of?
A10. Avoid red & processed meats, fatty foods, supplemental Vitamin C, sugary foods/beverages. DO eat nuts, grains, rice & beans.

Q11. Very popular question: Is coffee OK to consume? How many cups a day is OK?
A11. 2-3 6-8oz cups of coffee daily are fine.

Q12. If you have ascites/edema (water retention), what kinds of processed or salty foods should you limit consumption of?
A12. Avoid processed foods, salty foods, sausage, pizza, and baked goods like muffins. Minimize restaurant foods.

Q13. For patients w/issues such as nausea or lack of appetite- are smaller meals better than 3 square meals per day?
A13. 4-6 meals per day helps meet your calorie and protein needs. Remember to included a good source of protein w/ every meal.

Q14. Is the DASH diet one that you would recommend for all liver patients?
A14. DASH diet benefits most patients except for those on a low potassium diet.
Basic DASH Diet includes 7 day meal plan with 2000 calories, 100 gram protein, 1500 mg sodium-(link) As the responses from the experts keep coming in, we're moving onto our next topic- supplements, liver function, and medication

Q15. What is the best test to assess liver function?
A15. No single test. Blood tests + imaging assess functions and complications of Liver Disease. Liver biopsy can also provide valuable diagnostic info.

Q16. What pain medication can Liver Disease patients take?
A16. No more than 2gm acetaminophen (Tylenol and its related medications) in 24 hrs. Avoid NSAIDs if you have cirrhosis

Q17. Is it ok for patients with Liver Disease to take statin meds?
A17. Yes, statins may be taken to treat high cholesterol. Recent studies suggest statins may help patients with cirrhosis.

Q18. Is milk thistle okay to take?
A18. We usually refer people to speak with their nutritionists/providers/pharmacists to double check out supplements. Clinical evidence for milk thistle isn't established but may benefit some types of liver disease. Studies are inconclusive. However, available evidence suggests that milk thistle is likely harmless with minimal minor side effects.

Q19. Should you be consuming large amounts of protein? Are protein shakes ok? What are ways to consume protein w/o added sugar?
A19. A good guide is 25-30 g of protein per meal, unless you have chronic kidney disease. Focus on fish, chicken, dairy, and vegetable proteins. Protein shakes or bars may help if you can't eat enough.

Q20. Our last question before answering some from the chat: Are probiotics OK for someone to take if they have liver disease?
A20. Yes, but make it a food source like Greek yogurt or kefir. Speak to you doctor before taking any supplements.

Liver Chat participants
Q Is jogging safe for someone with stage 3 liver disease?
A There is no reason not to consider jogging with stage 3 fibrosis. Enjoy!

Q Should I expect my MELD score to drop after hepatitis c treatment?
A Generally yes, we do see improvements in MELD after treatment for HCV

Q At what bilirubin range should a patient get listed? Or is it MELD 15?
A Patients are evaluated for liver transplantation generally at meld15 or with symptoms of liver decompensated (confusion, ascites)

Q What causes liver to produce high HDL even though eat healthy all life?
A You're lucky if you have HDL cholesterol. Patients with low HDL and high LDL are at greater risk of heart disease.

Q Vitamin B12 shots post transplant?
A b12 shots should be provided if patients are deficient

Q Any advice on naturally reducing a FNH liver mass?
A There is no diet or natural therapy to reduce FNH.

Q Any specific suggestions for someone with Autoimmune Hepatitis?
A Would AIH require any specific requirements on diet or just good liver nutrition as highlighted in chat. Autoimmune hepatitis requires assessment with blood tests + liver biopsy. Rx with prednisone + azathioprine usually effective.

Q Are there specific risk factors for African American men and Liver disease?
A Actually fatty liver disease in African Americans, has a better prognosis.

More From ALF
October is big for the liver community. It's Liver Awareness Month- and it's also Liver Cancer Awareness Month, so we've teamed with Bayer to help raise awareness about the risk factors for this deadly disease. Learn more about liver cancer here.

Questions about liver disease? Need support or resource info? Call our helpline at 1-800-465-4837, 9am-7pm ET Mon-Fri.

