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In This Issue:
Alan Franciscus, Editor-in-Chief
HealthWise: Milk Thistle
Lucinda Porter, RN
HCV Drug Resistance
Disability & Benefits: Social Security and Blue Book Listings
Jacques Chambers, CLU
HCV Advocate Eblast
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—Alan Franciscus, Editor-in-Chief
The Institute of Medicine (IOM) recently released their report on a national strategy for the prevention and control of hepatitis B and C. Included in the recommendations was strong language – not only about the lack of response to hepatitis B and C, but more importantly about what needs to be put into place to provide comprehensive services to identify, diagnose, manage, treat and care for people affected by hepatitis B and C.
In 1970 the National Academy of Sciences established the Institute of Medicine to advise the government on issues related to medical care, research and education. The IOM created the Committee on the Prevention and Control of Viral Hepatitis Infections and populated it with experts from among the private and public health sectors including specialists in viral hepatitis. The IOM is a recognized think tank and adviser to the government in providing guidance for the prevention and control of various medical conditions and issues.
The report detailed many recommendations for the control and prevention of viral hepatitis in this country. This article will touch on some of the more important aspects and recommendations—more detailed information can be found in the entire IOM report that is about 200 pages long.1
Surveillance & Knowledge of HBV and HCV
The IOM report listed several measures that are currently lacking in the identification and surveillance of HCV and the poor knowledge and awareness base among health care and service providers, as well as the general public. The report noted that pertinent knowledge and awareness was lacking in people at risk for HBV and HCV. Recommendations included:
- Assessment of current surveillance techniques and development of better methods to identify acute and chronic HBV and HCV, based on the existing Centers for Disease Control and Prevention’s (CDC) Updated Guideline for Evaluating Public Health Surveillance Systems, and publishing the finding in a report. The CDC, in addition, should develop cooperative agreements with all state and territorial health departments to support surveillance of acute and chronic HBV and HCV. Included was a recommendation to capture information about HBV and HCV in populations that are not considered the ‘core’ population.
- The CDC should work with and develop, coordinate and evaluate outreach and educational programs that target at-risk populations and the general public to increase awareness and a better understanding of HBV and HCV.
Immunization – HBV
The report noted that, even with practice guidelines in place to test and vaccinate people at-risk for HBV, there are many missed opportunities. The IOM recommended that a delivery-room policy be put into place so that all full-term babies born to HBV-infected mothers receive the hepatitis B vaccine as soon as the babies are stable and washed. In addition, the IOM recommended that all states mandate complete or in-progress HBV vaccination of children as a requirement before attending school, and that efforts to vaccinate adults at-risk for HBV should be increased.
Viral Hepatitis Programs and Services
The lack of available services was duly noted by the IOM which issued these recommendations to establish and increase services at the federal, state and local levels. They include:
- Outreach and awareness to affected and general population
- Prevention of new or acute infections, including access to needle exchange and services, and immunization against HBV
- Testing of at-risk populations and diagnosis of people infected with hepatitis B and hepatitis C
- Development of systems for social and peer support
- Medical management of persons with chronic hepatitis B and hepatitis C
- Services should target high-risk viral hepatitis populations such as the foreign-born, people who inject drugs, pregnant women, jails and prisons, community health centers and other settings that serve populations that are at risk for hepatitis B and C.
These are sweeping recommendations that if implemented will greatly improve awareness, testing, immunization, disease management and treatment, as well as reduce the future disease burden of hepatitis B and C. Of course the big question is whether these recommendations will be implemented, especially considering the state of the economy. If we would only look to the future and see how much pain, suffering and money could be avoided by putting these strategies into place—it seems like such a “no-brainer”! But after all we are talking about a government that hasn’t taken any leadership role in hepatitis. What does the future look like for hepatitis B and C? Will these recommendations be implemented by the government? These are the big questions that remain to be answered.
Recommendations for Populations Considered
For foreign-born populations:
The CDC, in conjunction with other federal agencies and state agencies, should provide resources for the expansion of community-based programs that provide hepatitis B screening, testing, and vaccination services that target foreign-born populations.
