July 17, 2010

Can Human Liver Stem Cells repair or replace liver function deficiency associated with cancer, hepatitis, or genetic diseases?

Over 26,000 people die each year in the United States from chronic liver disease. One in ten Americans suffers from liver disease, and for many of them there are no effective treatments. The goal of our Liver Stem Cell Program is to repair damaged or diseased livers.

What have we accomplished so far?

Our work on liver stem and progenitor cells began in collaboration with Markus Grompe, Ph.D., of Oregon Health Science University. Dr. Grompe's work focuses on the discovery and development of methods for identifying and assessing the therapeutic potential of liver stem and progenitor cells. We obtained rights to a mouse model of liver failure developed by Dr.Grompe, the “FAH knockout mouse,” which lacks a key enzyme, FAH, or fumaryl-acetoacetate hydrolase. This mouse was developed to mimic a fatal human genetically-based liver disease called tyrosinemia type I. Toxic substances build up in these mice and cause liver damage. This model has allowed us to test methods for using cell transplantation to regenerate diseased livers.

We believe that a key accomplishment of the Liver Program was to develop proprietary monoclonal antibodies that enrich for distinct subsets of human liver cells. Using these antibodies we have identified a human liver stem-like cell which we call a human liver engrafting cell (hLEC). These cells produce human serum albumin in mouse serum following transplantation into immunodeficient mice, demonstrating that the hLEC, once transplanted, is a functional cell. We have filed a patent application on the hLEC and its uses in cell therapy for liver disease.

The program will focus on demonstrating the robust engraftment and function of these hLECs in animal models of liver degeneration (such as the FAH knockout mouse) as the next step in determining whether transplanted hLECs can be used to treat liver disease.

StemCells has also devised a culture assay that it uses to identify liver stem and progenitor cells. The culture supports the proliferation of hLECs and StemCells has shown that hLECs give rise to early bipotent progenitor cells that can produce two different types of liver cells, bile duct cells and hepatocytes.

It is also possible to infect this culture with human hepatitis virus to study the virus's effects on liver cells. The culture system could be used to test drugs that act on, or are metabolized by, human liver cells.

It is our belief that a source of well-defined human cells capable of engraftment and substantial liver regeneration will provide a cell-based therapeutic product available to many more patients than liver transplants. An in vitro culture system that can reproducibly grow human liver progenitor cells may also provide cells that can be modified genetically to correct inborn errors of metabolism.

What does the future hold?

StemCells' scientists have identified other monoclonal antibodies that divide the hLEC population into additional subsets of cells which can be tested for liver stem cell activity. We have also been developing additional models for examining the engraftment of the hLECs. Furthermore, in collaboration with scientists at Stanford University, we will test whether engrafted human liver cells can be infected by human hepatitis C virus. Engrafted humanized livers may provide a test system for the development of therapies or vaccines for hepatitis C infection.

Summary of Progress

We have identified a candidate human liver stem cell-like population referred to as a human liver engrafting cell (hLEC).

We have developed an in vitro culture assay for growing the hLECs and have demonstrated that hLECS give rise to progenitor cells that express markers for both bile duct cells and hepatocytes.

We have shown that the in vitro culture of hLECs also can permit infection of a human hepatitis virus, thereby having the potential to be an assay system to screen novel anti-viral compounds.

We have demonstrated the engraftment and survival (>6 months) of the candidate human LEC in an in vivo mouse model.

We have detected human albumin in mouse serum in animals transplanted with hLECs for 6 months.

We have established a culture system for expansion of sorted hLECs.


Medical marijuana users in New Mexico Jonesing for bigger supply

July 17, 6:37 PM Albuquerque Science Examiner Aaron Cowan

Supplies of “medical marijuana” are reported running low for the approximately 2000 patients who are currently approved to receive it as a treatment, according to at least one supplier in Albuquerque, New Mexico, as of July 17, 2010. In addition, it is estimated that about 200 new patients are approved to receive the drug every month. Patients can also apply for permits to grow it themselves, but apparently, the majority of patients rely upon suppliers instead. Fortunately, six new suppliers have been licensed in the state, but suppliers are limited in the number of plants they can have, and one supplier says that he has five times the patients that he is able to supply.

New Mexico has some fairly limited guidelines for medical marijuana use, first enacted in 2007, for use under a physicians direction. A patient must have cancer, glaucoma, multiple sclerosis, epilepsy, spinal cord damage, HIV/AIDS, or be in hospice to qualify. Conditions still pending approval by the Department of Health are Hepatitis C, post-traumatic stress disorder, and nerve pain. Suppliers can grow up to 95 plants at one time.

