ATTENTION ALL VETS

[SkyShark]

Today I spent the day at the VA hospital. I had to get blood work and a bunch of other stuff squared away.

While I was talking with my primary Doctor, he asked me if I had been tested for Hepatitis C. I said I didn't know. He then ordered the test. I asked why. He then asked, "When you were in the serivce did they use needles or did they use the air guns in basic?" I answered both. He then stated that they have found especially in Viet Nam Vets, but also Vets of the 80's and Early 90's have been popping up with Hepatitus C. He said they have found that the air guns from those times, may have caused a blood splash when shots were given and everyone down the line shared blood with everyone that got a shot in front of them.

He then informed me that they really weren't advertising it they were just getting all the Vets to take a test when they came in for appointments and stuff.

I advise everyone to go get the test to make sure.

FYI

[Steadfast]

I've lost a few friends to Hepitis C already & not just RVN vets but Korean vets of the same time frame as RVN too.

When I went in those Air Guns were the norm for getting shots. If ya moved when they were shooting you then you got cut. Of if the operator moved while shooting you, you got cut. Same difference, same result.

I've been elusive to get tested for Hep C myself.

Hey! Good to see you again SkyShark.

[Cat]

Thanks for the information SkyShark, I'll pass this along.


I was last to get shots in Basic Training and they used needles on the last 5 in line. I was lucky, everyone hated the air guns

[AngryPistols]

Thanks for the info Sharky, airguns for me and most of my Vet friends and I'll pass this along to them.

Angry

[resqparamedic]

Today I spent the day at the VA hospital. I had to get blood work and a bunch of other stuff squared away.

While I was talking with my primary Doctor, he asked me if I had been tested for Hepatitis C. I said I didn't know. He then ordered the test. I asked why. He then asked, "When you were in the serivce did they use needles or did they use the air guns in basic?" I answered both. He then stated that they have found especially in Viet Nam Vets, but also Vets of the 80's and Early 90's have been popping up with Hepatitus C. He said they have found that the air guns from those times, may have caused a blood splash when shots were given and everyone down the line shared blood with everyone that got a shot in front of them.

He then informed me that they really weren't advertising it they were just getting all the Vets to take a test when they came in for appointments and stuff.

I advise everyone to go get the test to make sure.

FYI

Thanks for the info. I appreciate the heads up and will pass it along.

[DJB]

Hep C is a serious disease and can have horrible consequences. I have spent a few months in the transplant ICU mostly managing liver failure and liver transplant patients. These are some of the sickest people in the hospital. I would not wish liver failure on anyone. Unfortunately I know of two medics from Bn (one from 1st the other from 3rd) who have HCV. Just think of all the blood they were exposed to in Bn. Below is an overview of HCV for those concerned.


DEFINITION — The term "hepatitis" is used to describe a common form of liver injury. Hepatitis simply means "inflammation of the liver" (the suffix "itis" means inflammation, and "hepa" means liver). There are many causes of hepatitis; examples include alcohol, certain drugs, poisonous mushrooms, and viruses. Hepatitis C is a virus that was isolated in 1989. Since then, a tremendous amount has been learned about the virus.

SYMPTOMS — Hepatitis C usually causes no symptoms when people first become infected. However, in approximately 80 percent of people, the virus becomes chronic and has the potential to cause liver damage, ranging in severity from mild to severe. This is in contrast to other types of viral hepatitis (such as hepatitis A) that usually make people sick when they first become infected (causing flu like symptoms and sometimes jaundice [yellowing of the skin and eyes]), but then are cleared from the body.

During its residence in the liver, the hepatitis C virus causes damage to the liver, but the amount of damage is variable, and is offset by the liver's ability to repair itself. Most infected patients, even those with progressing disease, have no specific symptoms. The most common symptom is fatigue, the cause of which is not entirely clear. The absence of symptoms does not necessarily mean that the infection is under control.

COMPLICATIONS — Hepatitis C produces ongoing inflammation in the liver over many years (show histology 1). In some patients scar tissue (called fibrosis) accumulates in the liver, which can eventually become extensive, leading to cirrhosis (a term used to describe a severely scarred liver) (show histology 2). Patients who have developed cirrhosis are at increased risk for developing complications since the scarred liver's ability to perform all of its many functions is diminished.

One of the most feared complications of cirrhosis is the development of liver cancer (called hepatocellular carcinoma), which occurs almost exclusively in patients who have already progressed to cirrhosis. It has been estimated that about 2 percent of people with cirrhosis (1 in 50) develop hepatocellular carcinoma each year. Therefore, the majority of people with cirrhosis due to hepatitis C will not get hepatocellular carcinoma. Patients with cirrhosis usually have regular blood tests and ultrasound examination to screen for hepatocellular carcinoma.

TRANSMISSION — The hepatitis C virus is spread by contact with blood. Thus, patients with hepatitis should avoid activities that could expose other persons to their blood. Examples include sharing a toothbrush, nail clippers, razors, and needles (show table 1).

