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100 Questions & Answers About Hepatitis C:
A Lahey Clinic Guide
Stephen C. Fabry, MD
Senior Staff Physician Gastroenterology and Hepatology Lahey Clinic Medical Center Assistant Professor of Medicine Tufts University School of Medicine
R. Anand Narasimhan, MD
Senior Fellow in Gastroenterology Lahey Clinic Medical Center Clinical Instructor of Medicine Tufts University School of Medicine
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Library of Congress Cataloging-in-Publication Data Fabry, Stephen.
100 questions and answers about hepatitis C : a Lahey Clinic guide / Stephen Fabry and R. Anand Narasimhan ; series editor, Andrew S. Warner. p. cm. Includes bibliographical references and index. ISBN-13: 978-0-7637-4077-1 ISBN-10: 0-7637-4077-2
1. Hepatitis C—Miscellanea. 2. Hepatitis C—Popular works. I. Narasimhan, R. Anand. II. Title. III.
Title: One hundred questions and answers about hepatitis C. RC848.H425F33 2006
Printed in the United States of America
09 08
07 06
This book is dedicated to our families.
Part 1: The Basics
Questions 1–8 provide background information for understanding hepatitis C, including:
• Can you give me an overview of the liver and liver disease?
• What is hepatitis C?
• Who should be screened for hepatitis C?
Part 2: Transmission
Questions 9–17 address concerns about how hepatitis is transmitted and prevention, including:
• What are the most common risk factors for hepatitis C?
• How can I prevent transmission of hepatitis C to other people?
• Can hepatitis C be spread through sexual contact
Part 3: Natural History and Symptoms
Questions 18–24 discuss symptoms and other factors associated with hepatitis C, including:
• What is the natural history of hepatitis C?
• What are the signs and symptoms of hepatitis C infection?
• Can the liver worsen while someone feels well?
Part 4: Testing and Evaluation
Questions 25–36 cover available tests and methods for evaluation, including:
• Can you give me an overview of testing and evaluation?
• What is a hepatitis C antibody test?
• What is a direct test for hepatitis C virus?
Part 5: Treatment
Questions 37–50 explore treatment options and choices, including:
• Can you give me an overview of treatment?
• Can hepatitis C be cured, and how is "cure" defined?
• What are the potential benefits of undergoing treatment for hepatitis C?
Part 6: Treatment Side Effects
Questions 51–62 address common side effects associated with treatment, including:
• Are there any treatment side effects?
• What are the side effects of interferon therapy?
• What are the side effects of ribavirin therapy?
Part 7: Special Situations
Questions 63–68 help patients cope with special situations, including:
• What if I have a new case of acute hepatitis C infection?
• Is acute hepatitis C treated differently?
• What if I have mild kidney disease or even kidney failure?
Part 8: Complementary and Alternative Medicine Options
Questions 69–79 explore the role of complementary and alternative medicine options, including:
• What is the role of complementary and alternative medicine options in hepatitis C?
• What can you tell me about milk thistle?
• What can you tell me about licorice root?
Part 9: Cirrhosis
Questions 80–85 provide answers about cirrhosis as it relates to hepatitis C, including:
• What is cirrhosis?
• How is cirrhosis diagnosed?
• What are the signs and symptoms of cirrhosis?
Part 10: Liver Cancer
Questions 86–91 answer common questions about liver cancer, including:
• Can you give me an overview of liver cancer and hepatitis C?
• What are the signs and symptoms of liver cancer?
• Who should be screened for liver cancer and how?
Part 11: Liver Transplantation
Questions 92–98 cover the risks, recurrence, and treatment before and after a liver transplant, including:
• Can you give me an overview of liver transplantation for hepatitis C?
• How are patients ordered on the transplant list, and what is the MELD score?
• What are the risks of surgery, and what is the difference between deceased donor and living donor liver transplantation?
Part 12: The Future
Questions 99 and 100 offer a candid account of the current rate of cure and reasons for tremendous optimism for the future, including:
• Are there any new treatment options for hepatitis C?
• What should I expect in the future?
Hepatitis C is a significant and growing problem in the United States and throughout the world. At least 4 million people in the United States have been exposed to this virus, and the majority of these people have a chronic infection. A small but significant percentage of patients with chronic hepatitis C will develop cirrhosis; unfortunately, many of these individuals will eventually die of liver failure and liver cancer. Today, hepatitis C is the most common indication for liver transplantation in many transplant centers. Doctors have become increasingly conscientious about screening for hepatitis C in patients with known risk factors for this disease. This effort has led to a huge increase in the number of diagnosed cases, although many patients with hepatitis C remain unaware of their condition. Treatment options have improved significantly over the last decade, with the overall cure rate now exceeding 50 percent. Neverthe- less, the management of patients with hepatitis C is complex and requires many complicated decisions to be made. Doctors realize that each and every patient has a unique medical and personal situation that requires careful decision- making. The care of patients with hepatitis C is clearly better when patients take an active role in this decision-making process.
We wrote this book for patients who are interested in becoming involved in this process. We are busy clinicians so we based this book, not only on the medical literature, but also on our personal experiences with patients. Over the years, we have been impressed with the amount of research that some patients pursue on their own. When we were first asked to write this book, we reviewed many other published books and found that those books did not provide the directed and in- depth medical information that is available in our book. Many of these other books were very general and discussed several different types of liver disease. Some focused primarily on the emotional aspects of hepatitis C, with few pages being devoted to discussing the medical facts. We have attempted to write a book that will allow patients to quickly find and understand the answer to any question they have about hepatitis C. We have filled the book with hard medical facts and references to major studies, but have filtered the information to make it more understandable. We have also addressed some of the emotional aspects of this disease and highlighted some alternative therapies. We are confident that this book will help patients better understand hepatitis C and make more informed medical decisions.
Stephen C. Fabry, MD R. Anand Narasimhan, MD
Hepatitis C is a devastating condition both physically and psychologically. It typically infects individuals without producing any symptoms and then silently damages the liver over many years, sometimes being discovered only after it has resulted in cirrhosis. Depending on the genotype, hepatitis C can be poorly responsive to therapy, and all of the currently available therapies have significant side effects and toxicity.
It is important for patients who are diagnosed with hepatitis C to have access to clear information regarding their condition. It is often difficult for patients to know which questions to ask or where to turn to have those questions answered accurately.
In this new book, Dr. Stephen Fabry and Dr. R. Anand Narasimhan, respected hepatologists with extensive experience in treating hepatitis C, provide patients with a place to turn. They have done a remarkably thorough job of anticipating questions that patients diagnosed with hepatitis C should want to have answered and have answered each of those questions in a clear and concise fashion. This book is essential reading for patients with hepatitis C who are seeking help in understanding their condition.
Daniel S. Pratt, MD Executive Director, Liver-Biliary-Pancreas Center Massachusetts General Hospital Harvard Medical School
The Basics
Can you give me an overview of the liver and liver disease?
What is hepatitis C?
Who should be screened for hepatitis C?
1. Can you give me an overview of the liver and liver disease?
The liver is an amazing and vital organ. The largest organ in the body, it is located on the right side of the abdomen underneath the rib cage (Figure 1). The average person's liver weighs between three and five pounds. Everyone is born with only one liver, so it is important to keep it functioning well. The liver per- forms many essential functions that are necessary for life. These functions include removing poisons and
Figure 1
Location of the Liver
drugs from the body, manufacturing many different types of proteins, storing energy, fighting infections, storing iron reserves, storing minerals and vitamins, and producing bile to help digest food.
The liver processes almost all foods, drugs, and toxins that enter the body into either safer or more usable substances. It produces many proteins, including clot- ting factors, albumin (which accounts for most of the protein in blood), and a variety of proteins that are used as transporters and receptors throughout the body. The liver serves as a major site of energy storage that can be tapped by other parts of the body when necessary.
Liver disease is very common in the United States. Approximately 25,000,000 Americans have a liver- related disorder, including 3.9 million people with hepatitis C. About 27,000 Americans die each year from chronic liver diseases, including as many as 10,000 people with hepatitis C. An estimated 26,000 new infections with hepatitis C and an estimated 60,000 new infections with hepatitis B occur each year.
To keep your liver healthy, you can take several simple steps. Be aware that alcohol can injure the liver either on its own or in combination with a liver disease such as hepatitis C. Because many medicines can affect the liver, it is important to monitor the liver when you are taking certain medications. This monitoring usually consists of blood tests, but occasionally a liver biopsy is necessary. You should also inform your doctor of any preexisting liver problems before you begin taking a new medicine. Chemicals, fatty foods, and obesity can also harm the liver.
greenish fluid pro- duced by the liver that contains biliru- bin, bile salts, choles- terol, and lipids. Bile flows through the bile ducts into the intestines, where it helps digest food.
by the liver that accounts for most of the protein in blood.
small needle is passed into the liver and a piece of the
liver is removed and then examined under
a microscope.
a preparation of a specific weakened or killed virus or bac- terium that is injected into the body to stimulate the immune system.
The liver per- forms many essential func- tions that are necessary for life. These functions include removing poi- sons and drugs from the body,
ing many dif- ferent types of proteins, stor- ing energy, fighting infec- tions, storing iron reserves, storing miner- als and vita- mins, and producing bile to help digest
Risks for contracting hepatitis A, hepatitis B, and hep- atitis C are discussed later in this book. Many people should be vaccinated against hepatitis A and hepatitis B, but no vaccine against hepatitis C is available right now.
Unfortunately, many liver diseases, including hepatitis C, often have no symptoms and can be difficult to diagnose. There are, however, certain signs and symp- toms that you can watch for—yellow eyes or skin, per- sistently dark urine, light-colored stools, swelling in the abdomen or legs, confusion, bleeding, itching, and fatigue. These problems are usually a marker of more serious liver dysfunction and possibly liver failure.
2. What is hepatitis C?
Hepatitis C is a virus that can cause inflammation and scarring in the liver and lead to liver failure and liver cancer. These complications do not develop in every- one who has hepatitis C. This virus can also affect other parts of the body such as the kidneys and nerves, although complications outside of the liver are very uncommon. Hepatitis C is a relatively new infection in humans. In fact, the growth of the U.S. hepatitis C virus (HCV)–infected population is believed to have begun around 1960. The pattern of spread has been different in other countries. For example, hepatitis C probably spread several decades earlier in Japan than it did in the United States.
The most common routes of transmission are blood transfusions and intravenous drug use. Today, signifi- cantly fewer new cases of hepatitis C occur from blood transfusions because blood products are effec-
tively screened for this virus. Instead, most new cases are related to intravenous drug use and the sharing of needles.
Hepatitis C is a single-stranded ribonucleic acid (RNA) virus that belongs to the family Flaviviridae and the genus hepacivirus. The virus has three basic parts: the RNA genome or code, a nucleocapsid core protein, and an outer surface protein complex (Figure 2). Hepatitis C is very good at evading the immune system because it mutates rapidly and the envelope protein can change and fool the body's defense mech- anisms. Many different strains of hepatitis C exist.
HCV Viral Components
(E1 and E2)
protein complex
a material inside cells that contains the genetic code for each specific individual. In humans, RNA copies carry the information from DNA out of the cell's nucleus. In the HCV, RNA is the pri- mary code needed for its replication.
Courtesy of the National Digestive Diseases Information Clearinghouse.
a major strain of a virus. Because the hepatitis C virus is continually changing or mutating, six major strains of this virus exist.
