| Hepatitis C | |
|---|---|
| Classification and external resources | |
Electron micrograph of hepatitis C virus purified from cell culture. The scale = 50 nanometers |
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| ICD-10 | B17.1, B18.2 |
| ICD-9 | 070.70,070.4, 070.5 |
| OMIM | 609532 |
| DiseasesDB | 5783 |
| MedlinePlus | 000284 |
| eMedicine | med/993 ped/979 |
| MeSH | D006526 |
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus (HCV).[1] The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure, liver cancer or life-threatening esophageal and gastric varices.[1]
The hepatitis C virus is spread by primarily by blood-to-blood contact associated with intravenous drug use in the developed world or poorly sterilized medical equipment and transfusions in the developing world. The virus persists in the liver in about 85% of those infected. This persistent infection can be treated with medication; peginterferon and ribavirin are the current standard therapy. Overall, between 50–80% of people treated are cured. Those who develop cirrhosis or liver cancer may require a liver transplant, and the virus universally recurs after transplantation.
An estimated 130–170 million people worldwide are infected with hepatitis C. No vaccine against hepatitis C is currently available. The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proven in 1989.[2] It is not known to cause disease in other animals.
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Hepatitis C infection causes acute symptoms in 15% of cases.[3] For those that do manifest symptoms, they are in general mild and vague, including a decreased appetite, fatigue, nausea, muscle or joint pains, and weight loss.[4] Most cases of acute infection are not associated with jaundice.[5] The infection resolves spontaneously in 10-50% of cases being more likely in those who are young and females.[5]
About 80% of those exposed to the virus develop a chronic infection,[6] with most experiencing minimal or no symptoms during the initial few decades of the infection[7] although chronic hepatitis C can be associated with fatigue.[8] Hepatitis C after many years becomes the primary cause of cirrhosis, and liver cancer.[9] About 10–30% of people develop cirrhosis over 30 years.[4][9] Cirrhosis is more common in those co infected with hepatitis B or HIV, alcoholics, and those of male gender.[4] In those who develop cirrhosis their risk of hepatocellular carcinoma is 20 fold greater or 1-3% per year[4][9] and if this is complicated by excess alcohol the risk becomes 100 fold greater.[10] Hepatitis C is the cause of 27% of cirrhosis and 25% of hepatocellular carcinoma worldwide.[11]
Liver cirrhosis may lead to portal hypertension, ascites (accumulation of fluid in the abdomen), easy bruising or bleeding, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. It is thus one of the common causes for needing a liver transplant.[12]
Hepatitis C is also rarely associated with sicca syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus, and B-cell lymphoproliferative disorders.[13] Thrombocytopenia is estimated to occur in 0.16% to 45.4% of people with chronic disease.[14] Putative associations with Hyde's prurigo nodularis [15] and membranoproliferative glomerulonephritis have been reported.[8]
The hepatitis C virus is a small, enveloped, single-stranded, positive-sense RNA virus.[9] It is a member of the hepacivirus genus in the family Flaviviridae.[8] There are seven major genotypes of the hepatitis C virus, which are indicated numerically from one to seven.[16] In the United States about 70% of cases are caused by genotype 1, 20% by genotype 2, and about 1% by each of the other genotypes.[4] Genotype one is also the most common in South America and Europe.[9]
The primary methods of transmission in the developed world is intravenous drug use while in the developing world the main methods are blood transfusions and unsafe medical procedures.[17] The cause of transmission remains unknown in 20% of cases[18] however in many of these are believed to be accounted for by intravenous drug use.[5]
Intravenous drug use is a major risk factor for hepatitis C in many parts of the world.[19] Of a review of 77 countries 25 had rates of hepatitis C in the intravenous drug user population of between 60% and 80%[6] including the United States[6] and China.[19] While twelve countries had rates greater than 80%.[6] Globally it is believed that ten million intravenous drug users are infected with hepatitis C with China (1.6 million), the United States (1.5 million), and Russia (1.3 million) having the greatest absolute numbers.[6]
Rates of hepatitis C among prison inmates in the United States are ten to 20 times that of the general population and this is attributed to high risk behavior such as intravenous drug use and tattooing with non sterile equipment.[20][21]
Blood transfusion, blood products, or organ transplantation without HCV screening is a significant risk for infection.[4] The United States instituted universal screening in 1992 and the risk subsequently has decreased to one in 10,000 to 10,000,000 per units of blood[18][5] down from a risk of one in 200 units of blood.[22] This low risk remains as there is a period of about 11–70 days between the potential blood donor acquiring hepatitis C and their blood testing positive depending on the method.[18] Some countries still do not screen for hepatitis C due to the cost.[11]
Those who have experienced a needle stick injury from someone who was HCV positive have about a 1.8% chance of subsequently contacting the disease themselves.[4] The risk is greater if the needle in question was hollow of the puncture wound was deep.[11] There is a risk from mucosal exposures to blood but this is also low and no risk if blood exposure occurs on intact skin.[11]