Sexual transmission — The virus can also be spread sexually, but the risk is much lower than for other types of viruses. The risk of transmission between stable monogamous sexual partners (ie, between sexual partners who have no other sexual contacts) is estimated to be approximately one in a thousand per year. Although use of a condom in this setting may decrease this risk, the United States Public Health Service and a consensus panel of experts from the National Institutes of Health have concluded that the risk is not sufficiently high to recommend routine use of condoms among monogamous sexual partners.

On the other hand, patients who do not have a stable monogamous sexual partner should use condoms. This is to protect patients with hepatitis C from new infections (such as human immunodeficiency virus (HIV) or other sexually transmitted diseases) as well as to protect the partner from acquiring hepatitis C.

The risk of transmitting the virus is higher in people who are infected with hepatitis C and with HIV. Furthermore, care of patients who are coinfected with HIV and HCV may differ from those with HCV alone. You should tell your clinician if you know that you are infected with HIV or think you may be at risk for infection.

Other transmission — There is no evidence that kissing, hugging, sneezing, coughing, sharing food, water, eating utensils or drinking glasses, casual contact, or other contact without blood exposure is associated with transmission of the hepatitis C virus. On the other hand toothbrushes, razors, and other objects that might be contaminated with blood should not be shared. This also applies to implements (such as straws) used to inhale cocaine or needles to inject drugs. Use of illicit drugs should be avoided since they are dangerous, potentially expose the user to a variety of diseases, and can limit treatment options for HCV. Daily use of marijuana has been associated with worsening liver disease. Thus, people with HCV should avoid it.

Transmission during pregnancy — The risk of transmitting hepatitis C during pregnancy may depend upon the level of virus in your blood stream. In general, the risk is about 5 to 6 percent (about 1 in 20) but is increased in people who are also infected with HIV (about 12 percent or 1 in . Speak to your clinician if you are pregnant or contemplating pregnancy.

RISK FACTORS FOR PROGRESSION — Researchers have studied large groups of patients with hepatitis C to find out what happens to them over time. Only about 20 percent (or one in five) will develop cirrhosis 20 years after first acquiring the infection. Most of the others will have some degree of inflammation in the liver, but without a significant amount of scarring.

Researchers have tried to identify factors that increase the risk of developing cirrhosis after patients have become infected with hepatitis C. The most important include:

Consumption of alcohol - People with hepatitis C who drink alcohol are at much greater risk for developing cirrhosis.
Amount of liver inflammation and scarring - Increasing amounts of inflammation make it more likely that the liver will become scarred.
Alcohol consumption — The amount of alcohol that is safe for people with hepatitis C to consume is not well established. Even small amounts (social drinking) have been linked to an increased risk of cirrhosis in patients with hepatitis C. Until more is known, most clinicians recommend completely avoiding alcohol.

Liver inflammation — There are many tools for determining how much damage the hepatitis C virus has caused. Blood tests and ultrasound examination of the liver are helpful, but are not the most accurate way to determine the severity of liver inflammation or scarring. Newer tests are actively being developed and some are already commercially available. However, none has yet been proven to be sufficiently accurate to replace liver biopsy.

The best test is a liver biopsy, which involves obtaining a tiny sample of the liver tissue and looking at it under a microscope. A liver biopsy is usually done as an outpatient procedure. You should discuss with your clinician whether it is required in your case. (See "Patient information: Liver biopsy").

Your clinician will obtain two other blood tests that are helpful for determining the best treatment and monitoring treatment:

Hepatitis C virus (HCV) RNA, which is a measure of the amount of virus circulating in your blood
HCV genotype, which determines the specific type of virus that you have (most people in the United States have type I)
SELF-CARE MEASURES — Avoiding alcohol is the best way to protect the liver from further damage. In addition, all people infected with hepatitis C should be vaccinated against hepatitis A and B, unless they are already known to be immune. Pneumococcal vaccine should be given every five years while influenza vaccination should be given yearly in addition to other routine vaccinations. Routine vaccinations included diphtheria and tetanus booster immunizations every ten years.

LONG-TERM MANAGEMENT — People who have developed cirrhosis should undergo regular screening for hepatocellular carcinoma, which is typically done with an annual or biannual (every other year) ultrasound examination plus a blood test (serum alpha fetoprotein level). In addition, a procedure called an upper gastrointestinal endoscopy may be done. This test uses a thin, flexible fiberoptic instrument to inspect the esophagus (food pipe) and stomach to evaluate for esophageal varices (enlarged veins in the esophagus). Varices develop in roughly 50 percent of patients with cirrhosis. (See "Patient information: Upper endoscopy").

Diet — No specific diet has been shown to improve the outcome in patients with hepatitis C. The best advice is to eat a normal, healthy, and balanced diet. It is reasonable to take a multivitamin without iron. Coffee consumption is safe.