Hepatitis C is a virus that can cause inflammation and scarring in the liver and lead to liver failure and liver can- cer.
The virus can be classified into 6 major genotypes and more than 50 subtypes. Genotypes tend to vary geo- graphically; in the United States, the most common genotypes are 1a and 1b. The specific genotype does not significantly alter the severity of disease, but it does affect the likelihood that an infected person will respond to treatment.
3. Who should be screened for hepatitis C?
The medical community has established general guidelines for the screening of diseases. Screening the entire population who might be at risk for a specific disease may be useful for diseases that occur frequently, such as hypertension or colon cancer. Other factors that need to be considered include the ease of the screening test, the cost of the test, the accuracy of the test, and the usefulness of the information gathered. For example, colon cancer screening is recommended for all people over the age of 50 because colon cancer is common, the screening test is relatively safe and accu- rate, and the identification and removal of polyps decrease the risk of colon cancer.
Screening of the entire population for hepatitis C is currently not recommended, for several reasons. Most patients with hepatitis C have an identifiable risk fac- tor; thus screening of low-risk patients would identify very few people with hepatitis C. Screening tests are not perfect and are more accurate when applied to a population at risk for developing the specific disease. Screening low-risk patients for hepatitis C would result in many "false positive" test results—that is, the
test is positive but the patient does not really have hepatitis C. Even though hepatitis C tests are rela- tively inexpensive, screening the entire population would be prohibitively expensive in terms of the cost per newly identified infection. Current guidelines therefore recommend screening only individuals with an identifiable risk factor.
We can identify people who have a higher risk for acquiring hepatitis C and in whom testing may be more useful. The recommendations for testing include the following groups:
• People with a history of intravenous drug use at any time in their life.
• People who received a blood transfusion, blood products, or an organ transplant before July 1992. (Screening of donated blood for hepatitis C began after this date.)
• Patients with hemophilia who received clotting fac- tors before 1987. (Processing of clotting factors to inactivate viruses began in 1987.)
• Patients with human immunodeficiency virus (HIV) infection.
• Patients with kidney failure on hemodialysis. (Con- taminated hemodialysis equipment can place dialy- sis patients at a high risk for acquiring hepatitis C.)
• Patients with abnormal liver tests.
• Children born to mothers with hepatitis C.
• Anyone who is exposed to hepatitis C–infected blood, such as a healthcare worker after a needlestick injury.
• Sexual partners of patients with hepatitis C.
• Household contacts of patients with hepatitis C.
• All blood donors. (They are screened for hepatitis C to protect the blood supply.)
Anyone with any of these risk factors should ask for a hepatitis C test given the high risk of infection.
a major surgical pro-
cedure that involves the removal of a dis- eased liver and its replacement with a healthy liver.
Currently, hepatitis C accounts for about 10,000 deaths per year in the United States.
4. How many people have hepatitis C?
Hepatitis C is a very common infection both in the
United States and throughout the world. An estimated 170 million people worldwide are infected with this virus. In the United States, almost 4 million people have a positive antibody test. Most of these people
have chronic hepatitis C and are at risk for developing cirrhosis and subsequent liver failure and liver cancer. Currently, hepatitis C accounts for about 10,000 deaths per year in the United States. This number is expected to increase in the next two decades due to the epidemiology and natural history of this infection. A large number of new infections occurred in the 1960s,
1970s, and 1980s. The peak disease burden from hepa- titis C is still ahead of us because progression to cir- rhosis can take 20 to 40 years.
Another way to look at the numbers is by noting that hepatitis C accounts for 15 percent of cases of acute hepatitis, 60 to 70 percent of cases of chronic hepatitis, and 50 percent of cases of cirrhosis, liver failure, and liver cancer. Roughly half of all liver transplants in the United States now involve patients with hepatitis C. This virus is so common that you probably know at least one other person who is infected with it.
5. What can hepatitis C do?
Although hepatitis C can have many effects, it prima- rily attacks the liver. Most people who are exposed to the virus develop a chronic infection. Many people with chronic hepatitis C develop inflammation in the liver, which can in turn lead to scarring. Severe scar- ring of the liver, which is called cirrhosis, can lead to liver failure and liver cancer. Fortunately, this progres- sion happens in only about 20 percent of patients with chronic infection. This risk is significantly higher in people who consume excessive amounts of alcohol. Another important point is that patients with cirrhosis do not immediately or even necessarily develop liver failure or liver cancer. Many patients with cirrhosis have an early-stage condition called compensated cir- rhosis, in which the liver still functions well and the person can lead a normal life. Patients with HCV- related cirrhosis have a 3 to 4 percent annual risk of developing liver failure and a 1.4 to 6.9 percent annual risk of developing liver cancer. Many of these patients are eligible for liver transplantation. Hepatitis C occa- sionally leads to problems outside of the liver, includ- ing cryoglobulinemia, glomerulonephritis, and porphyria cutanea tarda (Table 1).
6. Why is hepatitis C so difficult to treat?
Hepatitis C is a particularly difficult infection to treat, although treatments are available and have improved significantly in the last 15 years since the virus was dis- covered. Treatment limitations are related to both the characteristics of HCV and the medications that are
cation of hepatitis C,
in which antibodies
attack parts of the body and result in skin rashes, joint and muscle pains, and nerve and kidney
each kidney is made up of tiny structures called glomeruli that produce urine. In this type of kidney dis- ease, the glomeruli are inflamed.
a blistering skin dis-
ease that affects sun- exposed areas of the body due to an enzyme deficiency in the liver. It may be precipitated by hepa- titis C infection, iron overload, and alcohol
Table 1
Complications of Hepatitis C
Cirrhosis of the liver Liver cancer Cryoglobulinemia Glomerulonephritis Porphyria cutanea tarda
used to treat the infection. Thanks to research that is providing more information about the virus and new treatment options, we are entering an exciting time in terms of hepatitis C treatment.
Hepatitis C is particularly difficult to treat because the virus changes—that is, mutates—at an incredible rate. As mentioned earlier, there are six major HCV geno- types and many different subtypes. Its constant muta- tions allow the virus to evade the human immune system and establish itself as a chronic infection. These changes also allow the virus to resist therapy in many patients who receive the currently available treatments.
Current treatment options are nonspecific and affect the immune system in a generalized fashion that pro- duces many side effects. As a consequence, hepatitis C is hard to treat because many patients cannot safely take medications or have to stop treatment once side effects develop. Newer treatment options that directly target HCV and cause fewer side effects are under development and should become available within the next 5 years.
7. What should I do now that my doctor says I have hepatitis C?
There are a few things to do when given the diagnosis of hepatitis C. First—and most obviously—do not panic. Panic clouds judgment and can lead to poor deci- sion making. A diagnosis of hepatitis C is not a death sentence. Many patients will never develop severe liver disease, treatments are available, and liver transplanta- tion is an option in severe cases. However, you have just been given a serious medical diagnosis and you have a lot of things to do. Educating yourself is an important step, and reading this book should provide all of the information you need to have productive visits with your doctors. If you are looking for more information, the Internet is another source of almost limitless infor- mation. Of course, it is important to approach Internet sites carefully, because many sites have multiple agen- das. Government-sponsored sites tend to be unbiased, and many medical groups and organizations also have excellent sites. The "Resources" section at the back of this book lists a variety of useful websites.
Several lifestyle modifications can help patients with hepatitis C. The first and most important step to take is to avoid alcohol. You should also monitor all medications used (including over-the-counter [OTC] medicines), maintain a healthy weight, exercise, and eat a healthy diet.
Your doctor will next refer you to a specialist who has more training and experience in dealing with HCV- infected patients. This specialist will be a very impor- tant person in your life, so he or she should be someone whom you trust and feel comfortable with.
8. Can you tell me more about lifestyle modifications?
Lifestyle modifications are important for a person's general health in addition to helping with any chronic illness including hepatitis C. A specific question addresses the role of alcohol abstinence more directly, so here we will only say that avoiding alcohol is clearly the most important lifestyle modification that a HCV- infected person can make. You should also completely avoid recreational drugs. This question focuses on diet, exercise, weight control, medications, transmission, and support groups. Some of these issues are also addressed in other parts of the book.
Diet and exercise are increasingly recognized as impor- tant components of the management of many diseases and should be part of the overall approach a person takes to deal with hepatitis C. The benefits of diet and exercise are indirect, however, in terms of their effects on HCV. A healthy lifestyle will make you feel stronger, decrease your fatigue and depression, and help you tolerate the side effects of treatment better.
You should eat a normal, healthy, balanced diet. Recent guidelines recommend increasing your consumption of fresh fruits and vegetables, whole grains, and leaner meats and fish and minimizing your intake of processed foods, fats, and low-value carbohydrates.
Regular exercise can improve your physical and emo- tional condition by reducing stress, decreasing fatigue, and improving the function of the heart and
lungs. It may even improve the function of your immune system.
Diet and exercise will also help control any weight problems that you may have. Obesity is increasingly recognized as an independent risk factor for liver dis- ease and as an issue in patients with hepatitis C. Non- alcoholic fatty liver disease is the medical term for liver disease secondary to excessive fatty deposition; this condition is often a result of obesity. Hepatitis C treatments are less effective in patients who are over- weight. Clearly, controlling your weight is important for many different reasons.
The liver is involved in the processing of almost all med- ications. Anyone with hepatitis C should be careful with new prescription medications and even OTC medica- tions. Patients without cirrhosis can safely take most— but not all—prescription and OTC medications. Patients with cirrhosis need to be especially careful with their medications. Some common OTC medications, such as acetaminophen (found in Tylenol) and ibuprofen (found in Motrin and Advil), can be very harmful in patients with cirrhosis.
Hepatitis C can be spread sexually, although the risk is very low. Current guidelines call for patients with multiple sexual partners to practice "safe sex" with a condom to reduce the risk of transmission of hepati- tis C and other sexually transmitted infections such as HIV and hepatitis B. Patients in a monogamous relationship do not necessarily need to change their sexual practices. Spread of hepatitis C to a partner
in a stable, monogamous relationship occurs very rarely. We always recommend screening of the part- ner when we first evaluate a new patient with hepa- titis C and the partner is almost always negative unless he or she has other risk factors for acquiring hepatitis C.
Finally, support groups are available throughout the United States. Many people find them helpful for dealing with the emotional issues of a new diagnosis of hepatitis C or the many stresses of living with hepatitis C. Support groups can help you see that you are not alone and allow you to meet other people who are cop- ing with hepatitis C. These groups can give you an outlet for your feelings and frustrations. They also allow hepatitis C patients to share information, com- pare notes, and help one another.
What are the most common risk factors for hepatitis C?
How can I prevent transmission of hepatitis C to other people?
Can hepatitis C be spread through sexual contact?
9. What are the most common risk factors for hepatitis C?
Although there are many potential risk factors for the transmission of hepatitis C, breaching the skin and infecting the bloodstream is the most common way that a person contracts the virus. Consequently, intravenous drug use (IVDU) and blood transfusions are the two most common routes of infection. A history of IVDU is the most likely cause of infection in 60 percent of newly identified cases. In people with a history of IVDU, the risk of hepatitis C increases with the number of injec- tions and the sharing of needles. Hepatitis C infection is also associated with the use of intranasal cocaine, with the virus being spread from blood on shared straws.
Intravenous drug use (IVDU) and blood transfu- sions are the two most com- mon routes of infection.