Hope you all have a wonderful week and Halloween, until next time.
Bad Grandma - AKATina

Scotland - Liver cancer death rate rises by 52%

Liver cancer death rate rises by 52%
Death rates from liver cancer increased by 52% in the last 10 years, with the disease killing 572 Scots last year.

But new figures from the NHS showed that the cancer mortality rate for all forms of the disease fell by 11% over the decade to 2015.

The mortality rate for breast cancer - the most commonly diagnosed cancer for women - fell by 21%
Lung cancer death rates were down by 15.1% and there was a 16.4% decrease for bowel cancer.

A total of 16,011 deaths in 2015 were caused by cancer, with the report noting that "although the rate of deaths due to cancer has decreased over this period, the actual number of deaths due to cancer has not".

This is thought to be due to the increase in older age groups within the population and the fact that cancer is a relatively common disease among the elderly.

Cancer mortality rates have fallen by 14% among men over the last 10 years. The decrease in the mortality rate for females was lower at 6%.

Deaths from liver cancer were up from 320 in 2005, with the mortality rate increasing by 45.6% in males and by 68.6% for females.

"The increase in the mortality rate of liver cancer over the last 10 years by 52% reflects the increase in incidence of this type of cancer," the report said.

"Survival from liver cancer is poor in most cases. The main risk factors for liver cancer are alcohol and infection with hepatitis B and C."

Continue reading....

Monday, October 24, 2016

Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure

Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure
Jun Itakura , Masayuki Kurosaki , Chitomi Hasebe, Yukio Osaki, Kouji Joko, Hitoshi Yagisawa, Shinya Sakita, Hiroaki Okushin, Takashi Satou, Hiroyuki Hisai, Takehiko Abe, Keiji Tsuji, Takashi Tamada, Haruhiko Kobashi, Akeri Mitsuda, Yasushi Ide, Chikara Ogawa, Syotaro Tsuruta, Kouichi Takaguchi, Miyako Murakawa, Yasuhiro Asahina, Nobuyuki Enomoto, Namiki Izumi

Full Text Article -View Online Or Download PDF

Abstract
Backgrounds & Aims
We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection.

Methods
This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing.

Results
The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients.

Conclusion
Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors

Continue to full text article...



Scientists uncover why Hepatitis C virus vaccine has been difficult to make

Scientists uncover why Hepatitis C virus vaccine has been difficult to make

LA JOLLA, CA -- Oct. 24, 2016 -- Researchers have been trying for decades to develop a vaccine against the globally endemic hepatitis C virus (HCV). Now scientists at The Scripps Research Institute (TSRI) have discovered one reason why success has so far been elusive.

Using a sophisticated array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body's antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection.

"Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go," said co-senior author TSRI Associate Professor Mansun Law.

"We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses," said co-senior author Ian A. Wilson, TSRI's Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.

The report, published online ahead of print by the Proceedings of the National Academy of Sciences the week of October 24, 2016, is likely to lead to new and better HCV vaccine designs.

A Great Need

A working vaccine against this liver-infecting virus is needed desperately. HCV infection continues to be a global pandemic, affecting an estimated 130 to 150 million people worldwide and causing about 700,000 deaths annually from liver diseases including cancer. Although powerful antiviral drugs have been developed recently against HCV, their extremely high costs are far beyond the reach of the vast majority of people living with HCV infection. Moreover, antiviral treatment usually comes too late to prevent liver damage; HCV infection is notorious for its ability to smolder silently within, producing no obvious symptoms until decades have passed.

The Law and Wilson laboratories have been working together in recent years to study HCV's structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells.

Because this receptor-binding site on E2 is crucial to HCV's ability to infect its hosts, it has an amino-acid sequence that is relatively invariant from strain to strain. The receptor-binding site is also relatively accessible to antibodies, and indeed many of the antibodies that have been found to neutralize a broad set of HCV strains do so by targeting this site.

For all these reasons, HCV's receptor-binding site has been considered an excellent target for a vaccine. But although candidate HCV vaccines mimicking the E2 protein have elicited high levels of antibodies against the receptor-binding site, these antibody responses--in both animal models and human clinical trials--have not been very effective at preventing HCV infection of liver cells in laboratory assays.