Exercise — Exercise is good for overall health and is encouraged, but has no effect on the virus.

Prescription and nonprescription drugs — Many drugs require metabolism by the liver. Thus, it is always best to check with your clinician or pharmacist before starting a new prescription. As a general rule, unless your liver is already scarred, most drugs are safe for people with hepatitis C.

One important exception is acetaminophen (Tylenol); the maximum dose should be no more than 2000 milligrams or 2 grams (in divided doses) per 24 hours.

Herbal medications — Although many claims about herbal medications have been made (particularly on the internet), none has been proven to improve outcomes in patients with hepatitis C. In addition, some herbal medications have been associated with serious liver toxicity.

Support — Patients with hepatitis C should not underestimate the value of sharing their concerns with others who have the same diagnosis. The American Liver Foundation has helpful advice and listing of support groups (www.liverfoundation.org). Your clinician can also help find a local support group.

TREATMENT OPTIONS — The goal of treating people with hepatitis C is to prevent progression of the liver disease. As mentioned above, about 20 percent of people will develop cirrhosis 20 years after becoming initially infected. Therefore, people with hepatitis C who are young have a greater lifetime chance of developing cirrhosis and complications of cirrhosis. Unfortunately, it is not always possible to predict accurately in whom the disease will progress.

Currently, most patients are treated with a combination of pegylated interferon and ribavirin. This treatment is not easy since both drugs can cause side effects. The most common side effects are flu-like symptoms and fatigue, although many less common but potentially serious side effects can also occur. Nevertheless, most people get through treatment while going to work and functioning normally. It is important to ask about and understand the risks of treatment.

During therapy, the level of the virus in the blood (called viral load) will be monitored, with the goal of completely eliminating the virus. Therapy may be stopped early for those who do not respond; otherwise treatment is continued for six to 12 months (depending in large part upon the specific genotype).

Cure — The chance of being cured depends in part upon the specific type of hepatitis C virus (ie, the specific genotype). Overall, the chance is approximately 40 to 50 percent for the most common genotype (genotype 1 in the United States). The best chance (approximately 80 percent or more) occurs with genotypes 2 and 3. The recommended duration of treatment for genotype 1 is 48 weeks, whereas for genotype 2 and 3 it is usually 24 weeks. The clinician will discuss the likelihood of cure and whether treatment is a good option.

Patients must wait six months after therapy is completed to determine if they have been cured, since the virus can recur after therapy has been discontinued. Recurrence happens about 25 to 30 percent of the time. The absence of the virus for more than six months after stopping therapy amounts to a cure. Follow-up studies of these patients show no trace of the virus in the blood or liver for over 10 years.

NEW TREATMENTS — Even though combination therapy with interferon plus ribavirin cures about 50 percent of people (up to 80 percent with genotype 2 and 3), many are not cured. Thus, new treatments for hepatitis C are actively being developed. At the present time most are in early stages of testing. Your clinician may be able to help locate a clinical study of experimental treatments should this become an option.

REASONS TO BE OPTIMISTIC — If you have recently discovered that you or someone you care about has hepatitis C, there are many reasons to be optimistic:

Hepatitis C progresses slowly, and many people who harbor the virus will never get sick.
You are not alone; about 2.7 million people in the United States have hepatitis C virus in their blood. Treatment is available, and researchers are at work developing new treatments.



A more advanced overview...


INTRODUCTION — Infection with the hepatitis C virus (HCV) can result in both acute and chronic hepatitis. The acute process is most often asymptomatic; if symptoms are present, they usually abate within a few weeks. Acute infection rarely causes hepatic failure.

Acute HCV typically leads to chronic infection; 60 to 80 percent of cases develop chronic hepatitis (abnormal liver enzymes). Chronic HCV infection is usually slowly progressive; it may not result in clinically apparent liver disease in many patients if the infection is acquired later in life. Approximately 20 to 30 percent of chronically infected individuals develop cirrhosis over a 20- to 30-year period of time. Chronic HCV is the most common cause of chronic liver disease and the most frequent indication for liver transplantation in the United States.

The clinical features associated with acute and chronic HCV infection, and factors associated with the progression of chronic liver disease will be reviewed here. The epidemiology, diagnosis, and treatment of HCV are discussed separately. (See appropriate topic reviews.)

ACUTE HEPATITIS C — HCV is the cause of approximately 20 percent of cases of acute hepatitis in the United States [1]. The presence of HCV RNA in serum or liver is the first biochemical evidence of HCV infection. HCV RNA is detectable in serum by PCR within days to eight weeks following exposure, depending in part upon the size of the inoculum. Serum aminotransferases become elevated approximately 6 to 12 weeks after exposure (range 1 to 26 weeks). (See "Diagnosis and treatment of acute hepatitis C in adults").