Blood transfusions were a common route of transmis- sion until the virus was identified in the late 1980s and blood screening tests were developed for it. The risk of contracting hepatitis C from a transfusion dropped significantly after the routine testing of donated blood began. The current risk is approximately 1 in 100,000. Thanks to newer technology, the risk should be reduced to 1 in 1,000,000 in the near future.
Other risk factors for hepatitis C infection include infusion of clotting factor concentrates before 1987, organ transplantation prior to 1992, exposure to con- taminated medical equipment such as hemodialysis equipment, occupational exposure to blood such as healthcare workers with needlestick injuries, sexual activity that involves blood-to-blood contact, tattoos done without proper cleaning of equipment, mater- nal–fetal transmission, and shared personal care items.
10. How can I prevent transmission of hepatitis C to other people?
Anyone with hepatitis C should be careful about spreading the infection to other people. Viruses are spread through a variety of routes, and each virus has different risk factors for its transmission. For example, hepatitis A and E are transmitted through a "fecal- oral" route. In fecal-oral transmission, the infectious organisms enter the body through ingestion of con- taminated food and water. The organisms usually mul- tiply in the digestive system, exit the body through feces, and spread where poor sanitation allows contam- ination of food or water. Hepatitis A outbreaks, for instance, are commonly traced to food preparers with hepatitis A who have not adequately cleaned their hands. Hepatitis C virus (HCV) is spread through blood-to-blood contact in which HCV-infected blood comes in contact with another person's bloodstream. People with hepatitis C therefore need to be careful about exposing others to their blood.
As mentioned earlier, IVDU is the major risk factor for hepatitis C. Obviously, the most effective way to prevent the virus's transmission would be to enroll in a substance abuse program and stop using drugs. If you have made the decision to continue using drugs, never share syringes or needles with anyone else and use only sterile syringes and needles with a new alcohol swab.
Hepatitis C can be spread through sexual activity only if there is blood-to-blood contact. Patients should inform sexual partners of their infection and the risk of
transmission. Individuals in monogamous relation- ships can discuss this issue with their doctors and decide on the appropriate precautions. Patients who are sexually active with multiple partners should always use a new latex condom with lubricants to reduce the risk of bleeding. This practice will protect against the spread of hepatitis C and other infections that can be transmitted sexually. Hepatitis C patients should never donate sperm, ova, or blood.
Patients should always inform their doctors and den- tists about their hepatitis C diagnosis. In addition, healthcare workers should routinely wash their hands before and after every patient contact. Needles and other sharp instruments that have been exposed to patient blood are always handled carefully and dis- carded into special trash receptacles. Although there have been some reported cases involving possible transmission of HCV between patients who have shared instruments or supplies in dental and medical offices, they are very rare.
Blood must be cleaned thoroughly if it spills, because HCV can live for as long as 4 days on different surfaces. Bloodstains should be cleaned with a bleach solution consisting of 1 part bleach and 10 parts water. At home, do not share razor blades, toothbrushes, nail clippers, or other personal hygiene items with any family members; small amounts of blood on these items may spread infec- tion to others. Always dispose of used feminine hygiene products in plastic bags (Table 2).
Hepatitis C is not spread through casual contact so the sharing of cups, plates, and utensils is felt to be safe.
Table 2
Preventing Spread of Hepatitis C
Stop intravenous drug use Be aware of the risk of spread through sexual contact Do not donate sperm, ova, or blood Clean blood spills appropriately Do not share razor blades, toothbrushes, nail clippers, etc. Dispose of feminine hygiene products in plastic bags
11. Can hepatitis C be spread through sexual contact?
The risk of sexual transmission of hepatitis C is very low. One study evaluated approximately 900 people
who were partners of patients with hepatitis C. During
a 10-year follow-up period, three of these people
developed hepatitis C. However, all three had different types of hepatitis C than their partners, suggesting that sexual transmission was not the route of infection
in their cases.
Despite this study, you should still be cautious and
consider using a condom and lubricants as a matter of course. Because hepatitis C is spread most efficiently from blood-to-blood contact, the risk of transmission
is higher when blood is present. In particular, the risk
of transmission is increased during "rough" sexual activity or unprotected anal intercourse, where small skin injuries may allow blood-to-blood contact. The risk of sexual transmission is probably higher in certain groups, such as prostitutes and people with multiple
sexual partners. Hepatitis C does not appear to be spread through oral sex.
Most doctors recommend testing patients' sexual part- ners at the time of initial diagnosis. This result will give the patient and his or her partner a baseline study. It is very rare for a partner to test positive unless he or she has other risk factors for hepatitis C. Patients with multiple sexual partners should use condoms routinely. The Centers for Disease Control and Prevention does not specifically recommend that a patient with one long-term steady sex partner change his or her sexual practices after receiving a diagnosis of hepatitis C.
12. Can hepatitis C be spread through household contact?
Hepatitis C is rarely spread through household con- tact. Despite this, you should be cautious about possi- ble exposures that can spread the virus, perhaps screening all household contacts at the time of initial diagnosis. In terms of household risks, remember that hepatitis C is most efficiently transmitted via blood- to-blood contact. Razor blades, toothbrushes, nail files, and other personal items may have small amounts of blood on their surfaces. There is potential risk of transmission of the virus to other members of the household if a patient with hepatitis C has used these items.
Hepatitis C cannot be transmitted through saliva. Touching, hugging, and kissing are safe. The virus also will not be spread through coughing, sneezing, sharing food and drinks, or in bathrooms.
13. Can I still get hepatitis C from a blood transfusion?
A blood transfusion is the transfer of blood products
from one person to another. It may be performed during emergency situations such as surgery or uncon- trolled bleeding.
It was a long time before hepatitis C was identified as a specific virus and, unfortunately, many people who donated blood were infected with the virus before testing became available. For many years, the risk of contracting
hepatitis C at the time of a blood transfusion was as high
as 10 to 15 percent. This risk dropped in the 1980s when
donated blood began to be routinely tested for human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Thus, those with HCV who also had HIV or HBV would be identified. In addition, donated blood with abnormal liver tests (caused by HCV) were rejected. After isolation of HCV, screening tests were developed to assess donated blood for this virus as well. The risk of transmission via transfusion dropped signifi- cantly once donated blood was tested specifically for
hepatitis C. Currently, the risk of contracting hepatitis C from a blood transfusion is very low—approximately 1 in 100,000. Newer technology will be able to detect even smaller amounts of virus in the blood and reduce the risk
to 1 in 1,000,000 in the near future.
14. Can I give hepatitis C to my baby if I am pregnant?
Therefore, pregnant patients need not be screened for hepatitis C unless they have any of the risk factors pre- viously described.
Hepatitis C can be spread to the baby during child- birth. This risk is approximately 5 percent, and there is no known way to decrease this risk or prevent HCV transmission. The risk of transmitting hepatitis C through pregnancy increases if the mother has a high hepatitis C viral level or is infected with HIV. We do not know whether a vaginal delivery or cesarean sec- tion is safer in terms of minimizing the risk of trans- mission to the baby. If you have hepatitis C and become pregnant, you should find an obstetrician who has experience with this situation.
Newborns receive antibodies from their mothers to help them fight infections. This transfer of antibodies to the newborn will result in a positive antibody test for hepa- titis C immediately after birth. A positive test does not mean that the newborn has been infected with hepatitis C. More sensitive tests that look for the actual virus, such as the HCV ribonucleic acid blood test, must be given to document active infection. (Treatment of hepa- titis C in children is addressed in another question.)
15. Can I breastfeed if I have hepatitis C?
Breastfeeding appears to be safe, although this issue is very difficult to study scientifically. The virus can be detected in breast milk, but it is unlikely to cause transmission of hepatitis C to the child. One theory is that the production of acid in the stomach inactivates the virus. However, if the mother has chapped or cracked nipples, blood may be transmitted to the infant. In such cases, breastfeeding should be with-
held. It may be reasonable to periodically test an infant while he or she is breastfeeding from an HCV-infected mother.
16. What is the risk of acquiring hepatitis C from a needlestick injury?
Hepatitis C is a significant health risk for any healthcare worker who is exposed to the blood of an infected patient. A person's risk depends on the amount of virus in the blood and the type of tissue that the blood comes into contact with. This risk may be as high as 10 percent with certain exposures. Most exposures to healthcare workers occur with needlestick injuries. Hepatitis C transmission has also occurred when infected blood is splashed into the eyes of a healthcare worker.
After an exposure, two markers of hepatitis C infection are checked: a hepatitis C viral level and a hepatitis C antibody test. The viral level can turn positive within 10 days of exposure and correlates with active infection. Hepatitis C antibodies are usually detected within 1 month of exposure. These tests also provide baseline information about the person who was exposed.
No exact guideline specifies what should happen after an exposure to HCV. Immediate treatment is not always recommended because many people will fight off the infection and not develop chronic hepatitis C after such an exposure. People who acquire the virus but then fight off the infection will have a positive antibody but a negative viral level. A certain percent- age of people will develop hepatitis C that becomes chronic, as signaled by a positive antibody and a detectable viral level. The usual approach is to watch
these patients for 3 to 6 months to see if they can clear the infection on their own. If the virus is not cleared, treatment should be considered. Treatment of acute hepatitis C is discussed in a separate question.
17. Is there a vaccine to prevent hepatitis C?
A vaccine is a substance meant to help the immune
system respond to and resist disease. It usually consists
a small part or a killed version of the organism that
being targeted. The idea is to expose the immune
Unfortunately, there is no vaccine available that targets hepatitis C.
system to the organism in a controlled fashion so that antibodies to the organism form. If the person is later exposed to the real organism, then the immune system will respond immediately and fight off the infection. Viruses are very common targets of vaccines. In fact, vaccines have already been developed for hepatitis A and B.
Unfortunately, there is no vaccine available that targets hepatitis C. As discussed earlier, HCV has multiple genotypes and subtypes. The virus also mutates rapidly when replicating itself. These characteristics make it difficult to develop a vaccine that would be effective against HCV. There appears to be little chance of developing a hepatitis C vaccine anytime soon.
Natural History and Symptoms
What is the natural history of hepatitis C?
What are the signs and symptoms of hepatitis C infection?
Can the liver worsen while someone feels well?
18. What is the natural history of hepatitis C?
Hepatitis C usually takes several decades to progress to cirrhosis. This long time course of hepatitis C infection makes it difficult to study groups of patients and develop good models for its natural history. Sev- eral groups of people with a known infection source and time (such as tainted clotting factor products) have been followed for decades. In addition, there have been several retrospective (looking backward in time) studies, although this type of medical study tends to be less accurate.
Most people with chronic hepatitis C virus do not develop cirrhosis and its complications of liver failure and liver cancer. The following statistics summarize our current best estimates of the natural history of hepatitis C:
Most people with chronic hepatitis C virus do not develop cir- rhosis and its complications of liver failure and liver cancer.
• 55–85 percent of persons develop a chronic infection
• 20 percent develop cirrhosis (over a period of 20–40 years)
• 1–5 percent develop liver cancer or liver failure
• approximately 50 percent of liver transplants are done for patients with hepatitis C
Certain factors are associated with a higher risk for developing cirrhosis—most significantly, alcohol use. Other risk factors include an older age at infection, long duration of infection, male sex, human immunodefi- ciency virus (HIV) coinfection, and other conditions that compromise a person's immune system. The amount of fat in the liver and a person's race may also influence the risk of developing cirrhosis.