Enormous Flexibility

To understand why, the Law and Wilson laboratories teamed up with TSRI Associate Professor Andrew Ward and used electron microscopy and several other advanced structural analysis tools to take a closer look at HCV's E2 protein, in particular the dynamics of its receptor binding site. Their investigations focused on the "recombinant" form of the E2 protein, produced in the lab and therefore isolated from the rest of the virus. Recombinant E2 is a prime candidate for HCV vaccine design and is much easier to purify and study than E2 from whole virus particles.

One finding was that recombinant E2, probably due to its many strong disulfide bonds, has great structural stability, with an unusually high melting point of 85°C. However, the TSRI scientists also found evidence that, within this highly buttressed construction, the receptor binding site portion is extraordinarily loose and flexible in the recombinant protein.

"It adopts a very wide range of conformations," said study first author Leopold Kong, of TSRI at the time of the study, now at the National Institutes of Health.

Prior studies have shown that HCV's receptor binding site adopts a narrow range of conformations (shapes) when bound by virus-neutralizing antibodies. A vaccine that elicited high levels of antibodies against only these key conformations would in principle provide effective protection. But this study suggests that the E2 protein used in candidate vaccines displays far too many other binding-site conformations--and thus elicits antibodies that mostly do nothing to stop the actual virus.

Law and Wilson and their colleagues plan to follow up by studying E2 and its receptor binding site as they are presented on the surface of the actual virus. They also plan to design a new version of E2 or even an entirely different scaffold protein, on which the receptor binding site is stabilized in conformations that will elicit virus-neutralizing antibodies.

###

In addition to Law, Wilson, Ward and Kong, authors of the study, "Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen," included Rameshwar U. Kadam, Erick Giang, Travis Nieusma, Fernando Garces and Netanel Tzarum, all of TSRI; and David E. Lee, Tong Liu, Virgil Woods and Sheng Li, of the University of California, San Diego.

Support for the study was provided by the National Institutes of Health (AI079031, AI123861, AI106005, AI123365, GM094586, AI117905, GM020501 and AI101436) and TSRI's Skaggs Institute for Chemical Biology.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists -- including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www.scripps.edu.

Credit: Illustration by Christina Corbaci and Leopold Kong

Short-duration Treatment With Elbasvir/Grazoprevir and Sofosbuvir - HCV GT1 or GT3 with or without cirrhosis

Short-duration Treatment With Elbasvir/Grazoprevir and Sofosbuvir for Hepatitis C: A Randomized Trial
Eric Lawitz,1 Fred Poordad,1 Julio A. Gutierrez,1 Jennifer T. Wells,1 Carmen E. Landaverde,1Barbara Evans,2 Anita Howe,2* Hsueh-Cheng Huang,2 Jerry Jing Li,2 Peggy Hwang,2 Frank J.Dutko,2 Michael Robertson,2 Janice Wahl,2 Eliav Barr,2 and Barbara Haber2

This clinical study is the first to examine the treatment of patients infected with HCV GT1 or GT3 with or without cirrhosis with short durations of a novel regimen of EBR/GZR + SOF. Our data confirm that cirrhotic and noncirrhotic patients with HCV GT1 infection can be cured with 6–8 weeks of treatment, and that an 8–12 week regimen of EBR/GZR + SOF is safe and effective in cirrhotic and noncirrhotic patients with HCV GT3 infection, commonly regarded as one of the
most challenging patient populations to treat..
View Article - Download PDF

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.28877

PHYSICAL FINDINGS SUGGESTIVE OF CIRRHOSIS

ASCITES
An accumulation of excess fluid in the abdomen. Causes abdominal distention. Can be treated with a low sodium diet, and the use of diuretics, i.e. water pills.