For illicit-drug users:
Federal, state, and local agencies should expand programs to reduce the risk of hepatitis C virus infection through injection-drug use by providing comprehensive hepatitis C virus prevention programs. At a minimum, the programs should include access to sterile needle syringes and drug-preparation equipment because the shared use of these materials has been shown to lead to transmission of hepatitis C virus.
Federal and state governments should expand services to reduce the harm caused by chronic hepatitis B and hepatitis C. The services should include testing to detect infection, counseling to reduce alcohol use and secondary transmission, hepatitis B vaccination, and referral for or provision of medical management.
For pregnant women:
The CDC should provide additional resources and guidance to perinatal hepatitis B prevention program coordinators to expand and enhance the capacity to identify chronically infected pregnant women and provide case-management services, including referral for appropriate medical management.
For incarcerated populations:
The CDC and the Department of Justice should create an initiative to foster partnerships between health departments and corrections systems to ensure the availability of comprehensive viral hepatitis services for incarcerated people.
1Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Heather M. Colvin and Abigail E. Mitchell, Eds. Institute of Medicine of the National Academies. The National Academies Press, Washington, D.C. 2010
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HEALTHWISE: Milk Thistle
—Lucinda K. Porter, RN
People with chronic hepatitis C virus infection (HCV) who are interested in alternative medicine generally consider milk thistle (silybum marianum). This popular herb is a common ingredient in supplement blends that promote liver health. Researchers have investigated the efficacy of milk thistle and its components for a variety of conditions, including viral hepatitis, type II diabetes, cancer and toxin-removal from the liver.
Milk thistle (Silybum marianum) is a plant from the aster family. Silymarin is the active ingredient in milk thistle that is likely responsible for its medicinal qualities. Silymarin is actually a group of flavanoids, with silybin (aka silibinin) being the most powerful. Typically, milk thistle is sold in standardized amounts of 70 to 80% silymarin.
The February 2008 issue of Hepatology looked at milk thistle use among 1145 participants in the HALT-C study, sponsored by the National Institute of Diabetes and Digestive and Kidney Disease, headed by Leonard Seeff. In this HCV study, 44% of the subjects had used herbs at some point, with 23% using them at the time of enrollment. Among all participants, milk thistle was used by 33%, 17% upon enrollment. Although milk thistle users showed similar ALT levels and HCV viral loads to non-users, they showed fewer liver-related symptoms and improved quality of life. Researchers observed that this aspect of the study was uncontrolled and that milk thistle use was self-motivated. They concluded that “a well-designed prospective study can determine whether silymarin provides benefit to persons with chronic hepatitis C.”1
Continue reading before you run out and buy milk thistle. All milk thistle is not alike and what is in the bottle may not match what is promised on the label. In a startling report published by ConsumerLab.com (CL), only one of 10 products passed the necessary tests in order to carry the CL seal of approval.
CL is an independent organization that provides information and testing of nutritional products. They have been around for about ten years. Some information is free, but product reports are available only to subscribers. A one year subscription is $30 and worth every penny. www.consumerlab.com
What caught my attention about the milk thistle testing is that most supplements win CL’s approval. It’s a voluntary program, so presumably manufacturers feel confident enough to submit to testing. The failure of nine out of ten products is extraordinary. One can only imagine the quality of products that don’t agree to testing.
Two of the ten milk thistle products were disqualified for failure to meet the Food and Drug Administration’s (FDA) labeling requirements. Additionally, one of these products had different dosing information from jar to jar, all from the same lot number.
Seven of the remaining eight products did not provide the standardized amount of silymarin although they all claimed to have 80%. Actual amounts were between 47 and 67%. The only product to pass was Jarrow Formulas Milk Thistle. Although the amount of silymarin was not specified on the label, the manufacturer declared that the milk thistle extract contained 80% flavonoids. The actual testing confirmed that Jarrow Formulas Milk Thistle met the minimum industry standard of 70% silymarin.
The HCV Advocate and I do not endorse particular products or treatments. However, it seemed cruel to reveal that only one in ten milk thistle products passed muster without mentioning the name of the product. However, before you run out and buy milk thistle, there are other issues.