19. What are the signs and symptoms of hepatitis C infection?
Most people with hepatitis C infection have no signs or symptoms of liver disease. In medicine, a sign of a disease is a finding noticed by the doctor, while a symptom of a disease is a sensation noticed by the patient. Some patients will experience mild and non- specific symptoms including fatigue, mild discomfort over the liver, nausea, and a poor appetite. It is difficult to confirm that these symptoms are directly related to hepatitis C because they are common in many people without the infection. Similarly, most patients do not have any signs of infection. Once cirrhosis develops, there are subtle signs of early or "compensated" cirrho- sis and obvious signs of late or "decompensated" cir- rhosis. Signs of early cirrhosis include enlargement of the liver or spleen, spots on the skin, and certain blood test abnormalities. Signs of late cirrhosis include jaun- dice, muscle wasting, abdominal swelling, ankle swelling (edema), and confusion (Table 3).
excess fluid in the body that can cause swelling of the extremities and abdomen
Table 3
Signs and Symptoms of Cirrhosis
Abdominal pain Exhaustion Fatigue Decreased appetite Nausea Itching Easy bleeding & bruising Jaundice Palmar erythema Abdominal swelling Leg swelling Confusion
20. Can the liver worsen while someone feels well?
Deterioration of the liver can definitely occur while someone feels well. Although somewhat melodra-
matic, hepatitis C has been labeled the "silent killer."
As mentioned in the previous question, most patients
with hepatitis C have no symptoms. Despite feeling
well, some of these patients may have active inflam- mation and progressive scarring in the liver. This damage can continue for decades, so that many peo- ple develop cirrhosis without ever experiencing any symptoms. In this situation, the onset of symptoms
or signs of hepatitis C usually signifies the develop-
ment of liver cancer or liver failure. Some patients will develop symptoms earlier in the infection process—either from chronic infection or when cir- rhosis first develops.
Hepatitis C needs to be treated before people have signs and symptoms of liver failure because it is dangerous and less effective to treat patients with decom- pensated cir- rhosis.
Many people naturally want to put off treatment until
they feel sick. Obviously, waiting until serious problems arise is a very flawed approach to hepatitis C. Hepatitis
C needs to be treated before people have signs and
symptoms of liver failure because it is dangerous and less effective to treat patients with decompensated cir- rhosis. Once a person has decompensated cirrhosis, the only long-term option is liver transplantation. The best
time to treat a patient is early in the infection, when the person may have no symptoms. Opting for treatment is often a difficult decision to make because the therapy will usually make a person feel much sicker than hepati-
tis C itself. We would consider this a short-term sacri-
fice intended to gain a long-term benefit.
21. What is the best way to monitor the liver in hepatitis C?
There are many different ways to monitor the liver in hepatitis C (Table 4). Possible parameters that can be followed include symptoms, liver function tests, viral
levels, and liver biopsies. As discussed in the previous question, hepatitis C can worsen while someone feels well, so symptoms are not really a good way to monitor
a person's status. Similarly, blood tests, which include
liver function tests and viral levels, do not accurately show what is actually going on in the liver. These numbers can remain stable even as the condition of the liver worsens. The results of these blood tests often fluctuate significantly, and the levels do not correlate exactly with what is actually happening in the liver.
Patients are often preoccupied with their liver tests and viral levels, so doctors should emphasize that the num- bers are an unreliable monitoring tool. Completely normal liver function tests decrease the likelihood that
a person will have severe scarring in the liver. How-
ever, normal liver function tests do not definitively exclude significant disease.
The best test to monitor the liver is a liver biopsy. (Liver biopsies are discussed in more detail in Part 4,
Table 4
Monitoring Hepatitis C
Liver function tests Hepatitis C viral level Liver biopsy
"Testing and Evaluation.") A biopsy is often done as part of the initial evaluation to help decide on the need for treatment and to serve as a baseline against which to measure any future liver biopsies. While not perfect, a biopsy is considered the gold standard for assessing the amount of inflammation and scarring in the liver. Biopsies are the best way to monitor and follow the liver in patients who are not treated. The usual approach is to repeat a biopsy every 3 to 5 years. The need for treatment can be reassessed if the liver biopsy shows increasing amounts of scarring.
Robert's comments:
After testing positive for HCV, my doctor and I discussed the various options regarding further testing and treat- ment. We discussed the subject of biopsy at length. I was told that some people opt not to have it done, citing the risks such as internal bleeding. In view of this, I considered the fact that the biopsy would be my only accurate method of knowing the current condition of my liver. If I had not done it, I would have gone through treatment without knowing if there was any permanent damage and it would always have been on my mind.
22. What is the relationship between hepatitis C and alcohol?
In the United States, alcohol consumption is a major cause of chronic liver disease, cirrhosis, and liver fail- ure. Numerous studies have shown that the combina- tion of hepatitis C and alcohol increases the risk of developing cirrhosis. These studies have repeatedly arrived at the same conclusion: heavy alcohol use sig-
nificantly increases the amount of liver damage in patients with hepatitis C, and light alcohol use leads to milder increases in liver damage. The implication of these studies is both simple and obvious: patients with hepatitis C should not drink alcohol.
Active alcohol use is also considered a relative con- traindication to treatment. Most doctors require absti- nence before they will undertake a liver biopsy and begin treatment for several reasons. Active alcohol use leads to liver inflammation and can confound liver biopsy interpretation. Liver biopsy interpretation will be more meaningful in a patient who has refrained from using alcohol for an extended period of time. Current interferon-based regimens have multiple side effects and require close follow-up. Most doctors feel that a patient with active alcohol use will have a more difficult time assessing side effects and committing to the follow-up required during treatment. Ideally, patients should be abstinent and involved in an alco- hol treatment program before they start hepatitis C therapy.
Active alcohol use is also a contraindication to liver transplantation. Transplant programs require at least six months of complete abstinence, and many pro- grams also require active involvement in an alcohol treatment program.
The results of my biopsy indicated I had liver fibrosis at a stage of 2–3 (on a scale of 4). Although there is no way to be certain, I feel sure the combination of moderate to heavy alcohol use along with the virus was primarily responsible
a family of proteins that are naturally produced by the body and that fight off infection. There are three types: alfa, beta, and gamma. Alfa-interferon is used to treat hepati- tis C.
Numerous studies have shown that the combina- tion of hepati- tis C and alcohol increases the risk of devel- oping cirrho- sis.
for this staging, and that my liver condition would have been much better had it just been the virus alone.
23. Are there patient risk factors other than alcohol that cause hepatitis C to progress quickly?
Hepatitis C has a variable natural history, but certain factors appear to influence a person's risk of developing fibrosis and cirrhosis (Table 5). Established risk factors other than alcohol intake include male sex, older age of infection (older than 40 years), longer duration of infection, hepatitis B virus (HBV) coinfection, and HIV coinfection. Other immunocompromised condi- tions, including organ transplants, are also associated with increased rates of fibrosis. This risk is a major issue in patients who receive a liver transplant for hep- atitis C. Other risk factors for the development of cir- rhosis that are being investigated include the amount of fibrosis on liver biopsy, the amount of fatty tissue on liver biopsy, and race.
Table 5
Risk Factors for Developing Cirrhosis
Alcohol consumption Infection at older age Long duration of infection Male sex HIV coinfection Hepatitis B coinfection Immunocompromised conditions Fatty liver
Your doctor will assess all of these risk factors when making a decision about your treatment. Some risk fac- tors are obvious—for example, your age and sex. In addition, your history may give clues about when you acquired hepatitis C and how long you have had the infection. Tests for HBV and HIV can be performed at the initial evaluation. A liver biopsy will grade the amount of inflammation and scarring in the liver. Mod- ifiable risk factors, including alcohol use and obesity, need to be treated aggressively. These factors, used in conjunction with other information, will help your doc- tor decide on the correct treatment for you.
24. Can hepatitis C lead to problems outside the liver?
Although hepatitis C can lead to complications outside the liver, such problems happen in only 1 to 2 percent of HCV-infected people. The most common extrahepatic (not in the liver) complication is cryoglobulinemia, in which a person develops antibodies that attack other parts of the body. A patient with cryoglobulinemia can develop skin rashes, joint and muscle pains, nerve dam- age, and kidney damage. Other extrahepatic complica- tions include another type of kidney disease called glomerulonephritis and a skin disease called porphyria cutanea tarda. Although some other diseases may have an association with hepatitis C, the scientific data prov- ing these links remain sketchy.
It is important to be aware of these extrahepatic com- plications because treatment for hepatitis C may help prevent these diseases. Patients are sometimes sent for
HCV treatment when hepatitis C is diagnosed and felt to be the cause of the patient's kidney disease. In these patients, treatment is often indicated only for the extrahepatic complication and not to prevent liver damage.
Testing and Evaluation
Can you give me an overview of testing and evaluation?
What is a hepatitis C antibody test?
What is a direct test for the hepatitis C virus?
25. Can you give me an overview of testing and evaluation?
Your doctor can test and evaluate you for hepatitis C, the function of the liver, and the presence of other liver diseases in several different ways. The standard test for hepatitis C is an antibody test, which looks for evi- dence of antibodies to hepatitis C. In a patient with a risk factor for hepatitis C and abnormal liver function tests, a positive antibody test is almost always a sign of chronic hepatitis C. In confusing cases or when the doctor wants to confirm a diagnosis, the hepatitis C viral level can be checked. This test looks for the actual virus and can estimate how many viral particles are present. A viral level and a genotype test are also checked before treatment.
Liver function tests consist of a general panel of tests that are checked for many different reasons. They are typically performed while screening a patient with a risk factor for hepatitis C or for another medical prob- lem. If the liver function tests are abnormal, then addi- tional tests for hepatitis C and other liver diseases are performed. If a diagnosis of hepatitis C is already established, then liver function tests can provide a gen- eral sense of how much inflammation and scarring are present in the liver.
Liver function tests are not perfect—they do not always reflect what is actually happening in the liver. Other tests that help assess the amount of inflamma- tion and scarring in the liver include imaging studies such as an ultrasound and liver biopsy. An ultrasound can provide clues that suggest more advanced scarring
and can look for tumors, which sometimes develop in
patients with hepatitis C. A liver biopsy is the best test
for assessing the amount of inflammation and scarring
in the liver.
Your doctor will also test you for other types of liver diseases. Hepatitis A and B tests are routinely checked. Patients who are diagnosed with hepatitis C should be vaccinated against hepatitis A and B if they are not already immune to these viruses. Autoimmune hepa- titis and hemochromatosis should be excluded in patients with hepatitis C because the presence of either disease would significantly alter the manage- ment of hepatitis C.
26. What is a hepatitis C antibody test?
An antibody is a protein produced by the immune sys- tem that can identify and attack foreign objects in the body, such as bacteria and viruses. Antibody tests are commonly used to check for either active infection or
previous exposure to a specific bacteria or virus. When a person is infected with hepatitis C, the immune sys- tem counters the invading virus by producing antibod-
ies against hepatitis C in an attempt to fight off the
infection. A positive hepatitis C antibody test usually represents active infection because few people success- fully fight off the infection.
a liver disease char- acterized by an over- active immune system that attacks the liver.
an inherited disorder characterized by the abnormal accumula- tion of iron in the liver and other organs.