In terms of the scientific research, that’s where things get tricky. According to this article in Scientific American, the current federal restrictions which are still in place on marijuana research are hampering efforts to study it. However, there are some fairly serious organizations such as the MAPS organization, which has been working for over a decade to study the effectiveness of marijuana as a medicinal compound. Conditions like cancer, glaucoma, and HIV/AIDS do seem responsive to this type of treatment, acting as an anti-emetic, in the case of AIDS or chemotherapy treatments, for example, according to some in the medical community. Of course, there is far from universal agreement that the science supports the use of medical marijuana, so readers may wish to check out the pros and cons for oneself at this link.


Relapse of hepatitis C in a pegylated-interferon-α-2b plus ribavirin-treated sustained virological responder

This is the first documented case of late relapse I have seen.

Hepatology Research
Volume 40 Issue 6, Pages 654 - 660
Published Online: 25 May 2010
© 2010 The Japan Society of Hepatology

Case Report

Hideki Fujii, 1 Yoshito Itoh, 2 Naoki Ohnishi, 1 Masafumi Sakamoto, 1 Tohru Ohkawara, 1 Yoshihiko Sawa, 1 Koichi Nishida, 1 Takeshi Nishimura, 2 Kanji Yamaguchi, 2 Kohichiroh Yasui, 2 Masahito Minami, 2 Takeshi Okanoue, 3 Yasuo Ohkawara 1 and Toshikazu Yoshikawa 2

1 Department of Internal Medicine, Aiseikai Yamashina Hospital, 2 Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, and 3 Division of Gastroenterology, Saiseikai Suita Hospital, Osaka, Japan

Correspondence to Dr Yoshito Itoh, Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto 602-8566, Japan. Email: yitoh@koto.kpu-m.ac.jp


chronic hepatitis C • genotype 2a • sustained virological response • relapse • phylogenetic analyses


A 41-year-old woman with chronic hepatitis C was treated with pegylated-interferon (PEG-IFN)-α-2b plus ribavirin for 24 weeks. She had hepatitis C virus (HCV) genotype 2a (1600 KIU/mL), and her liver histology showed mild inflammation and fibrosis. Four weeks after the start of the therapy, she achieved a rapid virological response (RVR) and then a sustained virological response (SVR). Serum alanine aminotransferase (ALT) levels remained within normal ranges and HCV RNA continued to be negative. However, ALT levels flared with the re-emergence of HCV RNA in the serum 1.5 years after discontinuation of therapy. HCV RNA obtained from sera before therapy and after relapse shared a 98.6% homology with the E2 region, and phylogenetic analyses indicated that they were the same HCV strain. These results eliminated the possibility of a re-infection and strongly indicated a late relapse of the disease. Therefore, follow-up is necessary for chronic hepatitis C patients after SVR, even if they respond well to therapy, including RVR.

Received 15 September 2009; revision 23 November 2009; accepted 6 December 2009.

10.1111/j.1872-034X.2010.00641.x About DOI

The yellow symptom

Sunday July 18, 2010


Jaundice is not a disease, but it’s a warning sign not to be dismissed.

JAUNDICE in newborns is usually harmless and lasts only for a short time, but when you see an adult with yellow skin, it implies a serious health problem that requires urgent medical attention.

A sign, not a disease

Jaundice is a sign of many diseases. There is a yellow discolouration of the skin and sclera (the whites of the eyes) due to excess bilirubin circulating in the body. This is normally accompanied by very dark urine, pale stools (if patients have bile duct obstruction), and other symptoms, such as itchy skin and occasional nausea and loss of appetite.

Why is there excess bilirubin? Bilirubin is actually a natural “waste product” arising from the normal breakdown of old red blood cells (RBC) in your body. Under normal circumstances, bilirubin undergoes certain processes in the liver before it is excreted. Bilirubin metabolites are formed in the gut and passed out in the urine and faeces. Bilirubin is also the pigment that gives your urine and faeces colour.

Many reasons can contribute to excess bilirubin in the blood. It is mostly due to problems in the liver or obstruction in the bile ducts, both of which can lead to jaundice. In rare cases, excessive bilirubin is due to haemolytic anaemia, a disorder where an abnormally large number of red blood cells are broken down.