"Ascites" is fluid that accumulates in the abdominal (peritoneal) cavity. It is a complication of cirrhosis and appears as an abdominal bulge. The peritoneum is the inner lining of the abdominal cavity, which also folds over to cover the organs inside the abdomen such as the liver, gallbladder, spleen, pancreas, and intestines.
Ascites develops because of a combination of two factors:
(1) increased pressure in the vein system that carries blood from the stomach, intestines, and spleen to the liver (portal hypertension)
(2) a low level of albumin in the blood (hypoalbuminemia). Albumin, which is the predominant protein in the blood and which helps maintain blood volume, is reduced in cirrhosis primarily because the damaged liver is not able to produce enough albumin.

2017
Evaluation of Ascites
Analysis of Ascitic Fluid
Basic Management of Ascites
Management of Refractory Ascites

ASTERIXIS
An uncontrollable flapping of the hands that becomes noticeable when patients stretch out their arms, palms out, as if stopping traffic. Is associated with mental confusion, i.e. encephalopathy.
.
.
Testing For Asterixis
Extend the arms, spread the fingers, dorsiflex the wrist and observe for the abnormal “flapping” tremor at the wrist. If not immediately apparent, this tremor may be accentuated by asking the patient to keep the arms straight while the examiner gently hyperextends the patient’s wrist with a sweeping motion
An alternate method of testing for asterixis involves having the patient relax his legs while he lies supine with his knees bent. The feet should be kept flat on the table and as the legs fall to the sides, watch for flapping of the legs at the hip joint. This repetitively brings the knees back together
.
"Bilateral Asterixis": Metabolic encephalopathies, especially hepatic and renal, are the most common causes of bilateral asterixis. Those caused specifically by hepatic failure are known as “liver (or hepatic) flap”.
Other causes of asterixis include cardiac and respiratory disease, electrolyte abnormalities and drug intoxication. Electrolyte abnormalities known to cause asterixis include hypoglycaemia, hypokalaemia and hypomagnesaemia. Drug intoxications include barbiturate intoxication, alcoholism, phenytoin intoxication (“phenytoin flap”) and primidone intoxication. Wilson’s disease and focal brain lesions in the rostral midbrain tegmentum may also cause asterixis.
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CAPUT MEDUSAE
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Enlarged blood vessels that snake out from the belly button in a patient with ascites. The term Caput Medusae describes the appearance of distended and engorged umbilical veins which are seen radiating from the umbilicus across the abdomen to join systemic veins. It is a sign of severe portal hypertension with portal-systemic shunting through the umbilical veins. The name originates from the apparent similarity to Medusa's hair once Minerva had turned it into snakes.
.
Caput Medusae is distinguished from inferior vena cava obstruction by determining the direction of flow in the veins below the umbilicus; it is towards the legs in the former, and towards the head in the latter (as abdominal collaterals develop to bypass the blocked inferior vena cava and permit venous return from the legs).
.
EDEMA
.
Edema occurs when tiny blood vessels in your body (capillaries) leak fluid. This leakage can result from damage to or increased pressure in the capillaries, or from lowered levels of serum albumin, a protein in your blood. When your body senses the capillaries are leaking, your kidneys begin to retain more sodium and water than normal to compensate for the lost fluid from your blood vessels. This increases the amount of fluid circulating through your body, which causes the capillaries to leak more. The fluid from the capillaries leaks into the surrounding tissue, causing the tissue to swell.
. ,
Edema is caused by either systemic diseases, that is, diseases that affect the various organ systems of the body, or by local conditions involving just the affected extremities. The most common systemic diseases associated with edema involve the heart, liver, and kidneys. In these diseases, edema occurs primarily because of the body's retention of too much salt (sodium chloride). The excess salt causes the body to retain water. This water then leaks into the interstitial tissue spaces, where it appears as edema.
.
Pitting edema can be demonstrated by applying pressure to the swollen area by depressing the skin with a finger. If the pressing causes an indentation that persists for some time after the release of the pressure, the edema is referred to as pitting edema. Any form of pressure, such as from the elastic in socks, can induce pitting with this type of edema.
.
Peripheral edema, which is usually seen as pitting edema of the legs and feet, also occurs in cirrhosis. The edema is a consequence of the hypoalbuminemia and activation of the renin-angiotensin- aldosterone hormonal system, which prompt the kidneys to retain salt and water. The presence or absence of edema in patients with cirrhosis and ascites is an important consideration in the treatment of the ascites.
.
In patients with ascites without edema, diuretics must be given with extra caution. The reason for this is that a diuresis (induced increased volume of urine) that is too depleting or rapid in these patients can lead to a low blood volume (hypovolemia), which can possibly be followed by kidney and liver failure.
In contrast, when patients who have both edema and ascites undergo diuresis, the edema fluid in the interstitial space serves as somewhat of a buffer against the development of low blood volume. The excess interstitial fluid moves into the blood vessel saces to rapidly replenish the depleted blood volume