The standard hepatitis C virus (HCV) antibody test is
an enzyme immunoassay (EIA) test. This test is very
accurate when used to screen high-risk populations such as people with abnormal liver function tests or
people with clinical signs of liver disease. The hepatitis
C EIA test is not perfect, however. False positive
results are possible, especially when the person being tested has no risk factors for hepatitis C. A recombi- nant immunoblot assay (RIBA) is a more specific anti- body test that is often used to confirm a positive EIA and decrease the risk of false-positive results. A direct test for HCV is used to definitively confirm the pres- ence of active infection (see the next question).
Conversely, antibody tests can be unreliable and pro-
duce negative results in patients with active hepatitis C infection. During an acute infection, it takes approxi- mately 4 weeks for the antibody test to become posi- tive. During this period, a direct HCV test should be performed if acute hepatitis C is suspected. Hepatitis
C antibody tests may also be falsely negative if the per-
son does not produce enough antibodies for detection with the EIA or RIBA test. This happens in patients with conditions such as human immunodeficiency virus infection or congenital immunodeficiencies where the immune system does not function properly.
A direct viral test is necessary in these situations.
27. What is a direct test for the hepatitis C virus?
Direct tests for HCV look for the actual viral ribonu- cleic acid (RNA) in a patient's blood. These tests can detect even a small amount of virus because the viral RNA is amplified many times. The virus can be ampli- fied by several different methods, including poly- merase chain reaction (PCR) and branched deoxyribonucleic acid signal amplification. We will refer to the various direct tests simply as hepatitis C RNA tests or a hepatitis C viral level.
A hepatitis C RNA test can be classified as either a
qualitative test or a quantitative test, depending on
how the result is reported. A qualitative test is reported
as either positive or negative. Because it can detect a
very low level of virus, a qualitative test is administered after antiviral treatment is completed to check for a cure. A quantitative test detects not only the presence
of virus but also the amount of virus in the blood.
Quantitative tests are very helpful during treatment when the viral level is followed closely and used to make decisions about whether treatment should con- tinue.
The PCR assay is the most common RNA test cur- rently used in cases of hepatitis C. The result is reported as either copies per milliliter or international units per milliliter (IU/mL); one international unit is roughly equivalent to two copies. An RNA test is almost always done after a positive antibody test to confirm a new diagnosis of hepatitis C. An RNA test should also be performed in situations where antibody
tests are unreliable, such as in cases of acute hepatitis
C and in patients with compromised immune sys-
tems. The results of a quantitative RNA test are checked immediately before treatment begins. Because the viral level does not correlate with the
severity of infection, this level should not be followed
as a marker for disease progression. However, the viral
level does correlate with the chance of a response to treatment. Patients with a high viral load (usually defined as more than 2 million copies per milliliter) have a poorer response to treatment than do patients with a low viral load. The viral level is followed closely while patients are on treatment.
28. What is a genotype test?
The hepatitis C virus evades the immune system by mutating rapidly. The virus has evolved multiple strains, which are termed genotypes. A patient's geno- type can be determined through a blood test. Although the genotype does not influence the severity of disease and the risk of developing cirrhosis, certain genotypes respond to treatment much better than other genotypes. In fact, genotype is a major predictor of response to current treatments for hepatitis C. As a consequence, the genotype test is very important when deciding on whether to treat a patient and how long to continue the therapy.
There are 6 major HCV genotypes and more than 50 subtypes. Different parts of the world have varying predominant genotypes. In the United States, geno- type 1 is most common, accounting for about 75 per- cent of cases. Most of the remaining cases in the United States are genotypes 2 and 3, with an occa- sional genotype 4 patient. Genotype 4 is the most common genotype in Africa including Egypt, where 18 percent of the population has been exposed to hep- atitis C. Genotype 5 is the most common genotype in South Africa, and genotype 6 is the most common in Southeast Asia. Genotypes 7, 8, and 9 are closely related to genotype 6.
Most of the large treatment studies have been done in countries where almost all patients are genotypes 1, 2, and 3, so there are few data on treating patients with genotypes 4, 5, and 6. Genotype 1 is the most difficult to treat, whereas genotypes 2 and 3 tend to respond to treatment significantly better. It is important to know a patient's genotype when making a decision to treat
29. What are liver function tests?
Liver function tests are laboratory values used to evalu- ate the functioning of the liver. A variety of blood tests are available to assess the liver, including tests that reflect inflammation in the liver and tests that gauge the functioning of the liver (Table 6). Doctors usually order a standard group of tests called a liver panel that includes aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phos- phatase, and albumin. The aminotransferase (AST and ALT) levels reflect the amount of inflammation in the liver, and the albumin and bilirubin levels reflect the functioning of the liver. Alkaline phosphatase levels can rise in many liver conditions, but elevations are espe- cially likely when the bile ducts are blocked.
Liver function tests are not perfect. For example, a person can have a normal aminotransferase level and still have inflammation in the liver; similarly, a patient can have normal albumin and bilirubin levels and still have scarring in the liver. Because of this unreliability, many doctors recommend a liver biopsy even in patients with normal liver function tests. The many different patterns observed with liver function test abnormalities reflect different medical conditions and different levels of functioning in the liver.
Elevated liver function levels can occur in other med- ical conditions because the enzymes measured by these tests are present in other parts of the body besides the liver. For example, alkaline phosphatase is found in
a standard group of
laboratory tests used to evaluate the func- tioning of the liver. These tests usually measure the levels of aspartate amino- transferase (AST), alanine aminotrans- ferase (ALT), alkaline phosphatase, albu- min, and bilirubin.
breakdown of hemo- globin that is meas- ured to screen for or to monitor liver or gallbladder dys- function.
blood tests that measure enzymes found in liver cells. These levels are often elevated in patients with liver disease. Aspartate amino- transferase (AST) and alanine aminotrans- ferase (ALT) are the two most commonly measured.
Table 6
Liver Function Tests
Normal Values
Total Protein
6–8.2 g/dL
3.2–4.8 g/dL
2–4 g/dL
Alkaline Phosphatase
Total Bilirubin
0.2–1.3 mg/dL
Direct Bilirubin
< 0.3 mg/dL
bone and the placenta and can become elevated in bone disease and pregnancy. Likewise, AST is present in many parts of the body, including muscle, and its level will rise whenever muscle is destroyed, such as during a heart attack. These other conditions need to be considered when the patient does not have obvious liver disease.
Aminotransferase (AST and ALT) levels are used to measure direct injury to liver cells. These levels are often—but not always—elevated in patients with chronic hepatitis C. Elevated aminotransferases on routine blood test screening are often the results that lead to the initial diagnosis of hepatitis C. Several dif- ferent patterns of aminotransferase elevations can be meaningful in patients with hepatitis C:
Normal levels do not exclude more advanced liver disease, but severe scarring or cirrhosis is less com- monly seen in this situation.
• Aminotransferase levels can fluctuate in an individ- ual patient without having a direct correlation with what is actually happening in the liver.
• The ALT level is usually higher than the AST level in patients without cirrhosis. A reversal of this pat- tern—that is, AST level higher than ALT level— can be a marker for the development of cirrhosis.
• Very high levels (greater than 300 IU/L) should prompt evaluation for other conditions such as autoimmune hepatitis or an acute injury to the liver such as an acetaminophen overdose.
• Aminotransferase levels are followed during treat- ment, and most—but not all—patients who respond will have an improvement in the levels.
• An elevated ALT level is strongly suggestive of liver disease, whereas an isolated AST elevation can be seen in many conditions unrelated to the liver, including a heart attack and muscle disorders.
As mentioned earlier, the albumin and bilirubin lev- els that are included as part of a standard liver panel can reflect the functioning of the liver. Another blood test, called the prothrombin time (PT), reflects coagulation, or the body's ability to clot, and is also a good marker of liver function. This test is not in a standard liver profile, however.
The liver produces albumin, which is the main protein in blood. A shortage of albumin can lead to problems with fluid balance and the development of free fluid in the abdomen, a condition known as ascites. The albu- min level falls as liver function deteriorates; as a conse- quence, many doctors follow albumin levels closely in their patients with liver disease. One of the major
abnormal fluid accu- mulation in the abdomen that can develop when the liver does not func- tion properly.
grading systems for patients with cirrhosis uses the albumin level, bilirubin level, and PT to judge how well the liver is functioning. Kidney failure and mal- nutrition are other major reasons that a person might have a low albumin level.
The liver helps break down old red blood cells into bilirubin, which is then excreted into the bile ducts. In liver disease, the bilirubin level may become elevated because the liver is less efficient at clearing and pro- cessing old blood cells. As the bilirubin level increases, a person may develop yellow eyes or skin. This condi- tion, which is called jaundice, is a sign of poor liver function. Blockage of the bile duct, blood disorders, and even a benign hereditary condition called Gilbert's syndrome are other reasons that a person might have a high bilirubin level.
Alkaline phosphatase is an enzyme found mostly in the liver and bone. In particular, it is found in the cells that line the bile ducts of the liver. The bile ducts help drain the liver, so any process that blocks bile ducts can lead to an elevation of the alkaline phosphatase level. The most common conditions that lead to such eleva- tions are gallstones in the bile duct, cancers that block the bile duct, strictures of the bile duct, and liver dis- eases that attack the bile ducts. A mildly elevated alka- line phosphatase level is a nonspecific marker in a patient with hepatitis C. A very high level should prompt a search for one of the more common condi- tions that can cause an alkaline phosphatase elevation.
I remember having routine physicals prior to 1990 and seeing liver function tests (ALT and AST) that were ele-
vated from time to time. I was told at that time not to worry, as the elevations were not considered too important. In hindsight, it was probably an indication that the virus (and alcohol) was taking its toll. Unfortunately, HCV was not as well understood then as it is now, and it was in the early days of developing a test for it.
30. What is a liver ultrasound?
Blood tests provide a great deal of useful information about the liver but have several limitations, as discussed earlier. To gather even more information about their patients' conditions, doctors order a variety of radiologi- cal tests that can visualize the liver and other organs in the abdomen, including the gallbladder, kidneys, spleen, pancreas, and blood vessels. The most common imaging test of the liver—in cases of hepatitis C—is the ultra- sound. Computed tomography and magnetic resonance imaging scans are typically performed as follow-up measures when the ultrasound shows an abnormality; these tests are discussed in a later question.
An ultrasound can provide a lot of information about the liver and the severity of a patient's liver disease. When a patient develops cirrhosis, the size and texture of the liver and spleen may change. Patients who are experiencing liver failure may have a buildup of fluid in the abdomen (called ascites). As noted earlier, patients with hepatitis C and cirrhosis are at risk for liver cancer, and an ultrasound can sometimes pick up liver cancer. Ultrasounds are not perfect, however, so they are used in conjunction with other information when assessing a patient's condition.
Your doctor may order an ultrasound for you in many different circumstances. For instance, an ultrasound
fluid in the abdomen
is drained with a needle.
test may be performed if you have an abnormal liver test. If a person with known liver disease presents with abdominal pain, an ultrasound may be performed to look for abnormalities, such as liver masses or block- ages, in the blood vessels that supply the liver. An ultrasound is also useful to guide procedures such as a liver biopsy or a paracentesis (a procedure that drains
abdominal fluid in patients with ascites).
If you have an ultrasound, this is what you can expect. First, the technician applies a jelly directly to the skin; it will make the images clearer for the doctor reading the test. Next, the technician passes a smooth trans- ducer over the skin. The transducer produces sound waves that go through your skin and bounce against your internal organs. A computer processes this infor- mation to produce images that will appear on the screen. An ultrasound is not invasive, painful, or harm- ful. It can be performed on an outpatient or inpatient basis and takes less than an hour.