Common causes and symptoms of jaundice

In general, jaundice can be categorised into two types: obstructive jaundice and hepatocellular jaundice.

Obstructive jaundice

Obstructive jaundice, or cholestatic jaundice, is caused by blockage in the bile ducts due to gallstones, pancreatic cancer, or bile duct cancer (cholangiocarcinoma).

Individuals with obstructive jaundice typically have dark-coloured urine and pale stools because of the reduced flow of bile and bilirubin into the intestines. Pain and fever can be felt if gallstones are present. Because the pain is located at the upper part of the abdomen, patients often misconstrue it as gastric pain.

However, patients with obstructive jaundice due to gallstones usually have upper abdominal pain which radiates to the back. On the other hand, bile duct cancer is usually painless, but can cause weight loss over time.

Obstructive jaundice caused by pancreatic cancer usually presents with pain and weight loss. It is important to pick up pancreatic cancer early and physicians should think about pancreatic cancer, especially when patients present with “gastric pain”.

Hepatocellular jaundice

Hepatocellular jaundice is caused by an injury or inflammation of the liver cells. This could be due to:

● Medications (drug-induced jaundice) – Certain prescribed medications or traditional herbal supplements may interfere with liver function. This prevents bilirubin from being efficiently removed from the blood or excreted into the bile, thus leading to jaundice.

Alcohol hepatitis is another important cause of hepatocellular jaundice.

● Viral hepatitis – Hepatitis is a condition where the liver becomes inflamed and its ability to process and secrete bilirubin is largely discounted. Common forms of viral hepatitis include viral hepatitis A, B, and C. Viral hepatitis A is normally contracted through shell fish whereas viral hepatitis B and C are through blood products and body fluids.
● Chronic liver diseases – In chronic liver diseases (e.g. chronic hepatitis B, alcoholic liver disease), scar tissue can form in the liver. Scar tissue cannot do what healthy liver tissue does. As more scar tissue replaces the normal functioning liver tissue, the liver function deteriorates (e.g. unable to clean blood, digest food, and store energy).

Ultimately, there will be jaundice. By the time jaundice is noticeable, the condition may have already become serious, and patients may experience liver failure and complications of liver cirrhosis (hardening of liver).

Finding out what’s wrong

It is important for the doctor to determine the underlying health conditions leading to the jaundice so that appropriate treatment can be given to the patient. The jaundice usually resolves once the underlying cause is treated.

History and physical examination can suggest possible reasons for the jaundice. For instance, jaundice is most likely caused by alcoholic liver disease if the patient is a heavy drinker, or may be drug-induced if patient is taking new medications recently.

Presence of abdominal pain and fever may suggest blockage of the bile duct, usually by gallstones. If there is weight loss, it could be cancer related.

Liver function tests for measuring bilirubin and liver enzymes are helpful to determine if the jaundice is due to abnormal RBC destruction, inflammation of the liver, or obstruction or disease in the bile duct. A liver function test can help suggest what is the probable cause of jaundice. Blood tests can be done to test for hepatitis A, B, and C.

An ultrasound scan of the abdomen may help to detect obstructions in bile ducts, e.g. gallstones or pancreatic cancer.

Computerised tomography (CT) scans and MRI scans are especially useful to identify tumours in the pancreas and liver. It is also useful to detect bile duct tumour.

Endoscopic ultrasound is particularly useful to examine the pancreas for tumours or small gallstones in the gallbladder and bile ducts that cannot be detected by other methods. It is also useful to take some tissues using fine needle aspiration.

Treatment for jaundice

Before a doctor treats a jaundiced patient, he has to find out the cause first, so that treatment may be directed at the specific cause. For example, hepatitis B is treated with anti-viral drugs, while a procedure called Endoscopic Retrograde Cholangiopancreatography (ERCP) is performed to remove a gallstone in the bile duct or to insert a stent in the bile duct to unblock the blockage in the bile duct due to tumour.

If the jaundice is associated with alcoholic hepatitis, the patient has to stop alcohol intake.

The main treatment for bile duct cancer is surgery to remove the tumour, but operation is not always possible. When that’s the case, a small tube (stent) will be put into the bile duct to allow the bile to flow again and relieve the jaundice.


Jaundice can be prevented if your liver is healthy and functioning efficiently. While causes such as pancreatic cancer and bile duct cancer cannot be prevented, there are things you can do to protect your liver.