.
ENCEPHALOPATHY
An altered mental status leading to coma. Can be treated with animal protein restriction and a poorly absorbed sugar called Lactulose.
.
Hepatic encephalopathy is caused by disorders that affect the liver. These include disorders that reduce liver function (such as cirrhosis or hepatitis) and conditions in which blood circulation does not enter the liver. The exact cause of hepatic encephalopathy is unknown. An important job of the liver is to change toxic substances that are either made by the body or taken into the body (such as medicines) and make them harmless. However, when the liver is damaged, these "poisons" may build up in the bloodstream.

Ammonia, which is produced by the body when proteins are digested, is one of the harmful substances that is normally made harmless by the liver. Many other substances may also build up in the body if the liver is not working well. They can cause damage to the nervous system.
Patients with very mild hepatic encephalopathy may have normal memory, language and motor skills, but may have impairment of attention and decision-making, and may have impaired fitness to drive.
These patients usually have normal function on standard mental state testing but abnormal psychometric testing.

Patients with mild and moderate hepatic encephalopathy show decreased short-term memory and concentration with testing of mental state. They may also have a flapping tremor, fetor hepaticus (a sweet musty aroma of the breath), hyperventilation and hypothermia.

First Principles of Gastroenterology GI Textbook Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a complex, potentially reversible neuropsychiatric condition that occurs as a consequence of acute or chronic liver disease. It is characterized by changes of personality, consciousness, behavior and neuromuscular function

Early features include reversal of sleep pattern, apathy, hypersomnia, irritability and personal neglect. In later stages, delirium and coma may occur. Neurologic signs may include hyperreflexia, rigidity, myoclonus and asterixis. Asterixis is not specific to hepatic encephalopathy and may be present in other causes of metabolic encephalopathy. Seizures and lateralizing signs are uncommon and are
more commonly seen in acute than chronic liver failure.
Grading of hepatic encephalopathy
Grade 0: subclinical; normal mental status, but minimal changes in memory, concentration, intellectual function, coordination.
Grade 1: mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern such as inverted sleep cycle.
Grade 2: drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation.
Grade 3: somnolent but rousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech is present but incomprehensible.
Grade 4: coma, with or without response to painful stimuli

2017
Clinical Features
Diagnostic Tests
General Approach to the Management of HE
Medical Therapy for Hepatic Encephalopathy

2017
Minimal Hepatic Encephalopathy in Cirrhosis- How Long to Treat?
Omesh Goyal, Sandeep S. Sidhu, Harsh Kishore
Minimal hepatic encephalopathy (MHE) can reverse after short-term treatment. However, relapse rate of MHE after stopping treatment has not been studied so far. We aimed to evaluate long-term (9 months) efficacy of a short-term (3 months) treatment of MHE with lactulose/rifaximin, for maintenance of remission from MHE. Material and methods.
Download Full Text Article

FETOR HEPATICUS
A particularly foul "dead mouse" smell found on the breath. Frequently precedes coma. A distinctive musty, sweet breath odor characterizes hepatic encephalopathy, a life-threatening complication of severe liver disease. The odor results from the damaged liver’s inability to metabolize and detoxify mercaptans produced by bacterial degradation of methionine, a sulfurous amino acid. These substances circulate in the blood, are expelled by the lungs, and flavor the breath. 

GYNECOMASTIA
Gynecomastia due to the increased estrogen levels, which is due to the inability of the diseased liver to detoxify estrogen but may also be due to Aldactone, a drug used to control ascites
;.
Enlarged, tender breasts in men.