Hospital equipment has also been documented as a method of transmission of hepatitis C including: reuse of needles and syringes, multiple-use medication vials, infusion bags, and improperly sterilized surgical equipment among others.[11] Limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities are known to be the primary cause of the spread of HCV in Egypt, the country with highest rate of infection in the world.[23]
Whether hepatitis C can be transmitted through sexual activity is controversial.[24] While there is an association between high-risk sexual activity and hepatitis C, it is not known whether transmission of the disease is due to drug use that has not been admitted to or sex as a risk factor.[4] The majority of evidence supports there being no risk for monogamous heterosexual couples.[24] Sexual practices that involve higher levels of trauma to the anogenital mucosa such as anal penetrative sex or that occur when there is a concurrent sexually transmitted infection including HIV or genital ulceration do present a risk.[24] The United States government only recommends condoms to prevent hepatitis C transmission in those with multiple partners.[25]
Tattooing is associated with two to three fold increased risk of hepatitis C.[26] This can be due to either improperly sterilized equipment or contamination of the dyes being used.[26] Tattoos or piercings performed either before the mid-1980s, "underground," or nonprofessionally are of particular concern, since sterile techniques in such settings may be lacking. The risk also appears to be greater the larger the tattoo size.[26] It is estimated that nearly half of prison inmates share unsterilized tattooing equipment. [26] It is rare for tattoos in a licensed facility to be directly associated with HCV infection.[27]
Personal care items such as razors, toothbrushes, and manicuring or pedicuring equipment can easily be contaminated with blood. Sharing such items can potentially lead to exposure to HCV.[28][29] Appropriate caution should be taken regarding any medical condition that results in bleeding, such as cuts and sores.[29] HCV is not spread through casual contact, such as hugging, kissing, or sharing eating or cooking utensils.[29]
Vertical transmission of hepatitis C from an infected mother to her child occurs in less than 10% of pregnancies.[30] There are no measures that alter this risk.[30] It is not clear when during pregnancy transmission occurs but it is possible that it occurs both during gestation and at delivery.[18] A long labor is associated with a greater risk.[11] There is no evidence that breast-feeding spreads HCV, however to be cautious, an infected mother is advised to avoid breastfeeding if her nipples are cracked and bleeding,[31] or her viral loads are high.[18]
There are a number of diagnostic tests for hepatitis C including: HCV antibody enzyme immunoassay or ELISA, recombinant immunoblot assay, and quantitative HCV RNA polymerase chain reaction (PCR).[4] HCV RNA can be detected by PCR typically one to two weeks after infection while antibodies can take substantially longer to form and thus be detected.[12] Testing is not able to distinguish between acute and chronic infections.[11]
Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months based on the presence of its RNA.[7] Chronic infections are typically without symptomatic during the first few decades,[7] and thus it is most commonly discovered following the investigation of elevated liver enzyme levels or during a routine screening of high risk individuals.
Hepatitis C testing typically begins with blood testing to detect the presence of antibodies to the HCV using an enzyme immunoassay.[4] If this test is positive a confirmatory test is than performed to verify the immunoassay and to determine the viral load.[4] A recombinant immunoblot assay is used to verify the immunoassay and the viral load is determined by a HCV RNA polymerase chain reaction.[4] If there are no RNA and the immunoblot is positive it means that the person had a previous infection but cleared it either with treatment or spontaneously, if the immunoblot is negative it means that the immunoassay was wrong.[4] It takes about 6-8 weeks following infection before the immunoassay will test positive.[8]
Liver enzymes are variable during the initial part of the infection[7] and on average begin to rise at 7 weeks after infection.[8] Liver enzymes are poorly related with disease severity.[8]
Liver biopsies are used to determine the degree of liver damage present however there are risks from the procedure.[9] The typical changes seen are lymphocytes within the parenchyma, lymphoid follicles in portal triad, and changes to the bile ducts.[9] There are a number of blood tests available which try to determine the degree of hepatic fibrosis and thus alleviate the need for biopsy.[9]
Of those infected in the United States and Canada it is believed only 5–50% realize that they are.[26] Testing is recommended in those at high risk, which includes those with tattoos.[26] Screening is also recommended in those with elevated liver enzymes as this is frequently the only sign of chronic hepatitis.[32] Routine screening however is not recommended in the United States.[4]
As of 2011 no vaccine protects against contracting hepatitis C however a number are under development and some have shown encouraging results.[33] A combination of harm reduction strategies such as the provision of new needles and syringes and treatment of substance use decrease the risk of hepatitis C in intravenous drug users by about 75%.[34] The screening of blood donors is important at a national level as is adhering to universal precautions within health care facilities.[8] In countries where there is an insufficient supply of sterile syringes, medications should be given orally rather than via injection.[11]