● Avoid excessive intake of alcohol.
● If you have not had hepatitis A or B, get vaccinated.
● There is no vaccine available for hepatitis C, but you can reduce your risk by practising safe sex and avoiding injecting drugs or sharing intravenous drug needles. All the needles in hospitals nowadays are single-use.
● Make sure shellfish are cooked properly before eating to prevent hepatitis A.
● For people with gallstones, eating a low-fat diet helps to reduce the attack of pain. If the gallstones give you symptoms, remove it.

As with most diseases, timely and appropriate treatment saves lives, so seek medical help as soon as you notice any signs of jaundice, or experience intense abdominal pain and fever.

Dr Tan Huck Joo is the president of the Malaysian Society of Gastroenterology & Hepatology. The author is not associated with and does not endorse any brand or product. This article is courtesy of the Malaysian Society of Gastroenterology & Hepatology and supported by the VITAGEN Healthy Tummies Programme. For a free digestive health booklet or more information, please contact 03-5621 1408.


Impact of Peginterferon Maintenance Therapy on the Risk of Developing Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Virus

Mitchell L. Shiffman
Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, Va., USA

Address of Corresponding Author

Oncology 2010;78 (Suppl. 1):11-16 (DOI: 10.1159/000315224)

Key Words
Hepatocellular carcinoma
Hepatitis C virus
Sustained virologic response


The incidence of hepatocellular carcinoma (HCC) is increasing worldwide. This is largely to do with the epidemic of chronic hepatitis C virus (HCV) in the USA and other developed countries and an increasing prevalence of cirrhosis. The current treatment for chronic HCV is peginterferon (Peg-IFN) and ribavirin. Unfortunately, response rates are limited especially in patients with cirrhosis. Several observations have led to the hypothesis that continuing Peg-IFN as maintenance therapy in patients with chronic HCV and cirrhosis could reduce the risk of developing complications including HCC. However, three large prospective controlled trials of maintenance therapy have now failed to demonstrate that Peg-IFN maintenance therapy reduces complications of cirrhosis, HCC and liver-related mortality. In the HALT-C trial, the only one of these three studies for which HCV RNA data is available during maintenance therapy, only a minimal reduction in serum HCV RNA level was observed during maintenance therapy. It therefore remains uncertain if profound and persistent virologic suppression to undetectable levels of HCV RNA impacts the risk of developing HCC in patients with chronic HCV and advanced fibrosis or cirrhosis. Based upon the available data, there appears to be no rationale for utilizing Peg-IFN maintenance therapy in patients with cirrhosis and this approach does not reduce the risk of HCC.

Copyright © 2010 S. Karger AG, Basel

Author Contacts

Mitchell L. Shiffman, MD
Hepatology Section, Virginia Commonwealth University Medical Center
Box 980341, Richmond, VA 23298 (USA)
Tel. +1 804 828 4060, Fax +1 804 828 4945
E-Mail mshiffma@vcu.edu

Article Information

Published online: July 8, 2010
Number of Print Pages : 6


Is sexual contact a major mode of hepatitis C virus transmission?

Early View (Articles online in advance of print)
Published Online: 16 Jun 2010
Copyright © 2010 American Association for the Study of Liver Diseases

Rania A. Tohme 1 2 *, Scott D. Holmberg 1

1 Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Atlanta, GA
2 Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA

email: Rania A. Tohme (rtohme@cdc.gov)
*Correspondence to Rania A. Tohme, 1600 Clifton Road NE, Centers for Disease Control and Prevention Mailstop G-37, Atlanta, GA 30333

Potential conflict of interest: Nothing to report.

fax: 404-718-8585


Medical opinion varies considerably regarding the transmission of hepatitis C virus (HCV) through sexual contact. Based on the study design, representativeness of the study population, and the methods used for case ascertainment, we analyzed 80 qualifying reports regarding the evidence for or against sexual transmission. Regarding heterosexual transmission, the weight of evidence is that there is no increased risk of sexual transmission of HCV among heterosexual couples in regular relationships. This risk increases among persons with multiple sexual partners (adjusted odds ratio [aOR] 2.2-2.9), but this association may be confounded by increased likelihood of injection drug use with increased number of partners. There appears to be a real increased risk for women coinfected with human immunodeficiency virus (HIV) or other sexually transmitted infections (aOR 3.3-3.9) and especially for HIV-infected gay men who are having sex with one another compared with HIV-uninfected men (aOR 4.1-5.7). HIV-infected gay men increase their risk of such transmission in association with practices that lead to mucosal trauma (multiple sexual partners, fisting, use of sex toys) and the presence of genital ulcerative disease. Conclusion: This review should inform, and not distract from, recommendations to reduce the risk of HCV transmission. Health care providers need to pay special attention to sexual transmission of HCV among HIV-infected individuals. HEPATOLOGY 2010