First, why didn’t the products pass? ConsumerLabs suggested it was likely due to substandard milk thistle extract, often purchased from Chinese suppliers. Unfortunately, since herbs are not strictly regulated by the FDA, it is virtually impossible to know what is safe and effective.
Second, what is the scientific evidence for or against milk thistle? Why take milk thistle? Is it because you read about it in an article? Did you hear about a study, and if so, what do you know about the research? Or did you wander into your local health food store and ask a sales clerk to recommend something good for the liver.
Third, without specific product information, do you know how much milk thistle to take, what kind, when to take it and when you shouldn’t? Do you know if it interacts with other medications you may be taking? Are there any side effects? Apply the same common sense investigation to dietary supplements as you would to any medicine.
When it comes to research on dietary supplements and liver disease, milk thistle tops the list. There were 222 milk thistle listings on the U.S. Library of Medicine’s PubMed site dating back to 1952. Although this sounds like a lot of research, compare this to 122,853 listings back to 1957 for interferon. Although research has yet to prove the benefits of milk thistle, it has also not disproved it. This is largely due to inadequate testing or poor scientific methods.
Here are highlights of some current research:
The December 2009 issue of Gastroenterology published a French study headed by Ahmed-Belkacem, “Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase.” They used a commercially available intravenous preparation of silibinin. This is an encouraging beginning to more research.
According to the U. S. Department of Health and Human Services’ Agency for Healthcare Research and Quality (AHRQ), there is evidence that milk thistle may protect the liver.2 However, the research is unreliable due to poor scientific method, so it’s difficult to sort out the facts.
A search of Germany’s independent, evidence-based Cochrane Library revealed similar observations. According to Rambaldi A, Jacobs BP, and Gluud C “[There is] no evidence supporting or refuting milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Low-quality trials suggested beneficial effects. High-quality randomized clinical trials on milk thistle versus placebo are needed.”3
Another problem is the test product. AHRQ’s website states, “The largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials.”
If the issue isn’t already complicated, consider this – taken as a supplement, milk thistle is poorly absorbed. After digestion, very little is left for the liver. This is particularly true for older adults. As little as 10% of silymarin may be absorbed in the adult over age 60.
In an article in September 2009 Alternative Medicine Review, biomedical research Parris Kidd, University of California, Berkeley, notes how milk thistle’s most active flavonoid, silybin is poorly absorbed by the body. Kidd states, “silybin-phosphatidylcholine complexed as a phytosome provides significant liver protection and enhanced bioavailability over conventional silymarin.”4 Twenty years ago, an Italian research team reached the same conclusion based on a pharmacokinetic study of nine subjects.5
It all boils down to this – ignoring the lack of scientific research, and choosing to take milk thistle, what product does one buy? Although the Jarrow supplement has been tested by CL, it was not used in clinical research. The one that has been used in research is the Madaus, but it is not available in the U.S. Silybin-phosphatidylcholine, used in various U.S. studies, is available. However, research grade silybin-phosphatidylcholine is not necessarily identical to consumer products.
Talk to your medical provider before taking milk thistle, particularly if you take other drugs or supplements. Milk thistle is usually well-tolerated. It may have a laxative effect along with other gastrointestinal side effects. Allergic reaction is always a possibility, no matter what you are taking. Theoretically, milk thistle could lower blood sugar levels, so use caution if taking blood sugar-lowering medications. Exacerbation of hemochromatosis has been associated with ingestion of milk thistle.
Milk thistle should not be used by pregnant or breast-feeding women. People with a history of hormone-related cancers, including breast and uterine cancer and prostate cancer, may need to avoid milk thistle.
Since milk thistle is metabolized by the liver, it may interact with other drugs. However, despite earlier warnings about this, evidence of this is flawed. One strategy is to take milk thistle alone rather than in combination with other drugs, particularly oral contraceptives and coumadin. Milk thistle has a short half-life (4 hours).