HAIR LOSS
Hair becomes sparse in men from the face, chest and pubis, and under the arms in women.

JAUNDICE
A yellow discoloration of the skin due to an elevated bilirubin level.
The normal level of bilirubin in the blood is 1 mg/dL. If the concentration increases to 2 mg/dL, yellowing of the skin, sclera, and mucous membranes will become evident. Yellowing due to increased levels of bilirubin in the blood (hyperbilirubinemia), which then deposits in the tissues of the body, is called jaundice or icterus. Depending on the site of the problem, hyperbilirubinemia is usually dominated by either the unconjugated or conjugated type.

Jaundice can be classified according to the mechanism that produced it:
1. Hemolytic (prehepatic) jaundice
occurs when the liver cells are normal, but so much bilirubin is present that the capacity of the liver to take it up and/or conjugate it is exceeded. A typical cause is excessive breakdown of red blood cells (i.e., hemolytic anemia). In prehepatic jaundice, the type of bilirubin seen in the blood is largely unconjugated.
2. Hepatocellular jaundice
usually occurs when production of bilirubin is normal, but damage to the liver cells interferes with uptake, conjugation, or excretion of bilirubin. Depending on which factors predominate, bilirubin may be conjugated or unconjugated.
3. Posthepatic (obstructive)
is due to obstruction in the biliary drainage system, rather than to any problem with the hepatocytes themselves. Strictures or stones in the extrahepatic biliary tract, as well as tumors, may produce this type of jaundice. This "backed-up" bilirubin, which is conjugated, can get into the blood. .

SCLERAL ICTERUS
Yellow discoloration of the whites of the eyes [sclera], due to an elevated bilirubin level. 

 Low Blood Pressure
Many patients with cirrhosis or scarring of the liver develop abnormalities in their cardiovascular system as a result of their liver disease. All diseases that result in cirrhosis can lead to these cardiovascular changes but they occur more frequently in patients with more advanced disease.

It is believed that substances circulating in the blood that are normally cleared by a healthy liver can cause a generalized dilatation of the blood vessels throughout the body (except in the kidney where they are intensely constricted).

The generalized vasodilatation then results in a low blood pressure. Most patients with this form of low blood pressure are asymptomatic because of its very gradual onset and because of a compensatory increased blood flow from the heart. There is no specific treatment for the development of low blood pressure in patients with cirrhosis other than general, supportive care. The blood pressure will normalize after removal of the diseased liver and transplantation of a healthy liver. .
Source .

MUSCLE WASTING
Loss of muscle mass, seen in end-stage cirrhosis when the liver can no longer manufacture proteins.

2016
Does the liver accelerate ageing: Talking muscles and liver?
2013
Articles in Press - Muscle Cramps in Liver Disease

PALMAR ERYTHEMA
Bright red coloring of the palms, particularly at the base of the thumb and little finger. May be due to excess estrogen or liver disease.

Palmar erythema is reddening of the palms at the thenar and hypothenar eminences. It is associated with various physiological as well as pathological changes, the principal one of which is portal hypertension. It is also seen in patients with liver dysfunction

PAPER MONEY SKIN
Numerous small blood vessels that resemble the silk threads in a U.S. dollar bill. Commonly cover the upper body, often in association with spider naevi.

PAROTID GLAND ENLARGEMENT
 
Enlargement of a gland on the face located under the ear. Causes an unusual appearance of the protrusion of the earlobes straight out from the jaw.
 
SPIDER ANGIOMATA
Enlarged blood vessels that resemble little spiders. Usually found on the upper chest,back, face, and arms. Turn white when their center is touched [blanches].
Spider angioma is so named because of its appearance: a central, red, elevated area with surrounding broken blood vessels radiating outward like a spider's legs. Many children and adults have a spider angioma.

Causes Spider angiomas are associated with childhood, pregnancy, liver disease, birth control pills, estrogen treatment, and they develop for unknown reasons as well.

Signs & Symptoms
Spider angiomas classically appear as small, centrally raised bumps (papules)caused by a dilated arteriole (small artery). A network of dilated capillaries (tiny blood vessels) radiate from the arteriole. Pressing on the lesion causes the redness to disappear briefly, and there is a rapid return of redness once the pressure is lifted.

