December 8, 2013

Type 2 Diabetes Might Raise Risk of Liver Cancer

By Barbara Bronson Gray
HealthDay Reporter

But odds for malignancy are low; study found stronger connection for some minorities

SUNDAY, Dec. 8, 2013 (HealthDay News) -- People with type 2 diabetes might be at somewhat higher risk of developing liver cancer, according to a large, long-term study.

The research suggests that those with type 2 diabetes have about two to three times greater risk of developing hepatocellular carcinoma (HCC) -- the most common type of liver cancer -- compared to those without diabetes.

Still, the risk of developing liver cancer remains low, experts said.

Race and ethnicity might also play a role in increasing the odds of liver cancer, the researchers said.

An estimated 26 percent of liver cancer cases in Latino study participants and 20 percent of cases in Hawaiians were attributed to diabetes. Among blacks and Japanese-Americans, the researchers estimated 13 percent and 12 percent of cases, respectively, were attributed to diabetes. Among whites, the rate was 6 percent.

"In general, if you're a [type 2] diabetic, you're at greater risk of liver cancer," said lead author V. Wendy Setiawan, an assistant professor at the Keck School of Medicine at the University of Southern California.

Yet the actual risk of liver cancer -- even for those with type 2 diabetes -- is still extraordinarily low, said Dr. David Bernstein, chief of hepatology at North Shore University Hospital in Manhasset, N.Y.

Although liver cancer is relatively rare, it has been on the rise worldwide and often is associated with viral hepatitis infections and liver diseases, such as cirrhosis.

New cases of HCC in the United States have tripled in the past 30 years, with Latinos and blacks experiencing the largest increase, Setiawan said. During that time, type 2 diabetes also has become increasingly common.

What might the connection be?

It's possible that the increased risk of liver cancer could be associated with the medications people with diabetes take to control their blood sugar, said Dr. James D'Olimpio, an oncologist at Monter Cancer Center in Lake Success, N.Y. "Some medications are known to inhibit normal suppression of cancer," he said.

"Some of the drugs already have [U.S. Food and Drug Administration-ordered] black box warnings for bladder cancer," D'Olimpio said. "It's not a stretch to think there might be other relationships between diabetes drugs and pancreatic or liver cancer. Diabetes is already associated with a high risk of developing pancreatic cancer."

People with type 2 diabetes often develop a condition called "fatty liver," D'Olimpio said. In these cases, the liver has trouble handling the abundance of fat in its cells and gradually becomes inflamed. That situation can trigger a cascade of problems, including cirrhosis (a chronic disease of the liver), fibrosis (thickening and scaring of tissue) and, ultimately, cancer, he said.

D'Olimpio said fatty liver disease is the No. 1 cause of HCC. "[Type 2] diabetics have twice the chance of having a fatty liver, at least," he said. "If you're an African-American or Latino, that may make you even more susceptible."

People with type 1 diabetes, however, do not have an increased risk of liver cancer, he said.

The new research is scheduled for presentation Sunday at an American Association for Cancer Research meeting in Atlanta. The data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.

The study analyzed data collected between 1993 and 1996 from nearly 170,000 black, Native Hawaiian, Japanese-American, Latino and white adults. Researchers followed up with the participants about 16 years after they had answered a comprehensive health questionnaire. Over that time, about 500 participants had developed liver cancer.

Information about risk factors -- such as age, whether they had type 2 diabetes, alcohol intake, body-mass index (a measure of body fat) and cigarette smoking -- was analyzed, and blood tests for hepatitis B and hepatitis C were performed on about 700 of the participants, with and without liver cancer.

Whether people smoked or drank alcohol did not appear to change the relationship between having diabetes and getting liver cancer, the researchers said.

Although the study found an association between having type 2 diabetes and developing liver cancer, it did not prove a cause-and-effect relationship.

North Shore's Bernstein urged caution in interpreting the results. "It's a single study that talks about a large number of people with a common disease like diabetes and links it to liver cancer," he said. "We have a lot more learning to do and more work is needed to prove an association and define what the risk really is."

A study this month by the American Diabetes Association showed that many Americans are unaware that they are at risk for type 2 diabetes. D'Olimpio urged people to get the simple blood test, called fasting blood sugar, to test for diabetes.

The next step is to learn what role genetics may play in whether an individual with type 2 diabetes will develop liver cancer, study author Setiawan said.

More information

Learn more about liver cancer from the U.S. National Library of Medicine.

Copyright © 2013 HealthDay. All rights reserved.


5 Incredible Health-Care "Firsts" in 2013

by Sean Williams, The Motley Fool Dec 8th 2013 2:20PM
Updated Dec 8th 2013 2:22PM

No matter how good or bad of a year the stock market ultimately has, there are always positive takeaways and innovations that will stand head and shoulders above the rest.

As a health-care contributor, I'm privy to some of the most exciting research going on in life sciences and in improving patient quality of life. As you might imagine, that means there are an almost immeasurable number of new drug candidates being studied each year -- and to some extent it can even be difficult just to keep track of all the new Food and Drug Administration approvals year in, year out. Needless to say, 2013 didn't disappoint.


Source: Thinkpublic, Flickr.

The way I see it, 2013 ushered in five never-before-seen "firsts" for the health-care sector. As you know, our co-founders, David and Tom Gardner, love revolutionary companies and innovative ideas, as they tend to lend investors the greatest opportunity to profit over the long term.