The following adult doses are from Natural Standard and are based on clinical research levels:
- Silymarin (Legalon®) 230-600 milligrams per day divided into two to three doses
- Silipide® (IdB 1016) 160-480 milligrams per day in silybin equivalents
The Bottom Line
- Talk to your medical provider before taking milk thistle.
- There is no evidence that milk thistle will eliminate HCV.
- Milk thistle may provide some benefit to the liver but research has not proved or disproved this.
- Milk thistle varies between manufacturers. Do your research before you purchase.
- Milk thistle is poorly absorbed by the body, so if you take it, choose a formulation and dose that is bioavailable.
- Alcohol extracts should be avoided by anyone with alcohol-related liver disease.
- Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Seeff LB, Curto TM, Szabo G, Everson GT, Bonkovsky HL, Dienstag JL, Shiffman ML, Lindsay KL, Lok AS, Di Bisceglie AM, Lee WM, Ghany MG. Hepatology. 2008 Feb;47(2):605-12.
- Agency for Healthcare Research and Quality. Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects. Evidence Report/Technology Assessment no. 21. Rockville, MD: Agency for Healthcare Research and Quality; 2000. 01-E024.
- Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Rambaldi A, Jacobs BP, Gluud C. Cochrane Database of Systematic Reviews 2007, Issue 4.
- A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Kidd P, Head K. Alternative Medicine Review. 2009 Sep;14(3):226-46.
- Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Barzaghi N, Crema F, Gatti G, Pifferi G, Perucca E. European Journal of Drug Metabolism and Pharmacokinetics. 1990 Oct-Dec;15(4):333-8.
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HCV Drug Resistance
A new approach to hepatitis C treatment – specifically targeted antiviral therapy for hepatitis C, or “STAT-C” – promises to improve the likelihood of achieving a cure for hard-to-treat patients. But these new therapies also come with a drawback: HCV can develop drug resistance, making them less effective.
HCV Replication and Mutation
There are two basic approaches to fighting HCV: strengthening the body’s immune response and attacking the virus directly. Interferon-based therapy uses a manufactured version of a natural cytokine to boost immune function. HCV does not develop resistance to interferon over time.
STAT-C drugs block specific steps of the viral lifecycle. For example, HCV protease inhibitors (such as telaprevir and boceprevir) interfere with an enzyme encoded by the NS3/4A gene that processes proteins before they can be assembled into new virions (virus particles). HCV polymerase inhibitors disrupt the action of another enzyme, encoded by the NS5B gene, that copies viral genetic material. (The HCV lifecycle and how drugs work is explained more fully in the December 2009 HCV Advocate.)
Drug resistance can develop when a virus mutates, or changes its genetic code. HCV replicates very rapidly – at an estimated rate of 1012 virions per day – and is prone to errors as it copies its genetic material. The genetic code of mutated HCV is essentially an altered blueprint. Viral proteins consist of a chain of building blocks called amino acids. When the altered blueprint is used to make new proteins and enzymes, the directions call for insertion of a wrong amino acid.
For example, the NS3 protease enzyme produced by mutated HCV might have the usual amino acid valine (V) replaced by alanine (A) at position 107 of the chain – designated V107A. (See chart below for list of amino acids letter codes.)
In many cases, proteins containing the wrong amino acids do not work properly. This can make mutant HCV less “fit” than wild-type (non-mutated) virus, so it stays at a very low level or dies out. But in other cases, a “wrong” amino acid turns out to be right for the virus, giving it an evolutionary advantage. In fact, this is how viruses manage to survive constant attack by the immune system.
Mechanisms of Resistance
One such advantage is drug resistance – mutations that allow the virus to keep replicating despite the presence of a drug. Amino acid substitutions in the HCV protease or polymerase enzyme can change the protein’s shape and interfere with a drug’s action. For example, a small structural change to the shallow binding pocket of the NS3 protease makes it difficult for a protease inhibitor to fit in and perform its intended function.
HCV polymerase inhibitors are of two types, nucleoside analogs – which act as defective building blocks when the virus tries to copy its genetic material – and non-nucleoside inhibitors, which work by other mechanisms. The HCV NS5B polymerase has at least five sites that are potential drug targets.