SPONTANEOUS BACTERIAL PERITONITIS
Fever, and abdominal pain in a patient with ascites.
Spontaneous bacterial peritonitis (inflammation and infection of the membrane that is lining the abdominal cavity) is a complication of cirrhotic ascites that occurs in the absence of any intra-abdominal, surgically treatable source of infection.

TERRY'S NAILS ..

..
The normal pinkish color of the nails turns completely white, with the disappearance of the half-moon circles at the base of the nails. Clinical findings of liver diseases White nails. White nails are commonly seen in patients with cirrhosis and rarely in other diseases. They are due to opacity of the nail bed. Nails appear white and a pink zone is seen only at the tip of the nail. The lunula may be not distinguished.

Thrombocytopenia
Definition
Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets.

Description
The normal amount of platelets is usually between 150,000 and 450,000 cells per microliter of blood. A microliter is an amount equal to one one-millionth of a liter (a liter is almost equal to a quart). Platelet numbers are counted by having a blood sample collected and placing a measured amount of blood in a machine called a cell counter. When the platelet number drops below 150,000 cells per microliter of blood, this person is said to be thrombocytopenic.

Causes & symptoms
Abnormal reductions in the number of platelets are caused when abnormalities occur in any of the following three processes: decreased platelet production by the bone marrow; increased trapping of platelets by the spleen; or a more rapid than normal destruction of platelets. Persons with this condition easily bruise and can have episodes of excess bleeding (a hemorrhage).

Platelets come from megakaryocytes, which are produced in the material located within the center cavity of the bones (bone marrow). When abnormalities develop in the marrow, the marrow cells can lose their ability to produce platelets in correct amounts. The result is a lower than normal level of platelets in the blood. Drugs used in cancer chemotherapy can cause the marrow to malfunction in this way, as can the presence of tumor cells in the marrow itself. Normally, the spleen holds about one-third of the body's platelets as part of this organ's function to recycle aging or damaged red blood cells (the cells that carry oxygen in the blood). When liver disease or cancer of the spleen is present, the spleen can enlarge, resulting in a greater number of platelets staying in the organ. This condition results in abnormally low numbers of platelets in the blood.

Platelets can breakdown in unusually high amounts in persons with abnormalities in their blood vessel walls, with blood clots, or with man-made replacement heart valves. Devices placed inside blood vessels to keep them from closing (stents) due to weakened walls or fat build-up can also cause platelets to breakdown. In addition, infections and other changes in the immune system can speed up the removal of platelets from the circulation.

Diagnosis
Thrombocytopenia is diagnosed by having a blood sample taken and counting the platelets present in the sample. However, accurately determining the medical reason for this conditions is complex.
Once a low platelet count is verified, a careful evaluation of the function of the bone marrow and spleen are necessary. Improper functioning of either or both of these organs can cause thrombocytopenia. In addition, the causes for the abnormal spleen or marrow function must be investigated since different cancers, blood disorders, or liver disease can be the true cause for the drop in platelets found in the blood.

Treatment
If low platelet counts are caused by an enlarged spleen, removal of the spleen can help raise the platelet level, since the spleen is no longer there to capture the platelets. However, proper treatment for what causes the enlarged spleen is necessary as well. Low platelet counts can indicate more serious conditions. If a dysfunctional immune system is found to be the cause for this condition, drugs like steroids or gamma globulin can be used to help maintain platelet levels in certain cases. If low platelet levels are due to an abnormally low level of platelet production, transfusions of platelets can be given as well.

Prognosis
Thrombocytopenia can result in fatal bleeding, but it also can indicate various other, more serious, cancers and disorders that affect the blood cells. This condition requires thorough medical evaluation.

Prevention
There is no known way to prevent thrombocytopenia. ,
Key Terms to know: Gamma globulin: One of a group of proteins found in the blood that is involved in helping the body fight infections. Stent: A man-made surgical device, usually tube-shaped, that is placed into a blood vessel to keep it from closing. Transfusion: The transfer of blood from one person to another. Transfusions can be direct, in which blood is transferred from the donor to the recipient; or indirect, in which the blood is taken from the donor, stored in a container, and then given to the recipient.