Although there are literally dozens of examples to choose from, here are what I consider to be 2013's most notable health-care firsts.

1. FDA approves first oral, interferon-free hepatitis-C pill for genotype 2 and 3 patients.
There were literally a mountain of new FDA approvals that could have found their way onto this list, but I find nothing more exciting than Friday's approval of Gilead Sciences Sovaldi (previously sofosbuvir) for the treatment of hepatitis-C, genotypes 1 through 4.

Sovaldi is a pill that, like its predecessors, is administered in conjunction with interferon and a ribavirin to treat the most common form of hepatitis-C, genotype 1, as well as genotype 4. However, it was also approved to treat genotype 2 and 3 without the need for interferon, which, if you recall, has the potential to deliver to the patient unwelcome flu-like symptoms. It's the first time an oral hepatitis-C drug has been approved that is interferon-free, and not surprisingly, sales forecasts for next year are already streaming in at $1.9 billion (with a "B"), giving it a shot at perhaps taking the title of most successful drug launch in history away from Vertex Pharmaceuticals.

2. FDA approves first breakthrough therapy-designated drug.
Last year, in one of the biggest shakeups to the FDA in quite some time, the Food and Drug Administration Safety and Innovation Act was signed into law, allowing the FDA, for the first time ever, to designate experimental drugs as "breakthrough therapies." This designation was designed to be placed on therapies that demonstrate preliminary clinical evidence that led to a "substantial improvement on at least one clinically significant endpoint over [an] available therapy." In other words, the BTD designation was designed to help shuffle game-changing drugs more quickly through the development and review process and allow these companies to submit their new drug applications following early or mid-stage data in some cases.

This year, we saw our very first BTD drug getting approved in Roche's Gazyva. The drug, which is administered in combination with chlorambucil, is targeted at treatment-naive chronic lymphocytic leukemia (CLL) patients. Gazyva's approval was based on a 356-patient study, where it, in combination with chlorambucil, delivered an average progression-free survival of 23 months, compared with just 11.1 months for the chlorambucil arm in trials. Peak sales expectations for the drug, according to FierceBiotech, range between $1.5 billion and $2.5 billion.


Source: Medtronic.

3. FDA approves first artificial pancreas system for diabetics.
As you can imagine, there are an equally impressive number of medical devices that are approved each year, but none stood taller in my book than Medtronic's approval of its MiniMed 530G as a glucose-control treatment for diabetics.

This device is essentially an artificial pancreas for diabetic patients that's capable of injecting insulin into the body as needed, but also uses a sensor that will shut the insulin pump off for two hours if a patients' blood sugar falls below preset levels. Theoretically, this would mean less worrying for the patient about the potential for hypoglycemia, less need to remember when to inject with insulin, and more ability for patients to instead focus on managing their eating and exercise habits and get back to enjoying their life!

Admittedly, Medtronic isn't known for its diabetes business, but this first-in-class product has a chance to reinvigorate its stagnant diabetic division and forge ahead of its competition.

4. FDA rejects tobacco products for the first time.
It may seem rare nowadays that Congress agrees on anything, but in 2009 they did just that by passing a law that President Obama signed allowing the FDA to regulate certain aspects of the tobacco industry. While the FDA isn't allowed to ban nicotine, it is allowed to ban select chemicals in cigarettes and set product standards that tobacco producers have to follow if they want their product to make it to market. This year saw the FDA step in for the first time since this bill was signed into law in June 2009 and reject four tobacco products.

According to a New York Times report in late June, the FDA accepted two new versions of Newport cigarettes made by Lorillard but rejected four other brands that are, by law, left unnamed. This represents the first time in history that the FDA has stepped in and forbade the sale of a tobacco-product based on the negative health effects it could have on consumers. I suspect we're going to continue to see increasingly more stringent regulations on the tobacco industry in the coming years and would certainly suggest investors who want to take advantage of this sector look overseas for their best opportunities.



5. First time consumers can compare health insurance plans in a transparent marketplace.
The Patient Protection and Affordable Care Act, perhaps known better by its slang term, Obamacare, may not be the most popular of all laws, but it did do one thing for consumers that's never been done before: It created a transparent and open marketplace platform for the entire country to shop for health insurance.

Before Obamacare, insurers would be able to price their health insurance policies however they'd like because it was practically impossible for John and Jane Q. Public to get a comparable quote on a similar policy with another insurer. With the exception of eHealth, which currently has a tad over 1 million members and a select number of smaller private exchange platforms, this option just didn't exist. I would expect this open platform setting to really benefit insurers that offer policies on the lower end of the price spectrum, such as Centene . Perhaps I'm a bit biased, given that I signed up for a Centene-owned plan in my home state, but I believe price is going to play an important factor for a number of Americans in the upcoming year when selecting a health insurance plan, and Centene specifically targets that lower-income and/or cost-conscious bracket.

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The article 5 Incredible Health-Care "Firsts" in 2013 originally appeared on

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So You Want to Be a Hepatologist?

Volume 145, Issue 6 , Pages 1182-1185, December 2013

Bruce A. Luxon

published online 21 October 2013.