Ribavirin, which is used with pegylated interferon to help prevent HCV relapse, is also a nucleoside analog, but it has additional mechanisms of action, and resistance due to viral mutation has not been a concern in hepatitis C treatment.
The emergence of drug resistant mutations sometimes occurs randomly as HCV mutates to evade immune defenses, so an individual who has never been treated may harbor some strains, or quasispecies, that are naturally resistant (known as primary resistance). Most genetic screening studies have detected protease and polymerase resistance mutations at rates of <1% to 5% in previously untreated individuals. These variants are usually only a small minority of the total virus population, and so far they have not been linked to treatment failure – though some research does suggest reduced potency.
More often, resistance is due to continued viral replication and mutation in the presence of a drug. This can happen in two ways. A pre-existing naturally resistant minority variant can become the dominant strain if a drug knocks out the majority wild-type virus. Or, if a drug reduces but does not completely halt viral replication, wild-type HCV can evolve new mutations to evade the drug’s effects. Sometimes a mutation that allows the virus to escape the action of one drug will also make similar agents less effective, a phenomenon known as cross-resistance.
Experience treating hepatitis B and HIV led researchers to suspect that using single directly targeted anti-HCV agents – known as monotherapy – would likely promote resistance. As such, resistance testing is part of hepatitis C drug development from the earliest laboratory studies through the final clinical trials.
One or more amino acid substitutions that reduce antiviral potency have been identified for all the HCV protease and polymerase inhibitors currently in development. At the outset, STAT-C agents used as monotherapy may rapidly and dramatically decrease HCV RNA. But before long – days to months, depending on the specific agent – viral load may start to rise again (known as viral breakthrough), indicating that drug-resistant variants are gaining the upper hand.
But drug resistance does not necessarily lead to treatment failure. Even when a mutant virus is less susceptible, a drug still may be potent enough to keep replication under control. Sometimes multiple mutations must coexist to cause a notable decrease in effectiveness. And because HCV treatment is relatively short – typically 24-48 weeks – it does not present the risk of long-term resistance after taking a drug for years (as with hepatitis B) or even for life (as with HIV).
In the November 10, 2009 advance online edition of the Journal of Viral Hepatitis, A.J.V. Thompson and J.G. McHutchison presented an overview of HCV drug resistance, including data from laboratory studies and clinical trials.
Because HCV is difficult to grow in vitro, most laboratory studies use models called replicons that may not respond to drugs exactly like whole virus in the body. Genotypic tests, which examine viral gene sequences for substitutions known to confer resistance, do not always reflect what happens when HCV variants are exposed to drugs in the laboratory (phenotypic testing), which in turn may not predict clinical outcomes in patients.
Nevertheless, some clear patterns have emerged. As noted, the structure of the NS3 protease allows HCV to easily evade protease inhibitors, especially with mutations at positions 155 and 156. For HCV genotype 1, the A156S/T/V and R155K/Q/T substitutions confer resistance to telaprevir, boceprevir, and RG7227 (ITMN-191), especially when additional mutations including V36M and T54A are also present. Other mutations confer resistance primarily to specific drugs, for example V170A for boceprevir and D168V/A for RG7227.
Current polymerase inhibitor candidates produce smaller viral load decreases than protease inhibitors, but they also promote less resistance. Nucleoside analogs such as RG7128 appear to have a particularly high barrier to resistance. Among the non-nucleosides, most agents target only one binding site, and there appears to be no cross-resistance – and perhaps even synergy – between drugs targeting different sites.
To date, no mutations have been found to confer resistance to both protease and polymerase inhibitors, though researchers have produced replicons that simultaneously carry separate protease and polymerase mutations. Fortunately, HCV with protease and/or polymerase resistant mutations appears to remain as responsive as wild-type virus to standard therapy with pegylated interferon plus ribavirin.
Preventing and Overcoming Resistance
The surest way to prevent drug resistance is by completely halting viral replication, or even better, eradicating HCV altogether. With current drugs, however, many people continue to have some level of ongoing viral replication.
Another way to overcome resistance is combination therapy. In order to evade the action of multiple drugs, HCV would have to develop simultaneous mutations, which typically reduces viral fitness in other ways.