The majority of acutely infected patients are asymptomatic and have a clinically mild course; jaundice is present in fewer than 25 percent. As a result, periodic screening for infection may be warranted in patients who are at high risk for infection [2]. Additional symptoms are similar to those in other forms of acute viral hepatitis, including malaise, nausea, and right upper quadrant pain. In patients who experience acute symptoms, the illness typically lasts for 2 to 12 weeks. Fulminant hepatic failure due to acute HCV infection is very rare, but may be more common in patients with underlying chronic hepatitis B virus infection [3,4]. (See "Diagnosis and treatment of acute hepatitis C in adults").

CHRONIC HEPATITIS C — The risk of chronic infection after an acute episode of hepatitis C is high. In most studies, 80 to 100 percent of patients remain HCV-RNA positive, and 60 to 80 percent have persistently elevated liver enzymes (show figure 1) [5,6]. The rate of spontaneous clearance of virus after it has persisted for at least six months is very low. In one study, for example, 142 HCV antibody-negative patients with a history of intravenous drug use were prospectively monitored for HCV seroconversion [2]. During eight years of follow-up, seroconversion was documented in 30 percent. HCV RNA clearance occurred in only six patients (14 percent) who seroconverted by antibody testing; the median time to HCV RNA clearance was 19 months (range 14 to 45).

The mechanism responsible for the high prevalence of chronic infection is unclear. It may be related to the genetic diversity of the virus and its tendency toward rapid mutation, allowing HCV to constantly escape immune recognition [7,8]. (See "Characteristics of the hepatitis C virus").

Host factors may also be involved in the ability to spontaneously clear the virus. Among the factors that have been associated with an increased likelihood of HCV clearance are the presence of specific HLA-DRB1 and DQB1 alleles [9,10], high titers of neutralizing antibodies against HCV structural proteins [11,12], the persistence of an HCV-specific CD4 T-cell response [13,14], and white patients with relatively low peak levels of HCV viremia during acute infection [2]. Furthermore, lower rates of chronic infection have been reported after exposure in some populations. As an example, only 55 percent of a cohort of Irish women who had been infected after Rh immunization had HCV RNA detectable in serum (see below) [15]. Children also appear to have a relatively low rate of developing chronic infection after exposure. In one study that included 67 children who developed HCV antibodies after receiving contaminated blood transfusions, only 37 (55 percent) had HCV RNA in blood [16].

Symptoms — Most patients with chronic infection are asymptomatic or have only mild nonspecific symptoms [17]. The most frequent complaint is fatigue; other less common manifestations include nausea, anorexia, myalgia, arthralgia, weakness, and weight loss. The symptoms are rarely incapacitating and may be difficult to ascribe to liver disease alone (rather than to another illness such as depression); nevertheless, they may lead to a decrease in the quality of life [18,19], which may in part be accounted for by awareness of infection [20], and which can be improved following successful treatment [21].

Ondansetron (a 5-HT3 receptor antagonist) 4 mg twice daily significantly improved fatigue in a placebo-controlled trial involving 36 patients [22]. The rationale for its use was based upon the observation that serotonin is associated with fatigue in animal and human models [23]. Long-term efficacy is unclear and treatment may be associated with constipation. Fatigue improves in some patients who have a sustained virologic response following interferon-based therapy; in one of the largest series addressing this issue, fatigue improved in 29 of 83 responders versus 75 of 348 nonresponders (35 versus 22 percent) [24].

The symptoms of chronic HCV infection do not reliably reflect disease activity. One study, for example, evaluated a cohort of over 100 patients with chronic HCV infection and no clinical signs of cirrhosis who participated in two clinical studies at the National Institutes of Health [25]. Self-administered symptom scores were compared to those in 100 healthy blood donors without HCV. Fatigue was the most common complaint among both groups and occurred with similar frequency (62 percent in those with HCV versus 70 percent of controls). Abdominal pain, itching, and dark urine were the only complaints that were significantly more common among the HCV group, although they were present in only a small number of patients.

The lack of correlation between the symptoms of HCV infection and either the serum ALT concentration or liver histology has been confirmed in other reports; however, symptoms appear to be more common once cirrhosis develops [17]. One possible explanation is cognitive impairment, which has been demonstrated in patients with HCV independent of the severity of liver disease [26-29]. The mechanisms leading to the impairment are not well understood.

Serum aminotransferases — There is wide variability in serum aminotransferase concentrations among individual patients with chronic HCV infection over time. Up to one-third of patients have a normal serum ALT [6,30]. Slight enzyme elevations are usually seen in the remaining patients; only about 25 percent have a serum ALT concentration more than twice normal, and it is rare to find elevations more than 10 times normal.