31. What is a liver biopsy?
Evaluation with blood tests and radiological tests pro- vides a lot of information, but looking at actual liver tissue is often helpful and necessary to make a medical decision. A liver biopsy is performed in these cases. During a biopsy, a tiny cylinder of tissue is removed; a pathologist then views the sample under a microscope (Figure 3). A liver biopsy can provide critical informa- tion about the cause and extent of a patient's liver dis- ease. For example, if a patient presents with abnormal liver tests and a diagnosis is not clear after initial test- ing, a liver biopsy may be performed to find a diagno- sis. A biopsy may help identify causes of liver
Figure 3
Technique of Liver Biopsy
dysfunction such as drug reaction, autoimmune hepa- titis, alcohol use, or cancer for which blood tests and x- rays are often nonspecific.
In hepatitis C, a liver biopsy is usually performed to assess the degree of damage to the liver. If the liver has active inflammation, it can range from mild to severe. Mild disease is characterized by inflammation, but the appearance of liver cells is preserved. As the disease progresses, normal cells are replaced by fibrous tissue. The result may ultimately be cirrhosis, where the liver has scars, nodules (pockets of fibrous tissue), and an irregular appearance. A liver biopsy can also help
exclude other sources of liver disease, including alcohol use, iron overload, and autoimmune hepatitis.
Many staging systems have been developed for inter- preting a liver biopsy. The most widely used system assigns a number between 0 and 4 for the amount of inflammation in the liver (the grade) and a number between 0 and 4 for the amount of scarring in the liver (the stage) (Figures 4, 5, and 6). Doctors usually focus on the stage (amount of scarring) when deciding on the need for treatment. A stage 0 biopsy is considered normal, whereas a stage 4 biopsy has enough scarring to be classified as cirrhosis. Stages 1, 2, and 3 represent steps between stage 0 and stage 4.
If you have a liver biopsy, this is what you can expect. Your doctor may require you to get blood tests first to ensure that you do not have an increased risk of bleed- ing after the procedure. In addition, you should dis- continue any use of aspirin and aspirin-like products (such as ibuprofen) three to seven days before the biopsy. Ask your doctor about instructions regarding diet. Your doctor may perform the biopsy, or a member of the radiology department may handle the proce- dure. Initially, your skin will be cleaned with a solution to reduce the risk of infection. Then, the skin is numbed with a medication similar to the novocaine used in a dentist's office. Often, a noninvasive device called an ultrasound is used to guide the procedure. A sample of tissue is removed through a needle and sent to the pathology department for further processing. The biopsy may be performed on an inpatient or out- patient basis. Although it takes less than one-half hour, you will be monitored for several hours afterward.
The most common complication of a liver biopsy is
pain. This discomfort usually consists of a dull ache
in the right-upper abdomen or shoulder and resolves
within 2 hours with or without pain medications. Bleeding, infection, and drug reactions are other less common but potentially serious complications of a biopsy. Unrelenting pain is rare and could indicate a severe complication; notify your doctor immediately if it occurs.
The time prior to my biopsy was worse than the actual procedure because of my anxiety. The actual procedure was not that bad. There was some slight pain (more of a slight burning sensation) that extended internally across my abdomen. This pain disappeared after about 2 hours. The recovery time was 3 hours, with about half of that time spent lying on my right side (the entry side of the biopsy). The most important thing for the patient is to discontinue use of blood-thinning products before the biopsy. It is also very important to remain still during the procedure. I believe the biopsy needle passes close to some other organs.
A liver biopsy can provide critical infor- mation about the cause and extent of a patient's liver disease.
32. What if I have a positive antibody test but a negative hepatitis C RNA test?
Some patients are screened for hepatitis C and found
have a positive antibody test but a negative hepatitis
RNA test. Several different clinical situations can
result in this pattern of testing. First, the antibody test may be wrong. As discussed in a previous question, the
standard EIA antibody test sometimes produces false- positive results, especially in patients with no risk fac- tors for hepatitis C. A RIBA antibody test can be performed in this situation. If the RIBA test is nega- tive, the initial EIA antibody test result was most likely a false positive. In this situation, we would recommend rechecking the tests in 3 to 6 months to confirm this finding.
Once a false-positive antibody test has been excluded, several other possibilities need to be considered. A small percentage of patients who are exposed to hepati- tis C will successfully fight off the virus. A patient in this situation would have a positive antibody test because of the previous exposure to hepatitis C and a negative RNA test because his or her immune system has successfully cleared the virus. We would consider this possibility strongly in any patient with a known risk factor for hepatitis C. Another possibility in a patient with a known risk factor is that the virus level is so low that the RNA test cannot detect the virus. Studies have shown that viral levels can fluctuate significantly.
It is hard to differentiate between these two situations, although a patient who has successfully fought off hepatitis C would be expected to have normal liver function tests. Patients should be followed closely in both situations, with repeat testing performed on a regular basis. It will become obvious over time which situation applies.
One final scenario to consider is that the patient has been treated successfully for hepatitis C. A careful his- tory will make this fact obvious.
33. What about hepatitis A and hepatitis B?
Hepatitis C is one of many viruses that can cause
inflammation of the liver or hepatitis. Other viruses that primarily attack the liver include hepatitis A (HAV), hepatitis B (HBV), hepatitis D, and hepati- tis E. Viruses such as cytomegalovirus, infectious mononucleosis, and herpes simplex usually attack other parts of the body but can occasionally cause hepatitis. Hepatitis D is extremely rare and can only infect a person who has chronic hepatitis B. Hepati- tis E is similar to hepatitis A but is almost never seen in the United States. Hepatitis A and hepatitis
B are the two most important viruses in this group,
and every patient with hepatitis C should be tested for these viruses.
HAV is often spread through ingestion of contami- nated food or water. Epidemics are common in low- socioeconomic populations where sanitary conditions are less than ideal. Patients may be asymptomatic or may present with jaundice (yellow skin). Almost all patients who are infected with HAV recover fully. An important difference between HAV and HCV is that HAV never causes chronic hepatitis. Treatment of acute HAV consists of rest, fluids, and adequate nutri- tion; hospitalization is rarely required. HAV can be prevented with proper hand washing, a clean water supply, and adequate sewage disposal.
If a person has been or may be exposed to HAV, an
immunoglobulin (antibody preparation) can be adminis- tered to him or her to prevent infection. This measure
provides temporary protection against hepatitis A. A vac- cination against hepatitis A is also available; the vaccine provides longer (possibly lifelong) protection. Patients with hepatitis C are tested for hepatitis A to see whether they are immune to the latter infection. Many patients were exposed to hepatitis A as a child and have a natural immunity to it. If a patient is not immune to hepatitis A, he or she should be vaccinated. This recommendation is based on a study that suggested patients with chronic hepatitis C who are exposed to hepatitis A are more likely to develop liver failure than patients without hepatitis C.
Hepatitis B is spread through blood, sexual contact, use of intravenous drugs, and from mother to child during childbirth. More than half of the world's popu- lation has been exposed to or is infected with HBV. Most of these people live in areas where hepatitis B is endemic and are exposed to this virus at birth. Patients who acquire hepatitis B at birth do not develop acute hepatitis; instead, they typically develop a chronic infection. The United States is not an endemic area for hepatitis B, and less than 2 percent of the U.S. popula- tion has been infected or exposed to hepatitis B. Most cases in the United States are acquired as an adult.
Patients who are exposed to hepatitis B as adults usu- ally recover completely and do not develop chronic hepatitis. Symptoms of an acute infection may include joint pain, rash, fatigue, decreased appetite, and jaun- dice (yellow skin). About 5 to 10 percent of people who are exposed as an adult will not clear the virus and will develop chronic hepatitis. Complications from chronic HBV are similar to those seen with hepatitis C—that is, cirrhosis, liver failure, and liver cancer. Treatment of acute HBV is similar to treatment of
HAV and includes rest, fluids, and adequate nutrition. Treatment of chronic HBV is also available; options include interferon and nucleoside/nucleotide analogs that interfere with replication of the virus.
vaccination for hepatitis B is available and effective
up to 90 percent of people who receive the vaccine.
When it was initially developed, the vaccine was given
to anyone considered to be at high risk for exposure to
hepatitis B or at high risk for a severe infection if exposed. This population included immunocompro- mised patients, hemodialysis patients, chronic liver disease patients, healthcare workers, injection-drug users, and individuals with high-risk sexual partners. More recently, the vaccine has been used universally, and all children are vaccinated after birth.
Patients with hepatitis C should be screened for hepati-
tis B for two reasons: for evidence of chronic hepatitis B
and for evidence of immunity. Hepatitis B and hepatitis C share some risk factors, so people occasionally are diagnosed with both chronic hepatitis B and chronic hepatitis C. Treatment recommendations are different in
this situation. Patients who are not immune to hepatitis
B should be vaccinated for the same reason that vaccina-
tion against hepatitis A is recommended—that is, a per-
son with chronic hepatitis C who is exposed to hepatitis
B has a higher chance of developing liver failure.
34. What about other liver diseases and medications?
Many patients are diagnosed with hepatitis C when they undergo an evaluation for abnormal liver function tests. There is a standard panel of blood tests that are
checked in when a patient has abnormal liver function tests. These include tests for viral, metabolic, and immune liver diseases that can lead to abnormal liver function tests. Other patients are screened directly for hepatitis C because they have a risk factor such as intra- venous drug use. These individuals are also screened for other liver diseases because some (such as hepatitis B) share the same risk factors and others (such as autoim- mune hepatitis or hemochromatosis) change the man- agement of hepatitis C if they are present.
Hemochromatosis is a hereditary disorder character- ized by the abnormal accumulation of iron in organs including the liver, pancreas, joints, and heart. It is a relatively common disease in high-risk groups such as patients with a Northern European ancestry. This disorder can lead to cirrhosis, diabetes, abnormal skin pigmentation, arthritis, and heart abnormalities. Patients usually remain asymptomatic before the age of 40 because it takes many years for a person to accumulate enough iron to develop end-organ dam- age. Individuals with this disease may present with abnormal liver function tests, cirrhosis, liver failure, or liver cancer. Testing for hemochromatosis includes iron studies, genetic studies, and liver biopsy. All patients with hepatitis C should be screened for iron overload because management of the latter condition would involve removal of the excess iron through phlebotomy before hepatitis C therapy begins.
Autoimmune hepatitis is a rare liver disease character- ized by an overactive immune system that attacks the liver. It typically occurs in young to middle-aged women who often have other immune disorders such
as rheumatoid arthritis and thyroid disease. Diagnosis is difficult; it involves testing for special antibodies and usually requires a liver biopsy. This disease is treated by suppressing the immune system with medications such as steroids and other immunosuppressants. All patients with hepatitis C should be screened for autoimmune hepatitis because interferon can worsen the latter dis- ease by increasing the activity of the immune system. If a person has both hepatitis C and autoimmune hep- atitis, the autoimmune hepatitis needs to be treated first and brought under control. If a patient on hepati- tis C therapy develops very high aminotransferase lev- els, the doctor should be suspicious for autoimmune hepatitis and rule out its presence.
Drug toxicity is a common cause of abnormal liver func- tion tests and liver disease. Some medications may cause a reaction that depends on the dose. Others drugs may produce severe toxicity in the liver on a sporadic basis. Antibiotics, cholesterol-lowering medications, pain medications, anesthetics, hypertension medications, and seizure disorder medications have all been implicated as causes of liver disease. The doctor will take a careful medication history to rule out these possibilities.