UMBILICAL HERNIA

Patients with massive ascites may experience abdominal discomfort, depressed appetite, and decreased oral intake. Diaphragmatic elevation may lead to symptoms of dyspnea. Pleural effusions may result from the passage of ascitic fluid across channels in the diaphragm. Umbilical and inguinal hernias are common in patients with moderate and massive ascites. The use of an elastic abdominal binder may protect the skin overlying a protruding umbilical hernia from maceration and may help prevent rupture and subsequent infection. Timely large-volume paracentesis also may help to prevent this disastrous complication.

Umbilical hernias should not undergo elective repair unless patients are significantly symptomatic or their hernias are irreducible. As with all other surgeries in patients with cirrhosis, herniorrhaphy carries multiple potential risks such as intraoperative bleeding, postoperative infection, and liver failure because of anesthesia-induced reductions in hepatic blood flow. However, these risks become acceptable in patients with severe symptoms from their hernia. Urgent surgery is necessary in the patient whose hernia has been complicated by bowel incarceration.

Esophageal Varices
Esophageal varices are swollen veins in the lining of the lower esophagus near the stomach. Gastric varices are swollen veins in the lining of the stomach. The swelling of these veins is caused by liver disease. Swollen veins in the esophagus or stomach resemble the varicose veins that some people have in their legs. Because the veins in the esophagus are so close to the surface of the esophagus, swollen veins in this location can rupture and cause dangerous bleeding.

Esophageal varices almost always occur in people who have cirrhosis of the liver. Cirrhosis causes scarring of the liver, which slows the flow of blood through the liver. Scarring causes blood to back up in the portal vein, the main vein that delivers blood from the stomach and intestines to the liver. This "back up" causes high blood pressure in the portal vein and other nearby veins, and this is called portal hypertension. The backup of blood forces veins to enlarge in the vicinity of the stomach and esophagus. Esophageal varices usually have enlarged, irregularly shaped bulbous regions (varicosities) that are interrupted by narrower regions. Because the blood pressure inside the varices is higher than inside normal blood vessels, and the walls of the vessels (and esophagus) are thin, the veins rupture easily and can bleed profusely.

Symptoms
Portal hypertension often does not cause any symptoms, and sometimes is discovered only when the varices bleed. When significant bleeding occurs, a person will vomit blood, often in large amounts. People with massive bleeding feel dizzy and may lose consciousness. Some people bleed in smaller amounts over a longer period, and they swallow the blood rather than vomit. Their stools may contain red or tarry-black blood. People with bleeding from the esophagus usually also have symptoms of cirrhosis of the liver.

Diagnosis
To diagnose esophageal varices, a doctor will use an instrument called an endoscope, a thin, flexible tube with a camera at its tip that is inserted through the mouth so the doctor can see the walls of the esophagus and search for the source of bleeding. If bleeding is occurring in the esophagus, this procedure will be done as an emergency. Tiny instruments may be attached to the endoscope to provide treatment at the same time.

Expected
Duration Bleeding from esophageal varices can stop on its own or with treatment. However, bleeding esophageal varices can be fatal, particularly in people with severe liver disease. Half or more of people who survive episodes of bleeding from esophageal varices will have the problem return during the first one to two years. The risk of recurrence can be reduced with treatment.

2014
Variceal bleeding accounts for 70% of all cases of upper gastrointestinal bleeding in patients with cirrhosis.  Esophageal variceal bleeding spontaneously resolves in 40 to 50% of cases, but there is a 30 to 40% chance of early rebleeding in the first 6 weeks.

2017
Treatment of HCV in Patients with Compensated Cirrhosis
Treatment of HCV in Patients Awaiting Liver Transplantation
Treatment of HCV in Patients with Decompensated Cirrhosis

2016
This guide to the practical treatment of patients with cirrhosis summarizes recent developments. It includes advice on medical management, invasive procedures, nutrition, prevention, and strategies to protect the cirrhotic liver from harm.