Learning from the setbacks of hepatitis B and HIV treatment, researchers understand the benefits of using STAT-C agents in combination regimens from the outset, rather than adding additional drugs after resistance develops. Given how quickly resistance can emerge, the U.S. Food and Drug Administration now limits clinical trials of direct antiviral agents to three days of monotherapy.
Several studies have demonstrated that combining HCV protease inhibitors with pegylated interferon/ribavirin delays the emergence of resistance. In the PROVE trials, however, about 25% of participants who took telaprevir plus pegylated interferon without ribavirin developed resistance. Some trials start with a pegylated interferon/ribavirin “lead-in” period to drive down viral load before adding the direct antiviral agent.
Researchers are exploring combinations of STAT-C agents that work by different mechanisms in the hope of one day eliminating pegylated interferon/ribavirin. In the first such clinical trial (INFORM-1), presented last fall at the 2009 annual meeting of the American Association for the Study of Liver Diseases (AASLD), S. Le Pogam and colleagues showed that over 14 days, the protease inhibitor RG7227 plus the polymerase inhibitor RG7128 produced potent antiviral activity. Viral load declined by as much as 5 logs and no resistant mutations were detected, even in one patient in a low-dose arm who experienced viral breakthrough.
Using another novel approach, L. Delang and colleagues recently demonstrated that adding statin drugs (usually used to manage high cholesterol) to HCV protease and polymerase inhibitors enhanced antiviral activity and reduced emergence of resistant mutations.
In the coming years, hepatitis C therapy is likely to increasingly resemble HIV treatment, using complementary oral drugs that target different steps of the viral lifecycle. As such, it will draw on lessons from that field, such as the importance of good adherence, frequent viral load monitoring, and resistance testing to guide selection of the drugs most likely to be effective.
For more information see:
L. Delang et al. Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. Hepatology 50(1): 6-16. July 2009.
S. Gaudieri et al. Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology 49(4): 1069-1082. April 2009.
T. Kuntzen et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology 48(6): 1769-1778. December 2008.
S. Le Pogam et al. Combination therapy with nucleoside polymerase R7128 and protease R7227/ITMN-191 inhibitors in genotype 1 HCV infected patients: interim resistance analysis of INFORM-1 cohorts A-D. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston. October 30-November 1, 2009. Abstract 1585.
M.F. McCown et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrobial Agents & Chemotherapy 52(5): 1604-1612. May 2008.
A.J.V. Thompson and J.G. McHutchison. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). Journal of Viral Hepatitis 16(6): 377-387. November 10, 2009 [Epub ahead of print].
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Disability & Benefits: Social Security and Blue Book Listings
—Jacques Chambers, CLU
Social Security uses Disability Analysts who are neither doctors nor nurses to determine whether or not a person applying for disability meets their definition of disability which is:
(1) Due to a medical condition he/she is unable to perform the tasks of a job for which he/she is suited, AND (2) That condition either has or will last for at least twelve months or is expected to result in death.
To facilitate the process for Analysts and to maintain some uniformity throughout the country, Social Security publishes a book called, Disability Evaluation Under Social Security, or “The Blue Book” which includes a Listing of Impairments. If your medical condition is listed in that Listing of Impairments, and it meets the criteria given, then your claim is routinely approved.
The Listing for Chronic Liver Disease has been updated and revised. The new listing is given below, along with where to find it on the Internet:
5.05 Chronic liver disease, with:
A. Hemorrhaging from esophageal, gastric, or ectopic varices or from portal hypertensive gastropathy, demonstrated by endoscopy, x-ray, or other appropriate medically acceptable imaging, resulting in hemodynamic instability as defined in 5.00D5, and requiring hospitalization for transfusion of at least 2 units of blood. Consider under disability for 1 year following the last documented transfusion; thereafter, evaluate the residual impairment(s).