35. What other tests might be checked in a patient with hepatitis C?
Many other blood tests may be performed in a patient with hepatitis C. The PT, complete blood count, and basic metabolic profile, including kidney function, are routinely checked in all patients. Other, more specialized tests, such as cryoglobulin levels, a gamma GT, and a 5'- nucleotidase, are performed in specific situations.
also known as pro- thrombin time (PT). It reflects the body's ability to clot and is a marker of liver func- tion.
The PT reflects the blood's ability to clot. This test is a good marker of liver function because the liver manu- factures clotting factors. PT values can vary from lab
to lab, so this number is always converted to the inter-
national normalized ratio (INR), which adjusts for possible lab variation. As the liver fails and produces less clotting factors, the PT and INR values increase. The INR is part of a major scoring system for cirrhosis that is used to place patients on liver transplant lists.
Sometimes, doctors may purposely give medications that elevate the INR. For example, if a patient has an
abnormal heart rhythm, artificial heart valve, or history
of stroke, he or she may take blood thinners to reduce
the risk of stroke. Warfarin (trade name Coumadin) is the blood thinner most often used for this purpose. An increased INR in a patient who is taking warfarin does not necessarily mean that the person has liver disease.
A complete blood count is checked in all patients with
hepatitis C. The main tests in this blood panel include the white blood cell count, hematocrit, and platelet count. The platelet count is especially meaningful because it often decreases in patients with cirrhosis. As the liver becomes scarred, blood flow through the liver slows down. This delay leads to congestion and enlargement of the spleen, which can result in a low platelet count. A low platelet count is often the first sign that a patient has cirrhosis or even liver disease. The white blood cell count and hematocrit can also decrease in patients with more advanced liver disease. These levels are especially important to measure when considering treatment because interferon can suppress the bone marrow, which produces all of these blood
cells. These levels are followed closely in patients who are receiving treatment for hepatitis C.
A basic metabolic profile is also checked in all patients
with hepatitis C. The most important component of this blood panel is the creatinine (a measure of kidney function). The kidney and liver are closely connected, and kidney function is important to assess for several reasons. Hepatitis C can cause kidney problems, which need to be identified immediately. Kidney dysfunction also affects the medications that can be given to treat hepatitis C.
Gamma GT and 5-prime nucleotidase tests are per- formed when an elevated alkaline phosphatase level is found. An elevation in alkaline phosphatase can be a
marker of liver disease but may also signal the presence
of bone disease. Gamma GT and 5-prime nucleotidase
are liver-specific enzymes whose levels become ele- vated when the liver is the source of the elevated alka- line phosphatase levels.
Cryoglobulins are antibodies that the body produces in response to hepatitis C but that attack other parts of the body. This test is performed in patients with hepa- titis C who have arthritis or kidney disease.
36. What types of doctors are gastroenterologists and hepatologists?
After completing their undergraduate studies and medical school, physicians may receive training in a number of specialties. Gastroenterologists and hepa- tologists must first undergo 3 years of internal medi- cine training. These doctors then complete a
a physician whose
area of expertise includes liver dis- eases and liver trans- plantation.
mandatory 3-year fellowship in gastroenterology. Dur- ing this time, these doctors gain experience in all parts of gastroenterology, including liver diseases.
A hepatologist has completed further training after
internal medicine and gastroenterology. This training usually continues for 1 to 2 years after the fellowship ends. Hepatologists concentrate exclusively on patients with liver disease, including liver damage that may be due to viruses, alcohol, autoimmune causes, and drugs. When these patients have severe disease, they may require a liver transplant. Transplant hepatologists are experienced at evaluating these patients for transplant and guiding their therapies after transplant.
After you receive a diagnosis of hepatitis C, you may
be referred to a gastroenterologist or hepatologist for
further testing, evaluation, and treatment. Both types
of physicians can competently take care of you. If a
liver transplant is needed, you will meet surgeons who have trained specifically for this problem. Most centers that provide liver transplants have created multidisci- plinary teams whose members—nutritionists, social workers, infectious disease specialists, and psychia- trists—complement these physicians.
Can you give me an overview of treatment?
Can hepatitis C be cured, and how is "cure" defined?
What are the potential benefits of undergoing treat- ment for hepatitis C?
37. Can you give me an overview of treatment?
One of the most important questions for patients with hepatitis C is whether treatment is necessary and appropriate. This decision is never an emergency and should be considered carefully. Because hepatitis C progresses over years and decades, there is never a med- ical reason to start treatment urgently. There are many different ways to approach this decision. Some patients have already made a definitive decision by the time of their initial consultation with a gastroenterologist or hepatologist. Most patients, however, are confused and spend a long time discussing the risks and benefits of treatment. The decision-making process is different for every patient. The medical facts that are discussed here are applicable to everyone. The way that you assess the facts and the way that treatment fits into the rest of your life (family, work, friends) is always different and makes each decision-making process unique.
Several issues make this a difficult decision to reach. First, most patients with hepatitis C do not progress to cirrhosis and will never develop symptomatic liver dis- ease. Unfortunately, there is no way to predict with absolute certainty who will develop cirrhosis and when that will happen. The best current test is a liver biopsy, but it gives only a snapshot of what the liver currently looks like and is a less than perfect guide. Therefore, many patients who opt for treatment will probably never progress to cirrhosis even without treatment.
Second, current treatment options all have limitations. Therapy with interferon and ribavirin is limited by
unwanted side effects and variable cure rates, for example. Many patients are not candidates for treat- ment, and many patients choose to defer treatment because of these concerns.
Patients who do opt for treatment follow a standardized protocol. They take an interferon shot once a week and ribavirin tablets twice a day. The duration of therapy is determined by the viral genotype and the amount of disease found on the initial liver biopsy. The doctor checks the patient's viral levels on a regular basis, and treatment stops if the patient fails to meet predefined goals. Patients are monitored closely for side effects, and treatment is adjusted or stopped as needed. Most stud- ies report overall cure rates of about 50 percent.
I feel it is extremely important for patients to do their own research before starting treatment. The Internet has an overwhelming amount of information about this virus, and I feel it is your responsibility to yourself to gather as much information as you find pertinent or that explains topics that are not clear to you. Write it all down, whether or not it may be misleading. You may not understand certain test results, and they will not always be explained if you do not ask. Give your questions and comments to your doctor—it is his or her responsibility to explain them to you. Don't leave without understanding everything because you will need to make decisions based on this information, if you decide to continue with treatment.
Because hepa- titis C pro- gresses over years and decades, there is never a medical reason to start treat- ment urgently.
the standard defini- tion of cure in clinical studies—hepatitis C is not detected in blood 6 months after the end of treatment.
38. Can hepatitis C be cured, and how is "cure" defined?
A very common question is whether hepatitis C can be
cured; the answer depends on the definition of a "cure." The standard definition of a cure in clinical studies is that hepatitis C virus (HCV) cannot be
detected in blood tests 6 months after the end of treat- ment. This outcome is termed a sustained virological response (SVR). Long-term studies have shown that once a person achieves an SVR, the chance of a relapse
is very low. The general consensus is that patients who
Figure 7
Various Treatments
Chances of Achieving a Sustained Virological Response with
nificantly over the last decade, and the chance of a cure is significantly higher now than ever before.
39. What are the potential benefits of undergoing treatment for hepatitis C?
This is an important question for anyone considering the currently available treatment regimens with their many potential side effects. We therefore need and have a very good answer for this question: The goal of treatment for hepatitis C is to prevent the develop- ment of cirrhosis and the complications of cirrhosis including liver cancer and liver failure. This concept is easy to understand and makes sense. Infection with HCV leads to inflammation in the liver, which leads to scarring, which can eventually lead to cirrhosis. If the virus is removed from the body, the whole process is stopped. Scar tissue is permanent, so the scarring in the liver will remain fixed at the level where it was when the virus was eliminated. Assuming that cirrho- sis has not yet developed, the person should have almost no risk of developing liver-related complica- tions in the future.
The standard definition of a cure in clinical studies is that HCV cannot be detected in blood tests 6 months after the end of treatment. This outcome is termed a sustained virological response (SVR).
Unfortunately, large prospective studies that support this argument are not yet available. The problem is that hepatitis C leads to cirrhosis in only a minority of patients, and its progression to cirrhosis usually takes decades. Large groups of patients will need to be stud- ied for long periods of time before we have good scien- tific support for our theories. Smaller studies and retrospective studies, however, strongly suggest that patients who clear the virus following treatment have lower rates of fibrosis, a lower risk of developing liver cancer, and improved survival.
Some studies suggest that even patients with compen- sated cirrhosis will benefit from treatment. Cure of hepatitis C in a patient with compensated cirrhosis will not eliminate the risk of complications in the future but may significantly reduce the risk, from about 5 percent per year to about 2 percent per year. Success- ful treatment also has a major benefit in any patient who eventually needs a liver transplant. If the virus is eradicated before the transplant takes place, the risk of hepatitis C recurrence after transplant is much lower.
In general, no treatment is necessary for nonspecific symptoms of hepatitis C such as fatigue and muscle aches. In fact, treatment does not appear to improve these symptoms and is not warranted given its potential side effects. Once safer treatments become available, you might consider trying therapy to see if these nonspecific symptoms improve. An exception is the case in which symptoms are from extrahepatic complications such as cryoglobulinemia or glomerulonephritis. Treatment of hepatitis C can treat these illnesses and is often pursued regardless of the extent of baseline liver injury.
40. What is interferon?
Interferons are a family of proteins that are naturally pro- duced by the body to fight infections. Three classes of interferons exist: alfa, beta, and gamma. Each class has slightly different activities against viruses and bacteria.
Alfa-interferons were first approved by the Food and Drug Administration for treatment of hepatitis C in 1991; they originally required injections three times a week. Modifications since then have produced a longer- acting interferon that can be given just once a week. The initial standard interferons were "pegylated" by adding
an inactive molecule called polyethylene glycol to them. This alteration changes the way that the body recog- nizes and destroys the drug and allows the interferon to stay in the body for a longer period of time. As a group, these newer interferons are called peginterferons. Two peginterferons are currently available: peginterferon alfa-2b (Peg-Intron) and peginterferon alfa-2a (Pegasys). The dose of Peg-Intron given depends on the patient's weight and is calculated at 1.5 micrograms per kilogram per week. Pegasys is given as a fixed dose of 180 micrograms per week.
These two interferons appear to have similar effective- ness and side-effect profiles. To date, no large study comparing the two has been published and most gas- troenterologists consider them to be equivalent. The major downside to the interferons is that they have many potential side effects.
In addition to the development of peginterferons, the other recent major advance in treatment has been the addition of ribavirin to interferon as part of combina- tion therapy. This leads us to the next question.
which an inactive molecule called poly- ethylene glycol is added to standard interferon. This change increases the length of time that the drug remains active against hepati- tis C and allows for less frequent injec- tions.
feron produced by the pegylation of interferon alfa-2a.
41. What is ribavirin?
Ribavirin is a synthetic nucleoside that has antiviral activity. It was first studied in respiratory infections and is approved as a treatment for severe viral pneu- monias in infants and young children. Ribavirin was initially studied in hepatitis C as a single-agent ther- apy but was not effective in eliminating the virus when given by itself. Ribavirin was then combined with standard interferon; this combination resulted in a sig- nificant increase in the percentage of patients who had a sustained virological response. Cure rates increased
from approximately 20 percent to 40 percent in three large studies conducted in the 1990s, and ribavirin has been part of standard treatment for hepatitis C since then. When peginterferons were introduced, they were also used in combination with ribavirin.