There is generally a poor correlation between aminotransferase levels and liver histology [31,32]. As an example, a study of 90 patients with chronic hepatitis C found no correlation between histologic findings and serum ALT values unless the ALT was elevated more than 10-fold; these marked elevations were associated with periportal inflammation and necrosis (so-called piecemeal necrosis) [31]. The mean values of aminotransferases were significantly lower among patients with chronic persistent hepatitis (minimal activity) than those with chronic active hepatitis (mild to moderate activity); however, overlap of values was considerable between the different histologic groups. Patients with normal serum ALT almost always show histologic evidence of chronic inflammation, although the degree of injury is typically minimal or mild [25,30,33]. (See "Hepatitis C virus infection in patients with normal serum aminotransferases").

It has also been suggested that serum ALT is an accurate marker of the response to interferon therapy. However, a meta-analysis of studies found that the serum ALT did not correlate well with the histologic change in response to therapy; there was histologic improvement in a relatively high proportion of interferon-treated patients who did not normalize their serum ALT with treatment [34]. (See "Interferon in the treatment of chronic hepatitis C virus infection").

Despite the general lack of correlation between liver histology and serum ALT concentrations in chronic hepatitis C, some investigators have observed that the ratio of serum AST to ALT may be useful for predicting the presence of cirrhosis [35,36]. In one study of 139 patients, the mean AST/ALT ratio was higher among patients with cirrhosis than in those without cirrhosis [35]. An AST/ALT ratio 1 had 100 percent specificity and 53 percent sensitivity for cirrhosis using corresponding liver biopsy specimens as the gold standard. The positive and negative predictive values were 100 and 81 percent, respectively. However, two additional series found that the predictive accuracy of this ratio was not as high [37,38]. Thus, its clinical utility remains uncertain. (See "Patterns of plasma aspartate and alanine aminotransferase levels with and without liver disease").

Natural history — The natural history of chronic hepatitis C has been difficult to clearly define because of the long course of the disease [39]. Several studies have provided estimates of the proportion of patients with chronic infection who develop cirrhosis within 20 years [39-51]. As a general rule, estimates from retrospective studies (17 to 55 percent) have been higher than prospective studies (7 to 16 percent), possibly reflecting referral bias in the retrospective studies. A consensus statement issued by the National Institutes of Health suggests that the actual risk is closer to that derived from the prospective studies (www.consensus.nih.gov/cons/116/116cdc_intro.htm).

Studies of patients who acquired acute hepatitis C from a blood transfusion generally describe no increase in all-cause mortality if the follow-up is less than 25 years [41,42]. In an illustrative report, all cause mortality was similar among 222 hepatitis C-related cases compared to 377 controls (67 versus 65 percent), although liver-related mortality was increased (4.1 versus 1.3 percent) [42]. These observations may reflect that not all patients became chronically infected or developed significant liver disease following acute infection.

In contrast, studies of patients who presented with chronic hepatitis tend to report a more aggressive course with a high risk of cirrhosis, decompensation, and hepatocellular carcinoma. In one series from the United States, for example, 131 patients with chronic posttransfusion hepatitis C were evaluated a mean of 22 years after transfusion: 23 percent had chronic active hepatitis, 51 percent had cirrhosis, and 5 percent had hepatocellular carcinoma [43]. Hepatocellular carcinoma developed in an additional seven patients an average of 36 months after the initial visit. It was estimated that the mean duration of infection among patients who developed cirrhosis was 20.6 years. Similar data were observed in studies from Japan and France [44-46].

That the disease may not be progressive in all patients has been underscored in a growing number of studies [15,45,47-51]. In a large French series, the mean time to cirrhosis was 30 years [45]. It was estimated that 31 percent of patients would show no evidence of cirrhosis for at least 50 years. Similar results were described in another cohort study that followed 1980 women who had been infected with contaminated batches of anti-D immunoglobulin [52]. After 25 years, overt cirrhosis or advanced fibrosis had developed in only 0.5 and 1.5 percent of the cohort, respectively, while only one patient had been diagnosed with HCC [52].

In another report, serum samples stored between 1948 and 1954 from 8568 military recruits were analyzed for antibodies against hepatitis C and HCV RNA [49]. Of 8,568 samples, 17 (0.2 percent) were positive for HCV by RIBA, of which 11 were positive for HCV RNA. During 45 years of follow-up, liver disease occurred in only 2 of the 17 patients (12 percent) who were HCV positive by RIBA. Although more patients who were HCV positive died compared to those who were HCV negative (41 versus 26 percent), only one patient (6 percent) died of liver disease 42 years after the original blood sample was obtained.

The reason for differences in the susceptibility to disease progression among individual patients is incompletely understood. Host and viral factors that may be significant are discussed below.

Cirrhosis — Studies with 10 to 20 years of follow-up suggest that cirrhosis occurs in up to 50 percent of chronically infected patients [43,53,54], although, as discussed above, lower rates of disease progression have been described. Complications of hepatitis C are mostly confined to patients who have developed cirrhosis. This was illustrated in a prospective cohort study that included 838 patients with chronic HCV [55]. During follow-up averaging 50 months, 62 patients died (31 from liver disease and 31 from other causes). An additional 30 patients developed nonlethal complications related to cirrhosis. Thus, approximately 7 percent of the cohort developed liver-related morbidity and mortality during follow-up. The increased mortality occurred only among patients who had cirrhosis at the time of presentation.