John Del Valle, Section Editor

Hepatology is a discipline that has developed substantially over the past 3 decades, from one that featured many diagnoses but very few therapeutic interventions to a specialty in which we can effectively prevent and treat many liver diseases. Several therapeutic interventions for the complications of end-stage liver disease were well-described and considered standard of care, but had not been proven to be of benefit. Patients with liver disease were assigned to a variety of causes of their liver disease, but little could be done to improve their lifestyle or prevent morbidity and mortality. Liver transplantation, for instance, was still in its infancy. Other patients were correctly labeled as having inflammation of the liver and the term hepatitis was widely used. However, the exact cause of the hepatitis could not be established and hence a beneficial treatment could not be established. Fortunately, over the past 20–30 years hepatology has become a field of medicine where we can provide accurate diagnoses, beneficial treatment, and, more important, prevention of end-stage liver disease. Despite this increase in knowledge and efficiency in our medical care, the training of physicians with expertise to provide these services has not kept pace with the rapid expansion of our medical knowledge.1 In fact, more than 10 years ago, hepatology was viewed only as a subset of the vast field of gastroenterology.

Is There a Demand for Hepatologists? 

As we made advances in the diagnosis and treatment of liver diseases, it became apparent that the field of hepatology would grow. It also became clear that manpower needs would dictate the need for physicians with special expertise to provide adequate patient care. For gastroenterology trainees, an important date was July 1, 2001, when the Medicare colon cancer screening benefit was expanded to include screening colonoscopy for average risk individuals once every 10 years. As this economic incentive became widely established, hepatology quickly became a field of specialization which was less desirable for fellows.

The American Association for the Study of Liver Diseases (AASLD) represents the largest group of physicians interested in hepatology. In 2013 the society had >4000 dues-paying members. However, only about half of these physicians are based in the United States.2 Furthermore, only a few of these AASLD members indicated that their practice focuses on hepatology ≥50% of the time. Interestingly, most AASLD members in the United States are associated with an academic appointment at a teaching hospital and have their practice within a system with a liver transplant program. In 2013, there were 138 adult and pediatric liver transplant programs registered with United Network for Organ Sharing.3 There is a clear demand for hepatologists to join these transplant programs. However, many of these openings are unfilled. This is because the supplying of physicians with the required expertise in hepatology has not kept pace with the growing demand.

History of Certification of Expertise in Hepatology 

According to the membership survey of the AASLD, most current hepatologists did a fellowship in gastroenterology in which hepatology was emphasized.3 This was a personal choice of the trainee, because no specialized program existed for training in hepatology. In the mid to late 1990s, AASLD leadership commissioned a task force to determine whether hepatology was a distinct and separate entity within the field of gastroenterology. The consensus was that advanced and transplant hepatology not only had its own body of specialized knowledge and expertise, but that practicing gastroenterologists often did not consider themselves adequately prepared to care for patients with end-stage liver disease. The task force reported that most referrals to liver transplant centers and consult requests to transplant hepatologists came from gastroenterologists, not from primary care physicians, surgeons, or internists.

In 2000, the AASLD applied to the American Board of Internal Medicine (ABIM) to consider a certifying examination in transplant hepatology.4 The AASLD argued that advanced and transplant hepatology was clearly a distinct discipline, separate from gastroenterology; that there was a distinct body of literature which was devoted exclusively to the discipline; and that practicing gastroenterologists viewed certain colleagues as having unique expertise in hepatology.4

After some debate, the application was supported and the ABIM created a certifying examination, which was ready for its first administration in November 2006. This initial examination was taken by 214 ABIM-certified adult gastroenterologists. The pass rate was 88% and the minimum passing score was to answer 73% of the 175 questions correctly.4 After looking through various test validation statistics, the ABIM concluded the examination had performed as expected.5

By 2013, only 430 physicians have become board certified in transplant hepatology.6 Most of these candidates took the examination in the first year that it was offered because candidates' clinical experience was “grandfathered” in. Qualifying to take the transplant hepatology boards now requires specific clinical training in advanced and transplant hepatology.

Hepatology Training Pathways 

In the last 10 years, 3 pathways existed for physicians to become trained in hepatology. The first is a 1-year training program not associated with a GI training program and was not recognized by the Accreditation Council for Graduate Medical Education (ACGME). The second pathway is through an ACGME-recognized 1-year program, also separate from a GI training program. The third and most recent is an innovative pilot program that combines shortened training with new tools of medical education assessment. This last program is closely identified with a GI training program.

Advanced and Transplant Hepatology Not Associated With Gastroenterology Training 

An option that became popular in the late 1990s and early 2000s was an “isolated” fellowship devoted exclusively to advanced and transplant hepatology. These programs typically were not associated with gastroenterology training programs. They were often populated by internal medicine residents who saw the competition for traditional gastroenterology fellowships increasing and used this avenue to enhance their candidacy. In addition, many non-US graduates saw this as a way to improve their chances at either getting a residency or a gastroenterology fellowship.

These programs were typically 1-year positions with no established curriculum and had no formal recognition process. The AASLD provided support for many of these trainees in the form of competitive grants based on an institution's record of training physicians in liver disease. However, retrospectively, many of the young physicians who were supported in these programs did not turn out to be hepatologists. It is not clear how many succeeded in obtaining a gastroenterology fellowship. The author's personal experience suggests that a small minority of trainees who did this type of hepatology fellowship actually stayed in the practice of hepatology.