B. Ascites or hydrothorax not attributable to other causes, despite continuing treatment as prescribed, present on at least 2 evaluations at least 60 days apart within a consecutive 6-month period. Each evaluation must be documented by:
1. Paracentesis or thoracentesis; or
2. Appropriate medically acceptable imaging or physical examination and one of the following:
a. Serum albumin of 3.0 g/dL or less; or
b. International Normalized Ratio (INR) of at least 1.5.
C. Spontaneous bacterial peritonitis with peritoneal fluid containing an absolute neutrophil count of at least 250 cells/mm.3
D. Hepatorenal syndrome as described in 5.00D8, with one of the following:
1. Serum creatinine elevation of at least 2 mg/dL; or
2. Oliguria with 24-hour urine output less than 500 mL; or
3. Sodium retention with urine sodium less than 10 mEq per liter.
E. Hepatopulmonary syndrome as described in 5.00D9, with:
1. Arterial oxygenation (PaO2) on room air of:
a. 60 mm Hg or less, at test sites less than 3000 feet above sea level, or
b. 55 mm Hg or less, at test sites from 3000 to 6000 feet, or
c. 50 mm Hg or less, at test sites above 6000 feet; or
2. Documentation of intrapulmonary arteriovenous shunting by contrast-enhanced echocardiography or macroaggregated albumin lung perfusion scan.
F. Hepatic encephalopathy as described in 5.00D10, with 1 and either 2 or 3:
1. Documentation of abnormal behavior, cognitive dysfunction, changes in mental status, or altered state of consciousness (for example, confusion, delirium, stupor, or coma), present on at least two evaluations at least 60 days apart within a consecutive 6-month period; and
2. History of transjugular intrahepatic portosystemic shunt (TIPS) or any surgical portosystemic shunt; or
3. One of the following occurring on at least two evaluations at least 60 days apart within the same consecutive 6-month period as in F1:
a. Asterixis or other fluctuating physical neurological abnormalities; or
b. Electroencephalogram (EEG) demonstrating triphasic slow wave activity; or
c. Serum albumin of 3.0 g/dL or less; or
d. International Normalized Ratio (INR) of 1.5 or greater.
G. End stage liver disease with SSA CLD scores of 22 or greater calculated as described in 5.00D11. Consider under a disability from at least the date of the first score.
At the beginning of the listing for 5.00 Digestive System, the Blue Book elaborates on how they evaluate the various conditions. Section 5.00 (D) deals with chronic liver infection. The portions most applicable to HBV and HCV are reprinted below:
D. How do we evaluate chronic liver disease?
1. General. Chronic liver disease is characterized by liver cell necrosis, inflammation, or scarring (fibrosis or cirrhosis), due to any cause, that persists for more than 6 months. Chronic liver disease may result in portal hypertension, cholestasis (suppression of bile flow), extrahepatic manifestations, or liver cancer. (We evaluate liver cancer under 13.19.) Significant loss of liver function may be manifested by hemorrhage from varices or portal hypertensive gastropathy, ascites (accumulation of fluid in the abdominal cavity), hydrothorax (ascitic fluid in the chest cavity), or encephalopathy. There can also be progressive deterioration of laboratory findings that are indicative of liver dysfunction. Liver transplantation is the only definitive cure for end stage liver disease (ESLD).
3. Manifestations of chronic liver disease.
a. Symptoms may include, but are not limited to, pruritus (itching), fatigue, nausea, loss of appetite, or sleep disturbances. Symptoms of chronic liver disease may have a poor correlation with the severity of liver disease and functional ability.
b. Signs may include, but are not limited to, jaundice, enlargement of the liver and spleen, ascites, peripheral edema, and altered mental status.
c. Laboratory findings may include, but are not limited to, increased liver enzymes, increased serum total bilirubin, increased ammonia levels, decreased serum albumin, and abnormal coagulation studies, such as increased International Normalized Ratio (INR) or decreased platelet counts. Abnormally low serum albumin or elevated INR levels indicate loss of synthetic liver function, with increased likelihood of cirrhosis and associated complications. However, other abnormal lab tests, such as liver enzymes, serum total bilirubin, or ammonia levels, may have a poor correlation with the severity of liver disease and functional ability. A liver biopsy may demonstrate the degree of liver cell necrosis, inflammation, fibrosis, and cirrhosis. If you have had a liver biopsy, we will make every reasonable effort to obtain the results; however, we will not purchase a liver biopsy. Imaging studies (CAT scan, ultrasound, MRI) may show the size and consistency (fatty liver, scarring) of the liver and document ascites (see 5.00D6).