The development of cirrhosis is silent in the majority of patients in whom it occurs [43]. Although these patients tend to be more symptomatic than those with chronic hepatitis alone, no clinical symptom, physical sign, or laboratory test is either sensitive or very specific for the diagnosis. The physical examination may reveal hepatomegaly (68 percent in one series) or splenomegaly [43]. In our experience, however, most patients with cirrhosis do not have hepatomegaly.

Laboratory testing can be helpful in identifying patients with chronic hepatitis C who have cirrhosis. Suggestive findings include an elevation in the serum bilirubin concentration (40 percent), hypoalbuminemia (10 percent), or a decrease in the platelet count [56,57].

The serum alpha fetoprotein (AFP) concentration may be mildly elevated in chronic HCV infection and does not necessarily imply the presence of hepatocellular carcinoma or cirrhosis; up to 43 percent of patients with cirrhosis without hepatocellular carcinoma have a serum AFP between 10 and 100 ng/mL [17,58]. Nevertheless, an elevated serum AFP concentration requires imaging of the liver to rule out hepatocellular carcinoma. Serial testing for several months is warranted if the imaging studies are negative, since rising levels may be indicative of an occult malignancy.

Hepatic decompensation — Cirrhosis is a prerequisite for most of the major complications of liver failure in patients with chronic HCV infection; however, not all patients with cirrhosis develop these complications [58-60]. A study of 384 patients with compensated cirrhosis due to HCV found that the risk of developing hepatic decompensation was 3.9 percent per year (show figure 2) [58]. The most common form of decompensation was ascites, followed by variceal bleeding, encephalopathy, and jaundice (which is almost always a sign of advanced liver disease in patients with chronic hepatitis C).

In another report of 200 consecutive patients with compensated cirrhosis at baseline, the probability of survival after diagnosis of decompensated HCV-related cirrhosis was 51 percent at five years [60]. Overall mortality was 43 percent after a mean of 34 months. Ascites was the most frequent initial indicator of decompensation (48 percent).

Hepatocellular carcinoma — Deaths associated with chronic hepatitis C in the United States are more likely to be due to end stage liver disease rather than hepatocellular carcinoma (HCC). However, HCV accounts for approximately one-third of HCC cases in the United States. Estimates of the risk of developing HCC once cirrhosis has developed have varied from 0 to 3 percent per year in various reports (show figure 3 and show histology 1) [58,59].

In contrast to hepatitis B virus infection, HCC in patients with hepatitis C occurs almost exclusively in those with cirrhosis suggesting that it is cirrhosis that is the major risk factor. There is, however, suggestive experimental evidence that HCV infection itself can promote the development of HCC. Mice which were made transgenic for the HCV core gene developed adenomas and subsequent carcinoma within the adenomas [61]. (See "Epidemiology and etiologic associations of primary hepatocellular carcinoma").

Survival — Survival is generally not impaired until cirrhosis has developed. In the series of 384 patients with compensated cirrhosis described above, the 3, 5, and 10-year survival rates were 96, 91, and 79 percent, respectively (show figure 4) [58]. The five-year estimated survival rate was not affected by treatment with interferon. However, once decompensated cirrhosis occurred, the five-year survival fell to 50 percent. Similar results were found in another series in which the cumulative probability of survival free of liver transplantation was 92 percent at three years and 83 percent at five years [59]. Once decompensation developed, the probability of survival at three and five years declined substantially (57 and 51 percent, respectively). Survival may also be worse in patients who develop cryoglobulinemia [62].

The Centers for Disease Control estimates that 8,000 to 13,000 deaths occur each year in the United States from chronic HCV infection. Once complications of cirrhosis have occurred, liver transplantation is the only effective therapy. Recurrent HCV infection of the graft occurs in almost all patients, although the long-term survival after transplantation for HCV is similar to that for other causes of hepatic failure (60 to 80 percent). (See "Liver transplantation for hepatitis C virus infection").

Factors predictive of disease progression — Several factors may be important determinants of disease progression in individual patients, including age, ethnic background, gender, HCV-specific cellular immune response, viral diversity, alcohol use, daily use of marijuana, viral coinfection, environmental factors and geography. However, even in a relatively homogeneous population such as in the Irish study discussed above [15], the outcome is not uniform suggesting that unexplained factors influence the disease.