Many of these “isolated” hepatology training programs are now defunct. The reasons for this include their ambiguous curriculum, difficulty finding funding to provide salary support, and a lack of recognition by either the ABIM or by the ACGME.7

Advanced and Transplant Hepatology Training After Training in Gastroenterology 

In 2006, the ACGME allowed the creation of advanced and transplant hepatology training programs. Initial enthusiasm was high and many academic centers submitted the application paperwork to create hepatology training programs at their institutions (5).5 These programs require the hepatology training be done after completing gastroenterology training. Thus, a potential hepatologist selecting this route had the disadvantage of training 3 years in internal medicine, 3 years in gastroenterology, and then 1 additional year in hepatology. In addition, this route requires (by definition) that the hepatologist compete to get into a gastroenterology training program. In addition, the requirements for ABIM certification in transplant hepatology require that all candidates be board certified in gastroenterology. Thus, the requirements of the ACGME (for programs) and the ABIM (for individuals) have definitely lengthened and complicated the process of training hepatologists.

Under the current policy, the only way to become a credentialed hepatologist is to complete a 3-year fellowship in gastroenterology, complete an additional 1-year fellowship in advanced and transplant hepatology, and then pass the ABIM examinations in both gastroenterology and transplant hepatology.

However, it became clear that the ACGME and ABIM rules governing these programs discouraged trainees from entering this pathway. Currently, the ACGME website lists 39 programs that have a transplant hepatology fellowship. However, there are only 34 fellows enrolled for the 2013–2014 academic year.8 Given that many programs are approved for 2 fellows per year, these numbers reflect that the current paradigm for hepatology training is not succeeding in attracting hepatology trainees.

ABIM Pilot Program: Advanced and Transplant Hepatology Training “During” Training in Gastroenterology 

In 2012, the AASLD, with the input of other GI professional societies, worked with the ABIM to create a 3-year, combined GI/transplant hepatology training program. The initial goal was to create a training program that recognized and promoted the unique manpower needs in advanced and transplant hepatology. As mentioned, many of the “standard” transplant fellowship were not attracting applicants. Training directors created the template of a competency-based training program that combined training in gastroenterology as well as transplant hepatology. The training in gastroenterology per the ABIM suggestions would be assessed by the traditional standards of medical education, which existed in 2012, and the specifically developed tools of competency-based medicine education would be applied to the transplant hepatology year. This pilot program became available on July 1, 2012.6

The transplant hepatology pilot program sponsored by the AASLD and approved by the ABIM has several goals. The first was to be a front runner in medical education by deriving and implementing a competency-based training program using milestones and entrustable professional activities (EPAs).9 Milestones and EPAs are relatively new concepts in postgraduate medical training. Milestones are a series of developmental goals related to the current competencies, which are designed to help assess whether an individual trainee has met the competency. EPAs are concrete clinical activities that link to core competencies or milestones. They are designed to incorporate the professional judgment of competence by seasoned clinicians. As the trainee progresses through his education, the goal is to allow the trainee to build a collection (portfolio) of EPAs to document competence. Additional information for the internal medicine milestones is available online.9A second goal was to create a program that allowed trainees to sit for both gastroenterology and the transplant hepatology ABIM board examinations after they had successfully completed only 3 years of clinical training. A third goal was to produce 5–10 additional board-eligible transplant hepatologists each year.

Competency-Based Medical Education Innovations 

Following the new medical education goals of the ACGME, the transplant hepatology pilot program used EPAs to assess trainees. The supervising and oversight committee of the AASLD also developed a transplant hepatology in-service examination that will be made available to all programs participating in the pilot. Finally, competency-based medical education requires care transition measures, multisource feedback instruments, milestones, and performance measures.

Details of Incorporating the Pilot Program Into an Existing Gastroenterology Training Program 

The professional societies involved in training gastroenterologists and hepatologists did not wish to do increase competition for internal medicine residents to get into training slots. The pilot program must have an existing, traditional, ACGME-accredited transplant hepatology program. They also must have an ACGME-accredited gastroenterology program. The candidate must apply to his gastroenterology and transplant hepatology program directors, and should be judged to be competent in GI by the end of year 2 and on a trajectory to successfully complete GI training by the end of 3 years. Obviously, cooperation must exist between the gastroenterology and transplant hepatology training programs to ensure that there is sufficient volume of hepatology clinical opportunities both for the gastroenterology trainees as well as the hepatology pilot fellow. Some adjustment may be may be needed to ensure adequate manpower to cover the gastroenterology services, especially those that are not related to hepatology, such as advanced endoscopy, inflammatory bowel disease, and motility. The oversight committee felt that the transplant hepatology pilot fellows in many ways should still have similar duties to what they would have been during their third year of gastroenterology training. Specifically, the oversight committee felt that the training pilot fellow should continue in their continuity clinic, continue to perform standard endoscopies, participate in educational programs such as conferences, biopsy review, and morbidity and mortality conferences, and still take after-hours calls.

The process of identifying and approving candidates for this pilot program has been kept as simple as possible. The candidate fellow should be identified no later than the middle of the second year of training. Early identification is important to ensure that the fellow is on the “right trajectory” with regard to his/her GI clinical skills. Approval is needed from the candidate's institution Graduate Medical Education authority, typically the designated institutional official. Because the institution must have ACGME-approved transplant hepatology and gastroenterology fellowships, the candidate must get written approval from both program directors. A letter of intent is then sent to the AASLD Transplant Hepatology Pilot Program Steering Committee. If the institution and the candidate are approved, the committee recommends to the ABIM that the candidate be allowed to sit for the transplant hepatology boards after completion of 3 years of clinical training and after passing the gastroenterology boards. Current policy is that the ABIM must have documentation of the candidate's successful gastroenterology examination before the candidate will be allowed to sit for the transplant hepatology boards. This may change in the future, because there is some concern about a candidate's inability to prepare for and take both board examinations simultaneously.