The hepatitis C virus induces chronic infection in 50–80% of infected persons. Approximately 40-80% of these clear with treatment.[35][36] and is rare but not unheard of without treatment.[5] Those with chronic hepatitis C are advised to avoid alcohol and medications toxic to the liver.[4] As well they should be vaccinated for hepatitis A and hepatitis B.[4] Hepatitis C is the leading reason for liver transplantation in the Western world.[9] Ultrasound surveillance for hepatocellular carcinoma is recommended in those with accompanying cirrhosis.[4]
In general, treatment is recommended in those with proven hepatitis C virus infection liver abnormalities.[4] Current treatment is a combination pegylated interferon alpha and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on hepatitis C virus genotype.[4] When combined with ribavirin pegylated interferon-alpha-2a may be superior to pegylated interferon-alpha-2b however the evidence is not that good.[37] Improved outcomes are seen in 50–60% of people.[4] Combining either boceprevir or telaprevir with ribavirin and peginterferon alfa improves antiviral response for hepatitis C genotype 1.[38][39][40] Adverse effect with treatment are common with half of people getting flu like symptoms and a third experiencing emotional problems.[4] Treatment during the first six month is more effective than once hepatitis C has becomes chronic.[12] Thus if someone develops and new infection and it has not cleared after eight to twelve weeks 24 weeks of pegylated interferon is recommended.[12] In people with thalassemia ribavirin appears to be useful but increases the need for transfusions.[41]
Several alternative therapies are claimed by their proponents to be helpful for hepatitis C including milk thistle, ginseng, and colloidal silver.[42] No alternative therapy however has been shown to improve outcomes in hepatitis C.[42][43][44]
Responses to treatment vary by genotype. Sustained response is about 40-50% in people with HCV genotype 1 given 48 weeks of treatment.[9] Sustained response is seen in 70-80% of people with HCV genotypes 2 and 3 with 24 weeks of treatment.[9] Sustained response is about 65% in those with genotype 4 given 48 weeks of treatment. The evidence for treatment in genotype 6 disease is currently sparse, and the evidence that exists is for 48 weeks of treatment at the same doses as are used for genotype 1 disease.[45]
It is estimated that 130–170 million people or ~3% of the world's population or are living with chronic hepatitis C[46] It infects about 3–4 million people per year, and more than 350,000 people die yearly from hepatitis C-related diseases.[46] Rates have increased substantially in the 20th century due to a combination of intravenous drug use and intravenous medication or poorly sterilized medical equipment.[47]
In the United States about 2% of people have hepatitis C[4] with about 35,000 to 185,000 new cases a year. Rates have decreased in the Western world since the 1990s due to improved screening of blood before transfusion.[12] Annual deaths from HCV in the United States range from 10,000 to 20,000; expectations are that this mortality rate will increase, as those infected by transfusion before HCV testing become apparent.
Prevalence is higher in some countries in Africa and Asia.[48] Countries with particularly high rates of infection include Egypt (22%), Pakistan (4.8%) and China (3.2%).[46] It is believed that the high prevalence in Egypt is linked to a now-discontinued mass-treatment campaign for schistosomiasis, using improperly sterilized glass syringes.[11]
In the mid-1970s, Harvey J. Alter, Chief of the Infectious Disease Section in the Department of Transfusion Medicine at the National Institutes of Health, and his research team demonstrated how most post transfusion hepatitis cases were not due to hepatitis A or B viruses. Despite this discovery, international research efforts to identify the virus, initially called non-A, non-B hepatitis (NANBH), failed for the next decade. In 1987, Michael Houghton, Qui-Lim Choo, and George Kuo at Chiron Corporation, collaborating with Dr. D.W. Bradley from Centers for Disease Control and Prevention, used a novel molecular cloning approach to identify the unknown organism and develop a diagnostic test.[49] In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April 1989, the discovery of the virus, renamed hepatitis C virus (HCV), was published in two articles in the journal Science.[50][51] The discovery led to significant improvements in diagnosis and improved antiviral treatment.[49] In 2000, Drs. Alter and Houghton were honored with the Lasker Award for Clinical Medical Research for "pioneering work leading to the discovery of the virus that causes hepatitis C and the development of screening methods that reduced the risk of blood transfusion-associated hepatitis in the U.S. from 30% in 1970 to virtually zero in 2000."[52]
Chiron filed for several patents on the virus and its diagnosis.[53] A competing patent application by the CDC was dropped in 1990 after Chiron paid $1.9 million to the CDC and $337,500 to Bradley. In 1994, Bradley sued Chiron, seeking to invalidate the patent, have himself included as a coinventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court.[54][55]
World Hepatitis Day is on July 28th and is coordinated by the World Hepatitis Alliance.[56]
As of 2011 a number of further treatments are under investigation including: vaccines to treat hepatitis C, immunomodulators, and cyclophilin inhibitors.[57]
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