Host factors — Several observations suggest that host factors are important in the progression of chronic hepatitis C:

Progressive fibrosis of a number of organs has been associated with production of profibrogenic cytokines. The effect of one of these cytokines, transforming growth factor B1 (TGF B1), is enhanced by angiotensin II. A study involving 128 patients with various stages of HCV related liver disease found a significant relationship between the specific TGF B1 and angiotensin phenotype and the fibrosis stage, suggesting that genetic polymorphism of these genes may be an important determinant of the fibrosis progression rate [63].
Acquisition of HCV infection after the age of 40 to 55 may be associated with a more rapid progression of liver injury [45,64].
Children appear to have a relatively decreased risk of disease progression. In one series, for example, only 1 of 37 patients with HCV RNA in serum had elevated levels of serum aminotransferases, while only 3 of 17 (18 percent) who had liver biopsies approximately 20 years after exposure had histologic signs of progressive liver disease [16].
Complications of liver disease, particularly hepatocellular carcinoma, are more common in Japan than in the United States [65]; it is not entirely clear whether this is due only to host characteristics, or whether viral differences or the environment might also play a role. (See "Epidemiology and etiologic associations of primary hepatocellular carcinoma").
The host cellular immune response to HCV-specific targets appears to influence the severity of liver injury; however, its role in progressive liver injury is not clear [66]. Different genes in various HLA subregions also modulate the inflammatory response by complex interaction [67].
The progression of chronic hepatitis C is accelerated in HIV-infected patients [68,69]. (See "Epidemiology, natural history, and diagnosis of hepatitis C in the HIV-infected patient").
Patients who acquire the disease from a blood transfusion may be at increased risk for disease progression compared to those infected via other modes [58,70]. However, this relationship has not been confirmed in all studies [34].
Patients who have a high body mass index and hepatic steatosis are at increased risk for the development of fibrosis [71-73]; the risk of fibrosis in those with steatosis seems to be increased significantly with even moderate alcohol intake [74]. Moderate to severe steatosis has been associated with advanced fibrosis and a decrease in response to interferon-based therapy in some reports and may be associated with insulin-resistance in the absence of obesity or diabetes mellitus [75].
Progression may be slower and histology less severe in African Americans [76-78].
Daily use of marijuana has been associated with more rapid fibrosis progression, possibly through stimulation of endogenous, hepatic cannabinoid receptors [79]. (See "Emerging therapies for hepatic fibrosis").
Alcohol intake — Alcohol promotes the progression of chronic HCV [45,80], even in patients with a relatively low alcohol intake [81]. Alcohol increases HCV replication [81,82], and has also been linked to the acceleration of liver injury [83,84]. In one study, for example, patients with chronic HCV infection and cirrhosis had a greater total lifetime alcohol consumption (290 versus 190 kg) and greater total alcohol consumption during the period of infection with HCV (241 versus 147 kg) than those with chronic hepatitis alone [80]. As noted above, even moderate amounts of alcohol appear to increase the risk of fibrosis in patients with steatosis.

These observations probably explain the epidemiologic reports of a high prevalence of anti-HCV in alcoholic patients with cirrhosis and liver failure [85,86]. Thus, alcohol intake should be avoided in all patients with chronic HCV infection. (See "Hepatitis C and alcohol").

Viral factors — The effect of viral factors on disease progression is less certain. The size of the infectious inoculum (viral dose) does not appear to be important [87]. Data regarding the role of viral genotype and quasispecies in predicting outcome are too contradictory to reach definitive conclusions [45,88-91]. As an example, while some reports have suggested that genotype 1b is overrepresented among patients with cirrhosis and those with hepatocellular carcinoma [92,93], other studies found no such association after adjusting for disease duration or patient age [34,94,95]. This suggests a cohort effect (ie, patients infected with genotype 1b having had disease for longer).

Another observation is that the disease may be accelerated in patients who are infected by more than one HCV genotype suggesting that coinfection may have an additive or synergistic harmful effect [34,95]. Similarly, coinfection with hepatitis B and C may also result in more rapid disease progression [96,97].

The significance of HBV and HCV coinfection may be underestimated since many coinfected patients lack serologic markers of HBV infection. This was illustrated in a study in which HBV DNA and serologic markers for HBV in 200 HBsAg negative patients with HCV were compared with controls with liver disease who were HCV negative and negative for HBV serologic markers [97]. HBV DNA was present in one-third of patients despite the absence of HBsAg, and patients with HCV were significantly more likely to be positive for HBV DNA than controls (33 versus 14 percent). Furthermore, occult HBV infection was more common in patients with cirrhosis (33 versus 19 percent), and appeared to be associated with decreased interferon efficacy.

The reason why some patients with HCV who are infected with HBV lack HBsAg is unknown. While some of these patients have hepatitis B core antibodies, in others, all markers are absent. The lack of HBsAg does not appear to be related to mutations within the gene encoding for the region [97]. (See "Clinical manifestations and natural history of hepatitis B virus infection" section on "Coinfection with HCV or HDV").

On the other hand, while acute infection with HBV in patients who are already infected with HCV can be associated with severe acute hepatitis, many such patients also develop a persistent decline in HCV RNA replication [98]. However, as mentioned above, the chronic liver disease associated with dual infection may progress faster than chronic hepatitis due to HCV alone.