Current Participation in Pilot Program 

The pilot program is in its second year. In 2012–2103), there were 4 fellows. In 2013–2014, 3 fellows are participating.10 A total of 7 programs have joined in the pilot program effort. Candidates interested in pursuing a standard 4th-year transplant hepatology fellowship or the new pilot program should contact both the GI training program and the transplant hepatology directors at the institution of their choice. Additional information is available on the AASLD website.11 A specific letter written in May 2012 to all GI and transplant hepatology training program directors is available at this website. Overall feedback from program directors, both transplant hepatology and gastroenterology, has been positive.


The tremendous advances in clinical hepatology are a great success story in the practice of internal medicine. Hepatology has now evolved from an observational medical science to one that has a myriad of interventions, ranging from improved diagnostics, preventive strategies, and antiviral therapies, and, of course, liver transplantation. Therapies for viral hepatitis and liver cancer as well as the care of patients with end-stage liver disease have become increasingly complex. Care of patients with liver disease requires the special expertise of dedicated physicians. However, our training programs designed to developing physicians with this expertise have not kept pace with the medical advances. In fact, the length of the required hepatology training has been increased. Multiple barriers have been placed between internal medicine residents who are interested in hepatology and their career goal of being recognized as a hepatology expert.

Current training in transplant hepatology requires the candidate to successfully complete a traditional 3 year fellowship in gastroenterology. There are now 39 transplant hepatology programs accredited by the ACGME but these programs are having difficulty filling their training slots. The lack of success in attracting potential hepatologists is due to the competiveness of getting into gastroenterology programs, the 7 years required of post graduate training and the financial burden of perpetual training.

Under the leadership of the AASLD, the ABIM has approved a pilot program to train hepatologists that seeks to circumvent these pitfalls. Under special circumstances, candidates can complete their clinical training in both gastroenterology and hepatology in 3 years. They will be eligible to sit for the gastroenterology boards and if successful in passing the GI board examination, can sit for the transplant hepatology boards. Institutional programs and individual candidates for this pilot program are carefully selected by an AASLD committee that also has oversight into ensuring that the pilot program is innovative in its medical education. Pilot programs will utilize EPAs, newly developed milestones, a recently created transplant hepatology in-service examination, and will be monitored by many novel feedback instruments.

In summary, the growing need for physicians with an expertise in advanced and transplant hepatology has necessitated a change in our paradigm on how we train hepatologists. The future of hepatology has never looked brighter and the AASLD and its partners are committed to providing innovative educational and training avenues as we enter a new era in the world of liver diseases.


Conflicts of interest The author discloses no conflicts.

PII: S0016-5085(13)01497-2


© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.


Hepatocellular Carcinoma and Hepatitis B Virus: Family Matters

Clinical Gastroenterology and Hepatology
Volume 11, Issue 12 , Pages 1646-1647, December 2013

Brian J. McMahon, MD, MACP

published online 03 June 2013.

In much of the world, hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in men. In sub-Saharan Africa, most of eastern and southeast Asia, and the Pacific Islands, chronic hepatitis B virus (HBV) is the primary etiology for HCC, where the prevalence of chronic HBV infection ranges from 2% to more than 10% of the population.1 Several demographic, viral, and environmental factors have been found to increase the risk of HCC in HBV infection, which can help to identify those persons who should be targeted for regular surveillance to detect this tumor early, at a more treatable stage. More than 30 years ago, several case-control studies found family history of HCC to be a risk factor in relatives who were infected with HBV,2 but the magnitude of the risk previously was unknown. In this issue ofClinical Gastroenterology and Hepatology3 is an important article that takes advantage of a large population-based cohort study conducted in Taiwan, the REVEAL study, to better define and quantify the risk of family history of HCC. Briefly, the investigators screened more than 22,000 residents of 7 townships in Taiwan for HBV seromarkers and found almost 4000 to be positive for hepatitis B surface antigen (HBsAg). They then followed up those persons positive for HBsAg prospectively for 16 years and have written multiple publications regarding risk factors associated with HCC and cirrhosis that were found in this cohort.4, 5, 6

In this analysis, they examined the effect of a family history of HCC on the incidence of HCC in the entire population who were screened for HBV seromarkers. At baseline, all participants had filled out a questionnaire that included information on alcohol history and family history of HCC. All participants had a unique national health registration number that was used to link them to the National Cancer Registry. This allowed the investigators to identify cases of HCC both in the HBV-infected persons they were following up prospectively and the HBsAg-negative persons who were not tracked routinely after initial enrollment. The authors performed a multivariate analysis of other risk factors they had collected in the HBV-infected cohort including viral load, hepatitis B e antigen (HBeAg) status, and HBV genotype. They used a statistical method called RERI to examine the excessive risk caused by the interaction between HBV infection and family history of HCC, as well as looking at the attributable proportion that was the result of the interaction (AP) and the synergy index, which examines whether a synergistic or antagonistic interaction exists. They found a synergistic interaction between HBsAg positivity and family history, with highest risk of HCC found in those with both factors. When they examined RERI, AP, and synergy index they found evidence of a multiplicative interaction between family history of HCC and HBsAg positivity. The investigators previously showed that high levels of HBV DNA greater than 10,000 copies/mL and the presence of HBeAg at baseline were independent risk factors for HCC.4, 5 Their analysis in this article found that family history was significant and synergistic in HBV-infected patients who were HBeAg positive, HBeAg negative, or had HBV DNA levels greater than or less than the 10,000 copies/mL cut-off value. This means that a family history of HCC is a strong risk factor for the development of HCC in an HBsAg-positive person independent of viral load or HBeAg status. The authors found that the highest risk of all occurred in HBV-infected persons who had a family history of HCC and were HBeAg positive, in whom the cumulative risk of developing HCC during the follow-up period was 40%.

Previously, these investigators had found that basal core promoter and HBV genotype C compared with HBV genotype B (Asia) were independent risk factors for HCC and the precore mutation reduced the risk of HCC.7 Although the findings in this study again found that the basal core promoter and HBV genotype C were independent risk factors for HCC, and again, precore mutation was associated negatively with subsequent risk of HCC, none of the 3 significantly modified the effect of family history on HCC incidence.

The importance of this study is that it was a population-based longitudinal cohort study that showed the influence of family history on risk of HCC. Furthermore, it highlighted the magnitude of the risk of HCC that family history carries. The study provided strong evidence to support the American Association for the Study of Liver Diseases practice guidelines, which recommend regular surveillance for HCC every 6 months, with ultrasound of the liver for HBsAg-positive persons with a family history of HCC regardless of their age.8 Detecting HCC tumors early in HBV-infected persons, when they are smaller than 3 cm, allows for the use of potentially curable treatment with either radiofrequency ablation or surgical resection, which have been shown to prolong both tumor-free and overall survival. Tumors larger than 3 cm but smaller than 6 cm can be resected surgically, or, if Milan Criteria for liver transplant in HCC is met, could be treated by liver transplantation, which also is associated with good tumor-free long-term survival. Thus, active surveillance of those HBsAg-positive persons with a family history of HCC is a must.

The introduction of universal hepatitis B vaccination in children in most countries has shown that immunization against HBV can result in the prevention of HCC caused by this viral infection, as has been shown in population-based studies conducted in children in Taiwan, Thailand, and Alaska.9, 10, 11 However, the incidence of HCC in HBV chronically infected persons is low before infected males reach their late 30s and females reach their late 40s.12 Thus, it will take several decades for a large segment of endemic populations who received HBV vaccine in infancy and early childhood to reach middle age before we may witness a substantial global reduction in the incidence of HCC. In the meantime, a reduction in the rate of death from HCC, decompensated cirrhosis, and liver-related death could be accomplished by treating HBV-infected persons who are found to have cirrhosis, which has been shown in a randomized placebo-controlled trial of patients with compensated cirrhosis caused by HBV that also was conducted in Taiwan.13 Practice guidelines also recommend treating those with active liver inflammation and moderate fibrosis.14 It is not known whether treatment before the development of advanced fibrosis might reduce the future risk of HCC, but it would be unethical to conduct a randomized placebo-controlled trial to answer this question. However, population-based studies could be conducted to examine the effect of treating patients who fulfill criteria for therapy by evidenced-based practice guidelines on the incidence of HCC. These could be performed in population cohorts in whom the incidence of and risk factors for developing HCC have been reported previously and examining the incidence of HCC reported previously compared with that found subsequently after aggressive identification and HBV DNA suppression with antiviral agents of high-risk patients. This study raises the question, because risk of HCC in those with a family history is so high, should antivirals be used in those individuals who do not meet treatment guidelines to completely suppress HBV DNA, in hopes of decreasing the risk? This could be studied using a longitudinal cohort design in populations, such as the REVEAL cohort and the cohort of Alaska native persons with chronic HBV, which have sufficient numbers of HBsAg-positive patients with a family history of HCC.2, 15 A reasonable approach might be to suppress HBV DNA to undetectable levels with 1 of the 2 potent antiviral reverse-transcriptase inhibitors currently available, tenofovir or entecavir, and follow up these persons to see if the incidence would be reduced to less than that reported previously in these populations. Perhaps the subgroup that might yield the fastest answer to this question of earlier therapy might be those with a family history who are also HBeAg positive, in whom the authors found a 40% cumulative risk over a 16-year follow-up period.

In conclusion, the persuasive finding from this study is that persons infected with chronic HBV infection who have a family history of HCC deserve special attention, including regular surveillance for HCC, monitoring for active liver inflammation and fibrosis, and starting antiviral therapy as soon as they have met practice guidelines criteria. In addition, studies to determine if earlier administration of antiviral therapy to completely suppress HBV DNA in those HBV-infected persons with a family history of HCC are urgently needed.



AASLD clinical practice guidelines: A critical review of scientific evidence and evolving recommendations


Volume 58, Issue 6, pages 2142–2152, December 2013

Liver Biology/Pathobiology

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Christopher Koh1,*, Xiongce Zhao2,  Niharika Samala1, Sasan Sakiani1, T. Jake Liang1, Jayant A. Talwalkar3