Ribavirin is generally better tolerated than interferon but does have some potentially significant side effects. Two notable side effects are the development of a severe anemia and potential teratogenicity (develop- ment of birth defects). Ribavirin can cause serious birth defects, so the patient and his or her partner should not become pregnant while on treatment and for 6 months after the completion of treatment. Patients must use two forms of birth control during this period.
Ribavirin can be dosed either as a fixed dose or as a weight-based dose depending on the viral genotype of the patient being treated.
42. Who should be treated and who should not be treated?
Everyone with hepatitis C should be evaluated for possible treatment. The two major considerations are an individual's risk for developing cirrhosis and liver- related complications and the success rate and safety of the treatment being considered. As yet, there is no model that can predict with complete accuracy a par- ticular patient's risk of developing cirrhosis or decom- pensation from liver disease. Most doctors depend heavily on the results of the liver biopsy and recom- mend treatment when the biopsy reveals significant
inflammation and scarring. Some doctors will treat patients with a favorable genotype (2 or 3) without a liver biopsy if the patient is a good candidate and has no contradictions to therapy.
If treatment is felt to be appropriate, patients are care- fully assessed to see if therapy can be given safely. Combination therapy with interferon and ribavirin carries many risks, including depression, birth defects, infection, severe anemia, bone marrow depression, thy- roid disease, and worsening of an underlying autoim- mune disease. Treatment can also worsen quality of life if the patient suffers side effects such as fatigue, flu- like symptoms including fevers and muscle aches, loss of appetite, sleeping problems, and hair loss.
The National Institutes of Health (NIH) held a major meeting several years ago that produced the following guidelines for therapy with interferon and ribavirin:
Absolute Contraindications
Severe or uncontrolled psychiatric disease
Poorly controlled epilepsy
Active serious infection
Pregnancy or inadequate contraception
Severe heart disease
Advanced renal failure
Documented poor compliance
Everyone with hepatitis C should be evaluated for possible treat- ment.
Uncontrolled serious medical condition
Relative Contraindications
Hepatic decompensation
Solid-organ transplant (except liver)
Autoimmune disease
Neutrophils < 0.75 10 9 /L (low white blood cell count)
Platelet count < 50 10 9 /L (low platelet count)
Severe anemia
Ongoing alcohol or substance abuse
Your doctor will obviously assess you carefully prior to starting treatment. Further tests—for example, a preg- nancy test, stress test of the heart, or psychiatry con- sult—may be requested by your doctor before therapy begins if he or she has any specific concerns.
43. Can you describe current treatment protocols?
Over the last 15 years, the treatment of hepatitis C has evolved from standard interferon monotherapy (sin- gle-agent therapy) to combination therapy with stan- dard interferon and ribavirin to combination therapy with peginterferon and ribavirin. Occasionally, patients with special situations are treated with interferon monotherapy; these patients usually have an absolute contraindication to ribavirin. In this question, we will focus on the standard patient who is treated with com- bination therapy.
There are two peginterferons on the market: Peg- Intron and Pegasys. Although no study has directly compared the two, studies comparing each to standard interferon and ribavirin resulted in very similar SVR rates for both peginterferons. We will assume for now that they are equivalent and use the generic term peginterferon to apply to whichever one your doctor has chosen. The major decisions, then, are the dose and the duration of treatment. The major factors that influence these decisions are the genotype and the presence (or absence) of cirrhosis.
The peginterferons are given at a standard dose in all patients. Peg-Intron is dosed based on patient weight at 1.5 micrograms per kilogram per week. Pegasys is given as a fixed dose of 180 micrograms per week. Ribavirin is usually dosed based on the genotype. Genotype 1 patients are dosed by weight: 1,000 mil- ligrams daily in two divided doses in patients weighing less than 75 kilograms (165 pounds) and 1,200 mil- ligrams daily in two divided doses in patients weighing more than 75 kilograms. Genotype 2 and 3 patients are usually dosed at a standard 800 milligrams of rib- avirin in two divided doses. In some studies, weight- based ribavirin dosing is also used in patients with genotypes 2 and 3. Genotypes 4–7 are rarely seen in the United States. Because data on these genotypes are lacking, patients with these genotypes are usually man- aged much like genotype 1 patients.
All genotype 1 patients are treated for 48 weeks if they show appropriate viral level responses at weeks 12 and 24. An appropriate drop in viral levels at these time points is termed an early virological response (EVR) and is used to decide whether treatment should
refers to the appro- priate drop in hepati- tis C viral levels that determines whether treatment should continue.
continue. The EVR at 12 weeks is a 2-log (100-fold) decrease in the viral level, and the EVR at 24 weeks is an undetectable viral level. In other words, if your viral level has fallen less than 100-fold at the 12-week mark or is still detectable at the 24-week mark, your doctor will probably recommend stopping treatment because the chance of cure or SVR is close to zero. If the viral level is close to the cutoff, some doctors will continue treatment for an extra month to see whether an EVR is reached. If the goal viral level is reached after the extra month, treatment continues and an extra month is added on to the treatment duration at the end. Genotype 2 and 3 patients are usually treated for 24 weeks; their viral levels are not necessarily checked during treatment because of the high cure rates associ- ated with these genotypes.
Doctors may vary how they structure the treatment pro- tocol. Some doctors will continue therapy for harder-to- treat genotype 2 and 3 patients such as cirrhotics for a longer period of time such as 48 weeks. More recently, doctors have been checking viral levels at the 4-week mark. A rapid viral level drop over the first few weeks of treatment appears to correlate with a better overall cure rate. A recent study suggested that patients with geno- types 2 and 3 who have an undetectable viral level at the 4-week mark can be treated for 12 weeks instead of 24 weeks and still have similar SVR rates.
Let's summarize the treatment protocols from the genotype perspective:
Patients with genotype 1 will be treated with the standard peginterferon dose and weight-based rib-
avirin (1,000 milligrams or 1,200 milligrams daily) for 48 weeks. Treatment will be stopped at the 12- week mark if the viral level has not fallen 100-fold. Treatment will be stopped at the 24-week mark if the viral level is still detectable. • Patients with genotype 2 or 3 are usually treated with the standard peginterferon dose and ribavirin 800 milligrams daily for 24 weeks. Some doctors use weight-based ribavirin dosing in patients with genotype 2 or 3.
Your doctor will follow you very closely while you are receiving treatment. It is important that you are honest with your doctor about how you are feeling while on treatment. Blood tests will be performed almost weekly for the first month and then monthly for the rest of treatment. Office visits are scheduled at least monthly.
I was diagnosed with genotype 2, which was good news at the time because it responds to treatment much better than type 1 and it requires 24 weeks of treatment as opposed to 48 weeks with type 1. At week 4 of treat- ment, I had a negative viral load level, which was better news. Again at week 12, I was negative. My doctor dis- cussed the possibility of stopping treatment at this point, citing the study mentioned here. He explained that the study involved patients on a higher dose of ribavirin than I was on, so it was not an exact comparison for me. Because my side effects at this time were getting better, and because if I did relapse later I would have to restart treatment from the beginning, I decided to continue. If
you are faced with a decision like this, make sure you know your thyroid condition as well as your white and red blood cell counts, as this information will influence your decision. Your doctor must advise you as to the pros and cons of this situation, but the final decision is yours.
The approxi- mate cure rates are a 50 per- cent overall cure rate, a 40 to 45 percent cure rate in patients with genotype 1, and a 70 to 80 percent cure rate in patients with genotypes 2 and 3.
44. What is my chance of being cured?
This question can be answered in many different ways depending on how specifically a patient is character- ized. The approximate cure rates are a 50 percent over- all cure rate, a 40 to 45 percent cure rate in patients with genotype 1, and a 70 to 80 percent cure rate in patients with genotypes 2 and 3. Most of these num- bers were derived from three large studies published between 2001 and 2004. Because these studies did not use the same treatment protocols, it is hard to compare their results directly. All three studies compared the combination of a then-new peginterferon in combina- tion with ribavirin to standard interferon and ribavirin.
In 2001, Manns and colleagues published a study comparing the safety and efficacy of two different regi- mens of peginterferon alfa-2b (Peg-Intron) in combi- nation with ribavirin compared with standard interferon alfa-2b plus ribavirin. The high-dose Peg- Intron group had the best cure rates. This group received the now-standard Peg-Intron dose of 1.5 micrograms per kilogram but only 800 milligrams daily of ribavirin. The overall cure rate was 54 percent. Genotype 1 patients had a cure rate of 42 percent, and genotype 2 and 3 patients had a cure rate of 82 per- cent. We would expect a higher cure rate in the geno- type 1 patients if a higher ribavirin dose had been
used, and a review of the data correcting for weight supported this expectation.
In 2002, Fried and colleagues published a study com- paring the efficacy and safety of peginterferon alfa-2a (Pegasys) plus ribavirin, standard interferon alfa-2b plus ribavirin, and peginterferon alfa-2a and placebo. In this study, the dose of ribavirin was based on the patient's weight, as is now standard practice in genotype 1 patients. The Pegasys dose was the standard 180 micro- grams per week. The group that received Pegasys plus ribavirin had the best cure rates. The overall cure rate was 56 percent. Genotype 1 patients had a cure rate of 46 percent, and genotype 2 and 3 patients had a cure rate of 76 percent. Obviously, the results from these two studies were very similar despite differences in dosing of ribavirin and some other more technical differences.
In 2004, Hadziyannis and colleagues published a study in which all patients were treated with Pegasys but the ribavirin dose (800 milligrams daily versus weight- based 1,000–1,200 milligrams daily) and treatment duration (24 versus 48 weeks) were varied. The results of this study support the current treatment guidelines. Genotype 1 patients did better with 48 weeks of treat- ment and weight-based ribavirin. Genotype 2 and 3 patients did not benefit from longer-duration treat- ment or higher ribavirin doses.
All three studies concluded that better cure rates can be achieved when treatment discontinuations and dose reductions are minimized. Other factors besides geno- type affect the cure rate as well, as we will discuss in the next question. Creating a model that takes into
account all of these other factors poses quite a chal- lenge.
suppression of the body's immune sys- tem; used after trans- plants to prevent the body's immune sys- tem from damaging the transplanted organ.
45. What factors other than genotype affect my chance of achieving a response to treatment?
Genotype is clearly the most important predictor of a response to combination therapy. The cure rate for genotype 1 patients is approximately 40 to 45 percent, and that for genotype 2 and 3 patients is 70 to 80 per- cent. Once treatment has been started, the EVR points at 12 and 24 weeks are strong predictors of treatment response. Studies have also shown that response to treatment improves when patients are able to follow the treatment protocol exactly. The "80:80:80 rule" sums up this relationship: Response is better when patients take at least 80 percent of the peginterferon dose and 80 percent of the ribavirin dose 80 percent of the time. Maintaining the planned treatment regimen for the first 12 weeks appears to be especially important. Obvi- ously, following the treatment protocol 100 percent of the time is the best approach. Treatment interruptions and modifications can result from problems with patient adherence or from doctor-initiated changes in therapy because of side effects. This is why patients are screened carefully before starting therapy and follo