Received: 4 March 2010; Accepted: 8 June 2010

Digital Object Identifier (DOI)
10.1002/hep.23808 About DOI


Couple recalls Steinbrenner's penchant for giving

Becky Wells holds a letter she received from late New York Yankees owner George Steinbrenner after the baseball mogul provided assistance to help Wells overcome a bout of Hepatitis C in 1992. Steinbrenner, a Cleveland-area native who devoted much time and many resources to causes in his home state, died Tuesday at 80. (Abigail S. Fisher, Eagle-Gazette)

Late Yankees owner, a native Ohioan, helped with transplant that prolonged Lancaster woman's life

BY JOE ARNOLD • The Eagle-Gazette Staff • July 17, 2010

LANCASTER -- Tom and Becky Wells knew the real George Steinbrenner. The caricature splashed across the back pages of New York's tabloids for almost 40 years wasn't the man the Lancaster couple had come to know.
Sure Steinbrenner had power. And money? More than he could shake a bat at. But the late owner of the New York Yankees, who died Tuesday, knew how to wield both for good. As he went about fiercely transforming the Yankees from a laughingstock to a billion dollar empire, Steinbrenner quietly worked for his fellow man.
In 1992, Becky Wells was sicker than she'd ever been. Diagnosed with Hepatitis C following a blood transfusion, the disease led to cirrhosis of the liver and eventually early stage liver failure. Biweekly blood transfusions kept Becky alive for six months until her first liver was found.

"I didn't have very long to live when I had the transplant," she said. "It was life or death. I was one of the lucky ones."


Work forced Tom and Becky Wells to move from Lancaster to Tampa, Fla., in 1984. Tom was a salesman for Levy Awards & Promotional Products when he caught the eye of owner George A. Levy. By the time Becky fell ill, Levy, a well-known trophy and award manufacturer, had become a close friend of the couple.

Levy had introduced Tom to the Tampa Sports Club, and before long, Wells was president of the philanthropic group. Among the organization's most visible -- and generous -- members was Steinbrenner, a Cleveland native.

"He could be tough. He was a tough guy," Tom said. "But he was also good to a lot of people."

As word of Becky's illness spread within the Wells' circle of friends, it put into motion a series of events the couple believes started with Levy and Steinbrenner.

Steinbrenner, Becky said, was a well-known supporter of the Cleveland Clinic and the medical miracles the hospital performed almost daily. When Steinbrenner got wind of Becky's illness -- through Levy --he helped Becky obtain a liver after just six months on the organ waiting list, Becky said.

"Mr. Steinbrenner made some calls," she said. "He was on the board at the Cleveland Clinic, and the next think I knew, I had my liver."


The transplant, however, wasn't without complications. Becky actually was awarded two livers in 1992. After flying privately from Tampa to Cleveland, Becky and Tom got word that the liver earmarked for Becky was in Michigan, and a snowstorm had prevented the pilot in charge of picking up the organ from landing.

Four days later, the couple was told on a Sunday that another liver was available. Strapped for cash because of the flight earlier in the week, they wondered how they would arrange another short-notice flight.

"That time we were out of money, and our insurance wasn't going to cover it right away," Becky said. "Mr. Levy and Mr. Steinbrenner were instrumental in getting our transportation going."

Becky and Tom arrived in Cleveland in time for the transplant that has kept her alive since.


Save for occasional blood work and checkups, Becky hasn't had any problems with her new liver. She sent Steinbrenner a thank-you card years ago, and on it was a scene depicting Amish life. Steinbrenner wrote back thanking the couple for the card and fond memories of Ohio it brought back, Becky said.

They still cherish the letter.

Steinbrenner went on to become one of the most powerful owners in professional sports. As his Yankees won -- seven World Series championships and 11 American League pennants in 37 years -- he continued to give to dozens of charities, often stipulating that it be done anonymously.

"He was a good man," Becky said. "I think the media dwelled on his sports background and his temperament, but there was another side to George Steinbrenner. He was a very caring man and he helped an awful lot of people.

"I wouldn't be here without him."

Joe Arnold can be reached at (740) 681-4358 or at jarnold@nncogannett.com.