Article first published online: 18 OCT 2013

DOI: 10.1002/hep.26578

© 2013 by the American Association for the Study of Liver Diseases


The American Association for the Study of Liver Diseases (AASLD) practice guidelines provide recommendations in diagnosing and managing patients with liver disease from available scientific evidence in combination with expert consensus opinions. The aim was to systematically review the evolution of recommendations from AASLD guidelines and identify gaps limiting the evidence-based foundations of these guidelines. Initial and current AASLD guidelines published from January 1998 to August 2012 were reviewed. The AGREE II instrument was used to evaluate rigor and transparency of guideline development. The number of recommendations, distribution of grades (strength or certainty), classes (benefit versus risk), and types of recommendations were evaluated. Whenever possible, multiple versions were evaluated for evolving scientific evidence. A total of 991 recommendations from 28 guidelines on 17 topics were evaluated. From initial to current guidelines, the total number of recommendations increased by 36% (512 to 699). The largest increases were from chronic hepatitis B virus (HBV) (+71), liver transplantation (+53), and autoimmune hepatitis (AIH) (+27). Most current recommendations are grade II (44%) and less than 20% are grade I. The AGREE II evaluation showed global improvement in guideline quality. Both HBV and chronic hepatitis C guidelines had greatest increases in grade I recommendations (+383% and +67%, respectively). The greatest increases in treatment recommendations were from HBV (grade I, +1,150%), liver transplantation (grade II, +112%), and AIH (grade III, +105%). Conclusion: Despite significant increases in the numbers of recommendations within AASLD practice guidelines over time, only a minority are supported by grade I evidence, highlighting the need for developing well-designed investigations to provide evidence for areas of uncertainty and improving the quality of future guidelines in hepatobiliary diseases. (Hepatology 2013; 58:2142–2152)

American Association for the Study of Liver Diseases
American College of Cardiology
American Heart Association
Agency for Healthcare Research and Quality
autoimmune hepatitis
acute liver failure
Grading of Recommendation Assessment, Development, and Evaluation
hepatitis B virus
hepatitis C virus
hepatocellular carcinoma
Institute of Medicine
nonalcoholic fatty liver disease
primary biliary cirrhosis
primary sclerosing cholangitis
transjugular intrahepatic portosystemic shunt

Clinical practice guidelines are systematically developed statements that attempt to synthesize large amounts of available scientific information for providing best practices to healthcare providers.[1] These statements often represent the official opinion of single or multiple professional societies and are developed by individuals recognized for their expertise and contributions to the field. Topics often covered include conditions (diseases, signs, and symptoms) and technologies (diagnostic tests and therapeutic procedures) where recommendations about preferred approaches for patient management are provided. The creation of recommendations is often based on a formal review and analysis of the published literature along with weighing the strength of the available scientific evidence. In situations where the data are inconclusive or absent, recommendations are often based on consensus expert opinion.

Internationally, more than 3,700 clinical practice guidelines from 39 countries are identified within the Guidelines International Network database.[2] In the U.S., there are over 2,300 guidelines registered within the National Guidelines Clearinghouse which is supported by the Agency for Healthcare Research and Quality (AHRQ).[3] Given the variability in terms of breadth and depth from available clinical practice guidelines, the U.S. Congress has identified the importance of establishing rigorous processes for developing trustworthy, consistent, and scientifically valid documents. In turn, the Institute of Medicine (IOM) released eight standards for the development of clinical practice guidelines in March 2011.4 Within the framework of the IOM's recommendations, there has been little systematic review of the body of clinical practice guidelines put forth by various medical societies. Recently, clinical practice guideline catalogs from the American College of Cardiology (ACC)/American Heart Association (AHA) and all endocrinology guidelines published in North America from 2007-2010 have been examined.[5, 6]

The field of hepatology has experienced significant growth in the production of relevant scientific literature over the past few decades. However, the question of whether clinical practice guidelines have truly evolved with more evidence-based recommendations has not been systematically investigated. Thus, we performed a systematic review of the American Association for the Study of Liver Diseases (AASLD) clinical practice guidelines issued from January 1998 to August 2012 with the aim of evaluating the evolution of recommendations that have been issued over time. The ultimate goal was to evaluate methodological rigor and quality of reporting of AASLD guidelines, elucidate possible gaps that limit the use of evidence-based medicine to support certain recommendations within the AASLD guidelines, and to highlight potential opportunities for improvement.

Materials and Methods

Guideline Selection

All initial published versions of the AASLD practice guidelines for a given topic issued from January 1998 to August 1, 2012 were abstracted for data.[7-23] If available, the current updated versions for each topic was also evaluated.[18, 24-34] Current AASLD guidelines are defined as the most recently published document on a specific topic which is posted on the AASLD website as of August 1, 2012 ( For this investigation, only complete clinical practice guidelines and position papers were evaluated, thus focused updates were not included.

Evaluation of Methodological Rigor and Transparency

To evaluate the evolutionary process of guideline development and quality of reporting, the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used on all comparable guidelines and position papers.[35] The AGREE II has been widely used in the assessment of methodological rigor and transparency of guideline development and has been cited for its validity and reliability. Briefly, this tool that evaluates 23 items organized into six domains (scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence) followed by two global rating items (overall assessment) and includes a user manual that provides guidance on rating of each item. The scope and purpose domain evaluates the specific health questions covered by the guideline, target population, and the overall objective of the guideline. The stakeholder involvement domain evaluates the appropriateness of the guideline development group and its representation of the views of its intended users. The rigor of development domain evaluates the systemic methodology used to gather and synthesize evidence, methods of recommendation formulation, and the mechanisms to update them. The clarity of presentation domain evaluates the overall structure, format, and language of the guideline. The applicability domain evaluates barriers, facilitators, and ease of implementation and resource implications of guideline application. Finally, the editorial independence domain evaluates the extent to which external influences or competing interests may have affected the specific guideline.

For this study, three appraisers conducted the assessment (C.K., S.S., N.S.) after using the online training tools recommended by the AGREE collaboration. After guideline evaluation, domain scores were calculated (as per the AGREE II manual) by summing all individual scores in each domain and then scaling the total as a percentage of the maximum possible score for a given domain according to the formula:


Evaluation of Strength of Recommendations

All guideline recommendations published by the AASLD are classified by a “grade” or “level” of recommendation. The “grade” or “level” designations are synonyms and provide an assessment of strength or certainty for a given recommendation. For the purposes of this study, the grade/level designation will be designated as “grade” hereafter.

Since 1998, the AASLD practice guideline development program has used three evidence classification systems to grade recommendations. These include (1) the Infectious Diseases Society of America's Quality Standards; (2) the American College of Cardiology / American Heart Association system; and (3) the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup system (Table 1).[36-39] Despite the use of three systems, these schemes are based on the same criteria and comparable structure. Therefore, for the purposes of this study, a composite grade system was created to represent all of the issued recommendations:

  1. Data derived from multiple randomized controlled trials, or meta-analysis, involving a number of participants to be of statistical power and where further research is unlikely to change the confidence in the estimate of clinical effect.
  2. Data derived from a single randomized trial or nonrandomized studies, cohort or case-control analytic studies, and multiple time series where further research may change confidence in the estimate of the clinical effect.
  3. Evidence based on clinical experience, descriptive studies, opinion of respected authorities where further research is very likely to impact confidence on the estimate of clinical effect.
Table 1. Historical Summary of Grades of Evidence and Classes of Recommendations Used by the AASLD
Grade of Evidence
I = Evidence from multiple well-designed randomized controlled trials, each involving a number of participants to be of sufficient statistical power
II = Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case-control analytic studies, or well-designed meta-analysis
III = Evidence based on clinical experience, descriptive studies or reports of expert committees
IV = Not rated
I = Randomized controlled trials
II-1 = Controlled trials without randomization
II-2 = Cohort or case-control analytic studies
II-3 = Multiple time series, dramatic uncontrolled experiments
III = Opinion of respected authorities, descriptive epidemiology
A = Data derived from multiple randomized clinical trials or meta-analysis
B = Data derived from a single randomized trial, or nonrandomized studies
C = Only consensus opinion of experts, case studies or standard-of-care
High (A) = Further research is unlikely to change confidence in the estimate of the clinical effect
Moderate (B) = Further research may change confidence in the estimate of the clinical effect.
Low (C) = Further research is very likely to impact confidence on the estimate of clinical effect.
Class of Recommendations
A = Survival benefit
B = Improved diagnosis
C = Improvement in quality of life
D = Relevant pathophysiologic parameters improved
E = Impacts cost of health care
I = Conditions for where there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful and effective
II = Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment
Ila = Weight of evidence/opinion is in favor of usefulness/efficacy
Ilb = Usefulness/efficacy is less well established by evidence/opinion
III = Conditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not useful/effective and in some cases may be harmful
Strong (1) = Factors influencing the strength of the recommendation included the quality of evidence, presumed patient-important outcomes, and cost
Weak (2) = Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, or higher cost or resource consumption

Evaluation of Types of Recommendations

Another aim of this study was to evaluate the evolution of the type of recommendations issued by the AASLD. Recommendations provided in AASLD practice guidelines can be classified into three types:

  • (1) Recommendations based on known features of a given liver disease which should prompt further evaluation (i.e.: “Wilson Disease must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder.”[33]).
  • (2) Recommendations on specific testing for a given liver disease (i.e.: “Liver biopsy is recommended to stage the degree of liver disease in C282Y homozygotes or compound heterozygotes if liver enzymes (ALT, AST) are elevated or if ferritin is >1000 μg/L.”[30]).
  • (3) Recommendations on specific treatment for a given liver disease (i.e.: “UDCA in a dose of 13-15 mg/kg/day orally is recommended for patients with PBC who have abnormal liver enzyme values regardless of histological stage.”[31]).

Thus, all recommendations for this analysis were classified into one of three categories: (1) Feature of Disease Recommendation; (2) Diagnostic Recommendation; or (3) Treatment Recommendation.

Evaluation of Benefit Versus Risk of Recommendations

As previously discussed, three different guideline classification systems have been used during the evolution of AASLD practice guidelines. Depending on the system used, certain guidelines provided information regarding benefit versus risk for a given recommendation. This information is different from the “grade” of recommendation and was designated as the “class” of recommendation. In the final part of this analysis, we evaluated the evolution of “class” recommendations provided in multiple versions of guidelines for a specific liver disease topic. However, unlike the grade systems assessing strength and certainty, the “class” systems used over time differed greatly and the development of a composite scoring system could not be created for comparative analysis. Therefore, the “class” analysis was only performed on guidelines that used the same scoring system.


Historical Guideline Summary

From January 1998 to August 1, 2012, the AASLD issued 28 clinical practice guidelines on 17 topics, yielding a total of 991 recommendations. When examining the initial publication for each AASLD guideline topic, a total of 512 recommendations were issued. The three guidelines with the greatest number of recommendations include Vascular Disorders of the Liver (64), Hepatitis C (HCV) (49), and the Diagnosis and Management of Nonalcoholic Fatty Liver Disease (NAFLD) (45). Of these 512 recommendations, 14% were grade I recommendations, 40% were grade II, and 46% were grade III (Table 2). Regarding the types of recommendations, 14% were Feature of Disease recommendations, 28% were Diagnostic Recommendations, and 58% were Treatment Recommendations (Supporting Table 1).

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