4. Chronic viral hepatitis infections.
(i) Chronic viral hepatitis infections are commonly caused by hepatitis C virus (HCV), and to a lesser extent, hepatitis B virus (HBV). Usually, these are slowly progressive disorders that persist over many years during which the symptoms and signs are typically nonspecific, intermittent, and mild (for example, fatigue, difficulty with concentration, or right upper quadrant pain). Laboratory findings (liver enzymes, imaging studies, liver biopsy pathology) and complications are generally similar in HCV and HBV. The spectrum of these chronic viral hepatitis infections ranges widely and includes an asymptomatic state; insidious disease with mild to moderate symptoms associated with fluctuating liver tests; extrahepatic manifestations; cirrhosis, both compensated and decompensated; ESLD with the need for liver transplantation; and liver cancer. Treatment for chronic viral hepatitis infections varies considerably based on medication tolerance, treatment response, adverse effects of treatment, and duration of the treatment. Comorbid disorders, such as HIV infection, may affect the clinical course of viral hepatitis infection(s) or may alter the response to medical treatment.
(ii) We evaluate all types of chronic viral hepatitis infections under 5.05 or any listing in an affected body system(s). If your impairment(s) does not meet or medically equal a listing, we will consider the effects of your hepatitis when we assess your residual functional capacity.
b. Chronic hepatitis B virus (HBV) infection.
(i) Chronic HBV infection is diagnosed by the detection of hepatitis B surface antigen (HBsAg) in the blood for at least 6 months. In addition, detection of the hepatitis B envelope antigen (HBeAg) suggests an increased likelihood of progression to cirrhosis and ESLD.
(ii) The therapeutic goal of treatment is to suppress HBV replication and thereby prevent progression to cirrhosis and ESLD. Treatment usually includes a combination of interferon injections and oral antiviral agents. Common adverse effects of treatment are the same as noted in 5.00D4c(ii) for HCV, and generally end within a few days after treatment is discontinued.
c. Chronic hepatitis C virus (HCV) infection.
(i) Chronic HCV infection is diagnosed by the detection of hepatitis C viral RNA in the blood for at least 6 months. Documentation of the therapeutic response to treatment is also monitored by the quantitative assay of serum HCV RNA (“HCV viral load”). Treatment usually includes a combination of interferon injections and oral ribavirin; whether a therapeutic response has occurred is usually assessed after 12 weeks of treatment by checking the HCV viral load. If there has been a substantial reduction in HCV viral load (also known as early viral response, or EVR), this reduction is predictive of sustained viral response with completion of treatment. Combined therapy is commonly discontinued after 12 weeks when there is no early viral response, since in that circumstance there is little chance of obtaining a sustained viral response (SVR). Otherwise, treatment is usually continued for a total of 48 weeks.
(ii) Combined interferon and ribavirin treatment may have significant adverse effects that may require dosing reduction, planned interruption of treatment, or discontinuation of treatment. Adverse effects may include: Anemia (ribavirin‑induced hemolysis), neutropenia, thrombocytopenia, fever, cough, fatigue, myalgia, arthralgia, nausea, loss of appetite, pruritus, and insomnia. Behavioral side effects may also occur. Influenza‑like symptoms are generally worse in the first 4 to 6 hours after each interferon injection and during the first weeks of treatment. Adverse effects generally end within a few days after treatment is discontinued.
6. Ascites or hydrothorax (5.05B) indicates significant loss of liver function due to chronic liver disease. We evaluate ascites or hydrothorax that is not attributable to other causes under 5.05B. The required findings must be present on at least two evaluations at least 60 days apart within a consecutive 6-month period and despite continuing treatment as prescribed.
Before filing for Social Security Disability, you should review these listings to see if you meet one of them and, if so, the proper documentation is included in your medical record.
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