Liver biopsy — The best clinical predictor of disease progression in chronic HCV infection is the amount of inflammation and fibrosis on liver biopsy. This relationship was illustrated in a study of 70 patients with chronic HCV infection (show figure 5) [54]:

Patients with mild inflammation (portal inflammation alone or with only focal periportal extension) and no fibrosis had only a 1.2 percent annual risk of progressing to cirrhosis (show histology 2)
Patients with moderate chronic hepatitis (periportal inflammation usually involving more than 30 percent of the limiting plate) had a 4.6 percent annual risk of developing cirrhosis; more than 90 percent developed cirrhosis within 20 years of the time of the biopsy (which was not the onset of infection)
Nearly all patients with severe inflammation or bridging fibrosis developed cirrhosis within 10 years (show histology 3)
Predictive models — Many of the reports discussed above have included multivariate models that can help predict disease progression in individual patients. In one study clinical and laboratory variables among 247 patients with varying degrees of HCV histologic severity were analyzed [34]. Death from liver failure, the development of hepatocellular carcinoma, or liver transplantation were considered together in the statistical analysis [34]. A history of hepatic decompensation (defined as at least one episode of ascites, jaundice, hepatic encephalopathy, or gastrointestinal bleeding of variceal origin) and the serum albumin concentration were independent predictors of the above outcomes. Patients without a history of decompensation and a serum albumin concentration greater than 4.1 mg/dL (41 g/L) had only a 3 percent chance of developing one of the endpoints within five years versus approximately 6 percent in patients with one of these factors, and 40 percent in patients with both factors.

Similar results were observed in a study that included 455 patients who were followed for a median of 4.7 years [99]. On multivariate analysis, the only independent predictors of progression were sporadic transmission, advanced fibrosis, and a low albumin.

Disease course during pregnancy — Relatively few studies have examined the course of HCV infection during pregnancy. The available data suggest that women chronically infected with hepatitis C may have an uneventful pregnancy without worsening of liver disease or increased risk of fetal malformations. Furthermore, one study suggested that pregnancies may even have a beneficial effect on the long-term progression of liver fibrosis [100]. (See "Pregnancy in women with underlying chronic liver disease" and see "Perinatal transmission of hepatitis C virus").

Disease course during corticosteroid use — Patients with chronic HCV can have coexisting conditions that require treatment with corticosteroids. The effect of corticosteroids on HCV has been best studied in the transplant setting where steroids increase HCV viral load, the clinical consequences of which are unclear. (See "Liver transplantation for hepatitis C virus infection").

Patients with HCV exposed to corticosteroids in the nontransplant setting also experience an increase in HCV viral load. The effect on aminotransferases is variable, although they tend to decrease [101,102]. In an illustrative study, ten patients with chronic HCV were given a seven week course of tapering prednisone [101]. Serum ALT levels decreased in eight patients (from 184 to 84 U/L) and then rebounded in seven after discontinuation. HCV RNA levels increased during therapy (by about one log) and then decreased to pretreatment values within an average of 2.8 weeks (range 1 to 5). In contrast, serum aminotransferases and bilirubin increased in another report in which treatment was continued for 16 weeks [103]. However, there was no significant change on liver histology.

The effect of these changes on the natural history of HCV is uncertain. It is doubtful that a short-course of corticosteroids would have a major impact on the progression of liver disease. In patients who require long-term steroids, it is reasonable to repeat a liver biopsy in two to three years to see if histologic progression has occurred.

The situation may be more complicated in patients with autoantibodies in whom there exists the possibility of a coexisting autoimmune hepatitis. As a general rule, treatment should first be directed toward autoimmune hepatitis because of the danger of exacerbating autoimmune hepatitis with interferon based regimens. (See "Treatment of autoimmune hepatitis").

EXTRAHEPATIC MANIFESTATIONS OF CHRONIC HEPATITIS C — A number of extrahepatic diseases have been associated with chronic HCV infection. Most cases appear to be directly related to the viral infection:

Hematologic diseases such as essential mixed cryoglobulinemia and lymphoma
Renal disease, particularly membranoproliferative glomerulonephritis
Autoimmune disorders such as thyroiditis and the presence of autoantibodies
Dermatologic conditions such as porphyria cutanea tarda and lichen planus
Diabetes mellitus
In one series of 321 patients, at least one extrahepatic manifestation was observed in 38 percent (show table) [104]. (See "Extrahepatic manifestations of hepatitis C virus infection").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Hepatitis C"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.patients.uptodate.com, which includes this and other topics.

[rj50]

wtf, is somebody going to be held accountable?

[42L5V]

When I did my retirement physical (phase I), I had to sign a statement to either accept or deny the Hep C test.

Testing is conducted during transition physicals unless you're stupid enough to turn it down.

[Silverback]

wtf, is somebody going to be held accountable?

Yeah...let's sue someone!

[Hoover]

:Bump: