Hepatitis D, also referred to as Hepatitis D virus (HDV) and classified as Hepatitis delta virus, is a disease caused by a small circular RNA virus.
HDV is considered to be a subviral satellite because it can propagate only in the presence of another virus, the Hepatitis B virus (HBV).
Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or via infection of an individual previously infected with HBV (superinfection).
Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone.
These complications include a greater likelihood of experiencing liver failure in acute infections and a greater likelihood of developing liver cancer in chronic infections.
In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.
Genome
The HDV genome exists as a negative sense, single-stranded, closed circular RNA.
Because of a nucleotide sequence that is 70% self-complementary, the HDV genome forms a partially double stranded RNA structure that is described as rod-like.
With a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals.
It has been proposed that HDV may have originated from a class of plant viruses called viroids.
Evidence in support of this hypothesis stems from the fact that both HDV and viroids exist as single-stranded, closed circular RNAs that have rod-like structures.
Likewise, both HDV and viroids contain RNA sequences that can assume catalytically active structures called ribozymes.
During viral replication, these catalytic RNAs are required in order to produce unit length copies of the genome from longer RNA concatamers.
Finally, neither HDV nor viroids encode their own polymerase.
Instead, replication of HDV and viroids requires a host polymerase that can utilize RNA as a template.
RNA polymerase II has been implicated as the polymerase responsible for the replication of HDV.
Normally RNA polymerase II utilizes DNA as a template and produces mRNA.
Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.
Delta antigens
A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV produces two proteins called the small and large delta antigens (HDAg-S and HDAg-L, respectively).
These two proteins are produced from a single open reading frame.
They are identical for 195 amino acids and differ only by the presence of an additional 19 amino acids at the C-terminus of HDAg-L. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection.
HDAg-S is produced in the early stages of an infection and is required for viral replication.
HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles.
Transmission
HDV is rare in most developed countries, and is mostly associated with intravenous drug abuse.
However HDV is much more common in Mediterranean countries, sub-Saharan Africa, the Middle East, and countries in the northern part of South America.
In all, about 20 million people may be infected with HDV.
Tuesday, July 7, 2009
HEPATITIS C
The hepatitis C virus (HCV) is spread by blood-to-blood contact.
Most people have few, if any symptoms after the initial infection, yet the virus persists in the liver in about 85% of those infected.
Persistent infection can be treated with medication, peginterferon and ribavirin being the standard-of-care therapy.
Only 51% are cured overall.
Those who develop cirrhosis or liver cancer may require a liver transplant, and the virus universally recurs after transplantation.
An estimated 270-300 million people worldwide are infected with hepatitis C.
Hepatitis C is a strictly human disease.
It cannot be contracted from or given to any animal.
Chimpanzees are able to carry the disease for lab work, but the animals do not get sick.
The inability to perform animal testing has severely limited attempts to study and cure the disease in a nonhuman in vivo environment.
No vaccine against hepatitis C is available.
The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proved conclusively in 1989.
It is one of five known hepatitis viruses: A, B, C, D, and E.
Signs and symptoms
Acute
Acute hepatitis C refers to the first 6 months after infection with HCV.
Between 60% to 70% of people infected develop no symptoms during the acute phase.
In the minority of patients who experience acute phase symptoms, they are generally mild and nonspecific, and rarely lead to a specific diagnosis of hepatitis C.
Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms.
The hepatitis C virus is usually detectable in the blood within one to three weeks after infection by PCR, and antibodies to the virus are generally detectable within 3 to 15 weeks.
Up to 50% of persons infected with HCV clear the virus from their bodies during the acute phase as shown by normalization in liver enzymes (alanine transaminase (ALT) & aspartate transaminase (AST)), as well as plasma HCV-RNA clearance (this is known as spontaneous viral clearance).
The remaining 60-85% of patients infected with HCV develop chronic hepatitis C, i.e., infection lasting more than 6 months.
Previous practice was to not treat acute infections to see if the person would spontaneously clear; recent studies have shown that treatment during the acute phase of genotype 1 infections has a greater than 90% success rate with half the treatment time required for chronic infections.
Chronic
Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months.
Clinically, it is often asymptomatic (without symptoms) and it is mostly discovered accidentally.
The natural course of chronic hepatitis C varies considerably from one person to another. Although almost all people infected with HCV have evidence of inflammation on liver biopsy the rate of progression of liver scarring (fibrosis) shows significant variability among individuals. Accurate estimates of the risk over time are difficult to establish because of the limited time that tests for this virus have been available.
Recent data suggest that among untreated patients, roughly one-third progress to liver cirrhosis in less than 20 years. Another third progress to cirrhosis within 30 years.
The remainder of patients appear to progress so slowly that they are unlikely to develop cirrhosis within their lifetimes.
In contrast the NIH consensus guidelines state that the risk of progression to cirrhosis over a 20-year period is 3-20 percent.
Factors that have been reported to influence the rate of HCV disease progression include age (increasing age associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV coinfection (associated with a markedly increased rate of disease progression), and fatty liver (the presence of fat in liver cells has been associated with an increased rate of disease progression).
Symptoms specifically suggestive of liver disease are typically absent until substantial scarring of the liver has occurred. However, hepatitis C is a systemic disease and patients may experience a wide spectrum of clinical manifestations ranging from an absence of symptoms to a more symptomatic illness prior to the development of advanced liver disease. Generalized signs and symptoms associated with chronic hepatitis C include fatigue, flu-like symptoms, joint pains, itching, sleep disturbances, appetite changes, nausea, and depression.
Once chronic hepatitis C has progressed to cirrhosis, signs and symptoms may appear that are generally caused by either decreased liver function or increased pressure in the liver circulation, a condition known as portal hypertension.
Possible signs and symptoms of liver cirrhosis include ascites (accumulation of fluid in the abdomen), bruising and bleeding tendency, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy.
Hepatic encephalopathy is due to the accumulation of ammonia and other substances normally cleared by a healthy liver.
Liver enzyme tests show variable elevation of ALT and AST.
Periodically they might show normal results.
Usually prothrombin and albumin results are normal, but may become abnormal, once cirrhosis has developed.
The level of elevation of liver tests do not correlate well with the amount of liver injury on biopsy.
Viral genotype and viral load also do not correlate with the amount of liver injury.
Liver biopsy is the best test to determine the amount of scarring and inflammation.
Radiographic studies such as ultrasound or CT scan do not always show liver injury until it is fairly advanced.
Chronic hepatitis C, more than other forms of hepatitis, can be associated with extrahepatic manifestations associated with the presence of HCV such as porphyria cutanea tarda, cryoglobulinemia (a form of small-vessel vasculitis) and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN).
Hepatitis C is also rarely associated with sicca syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus and with B-cell lymphoproliferative disorders.
Virology
The Hepatitis C virus (HCV) is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus. It is the only known member of the hepacivirus genus in the family Flaviviridae. There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.).
The hepatitis C virus (HCV) is transmitted by blood-to-blood contact.
In developed countries, it is estimated that 90% of persons with chronic HCV infection were infected through transfusion of unscreened blood or blood products or via injecting drug use or sexual exposure.
In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products. There has not been a documented transfusion-related case of hepatitis C in the United States for over a decade as the blood supply is vigorously screened with both EIA and PCR technologies.
Although injection drug use is the most common routes of HCV infection, any practice, activity, or situation that involves blood-to-blood exposure can potentially be a source of HCV infection.
The virus may be sexually transmitted, although this is rare, and usually only occurs when an STD that causes open sores and bleeding is also present and makes blood contact more likely.
Transmission
Several activities and practices were initially identified as potential sources of exposure to the hepatitis C virus. More recent studies question this route of transmission.
Currently it is felt to be a means of rare transmission of hepatitis C infection.
Injection drug use
Those who currently use or have used drug injection as their delivery route for drugs are at increased risk for getting hepatitis C because they may be sharing needles or other drug paraphernalia (includes cookers, cotton, spoons, water, etc.), which may be contaminated with HCV-infected blood. An estimated 60% to 80% of intravenous recreational drug users in the United States have been infected with HCV.
Harm reduction strategies are encouraged in many countries to reduce the spread of hepatitis C, through education, provision of clean needles and syringes, and safer injecting techniques.
For reasons that are not clear transmission by this route currently appears to be declining in the US.
Blood products
Blood transfusion, blood products, or organ transplantation prior to implementation of HCV screening (in the U.S., this would refer to procedures prior to 1992) is a decreasing risk factor for hepatitis C.
The virus was first isolated in 1989 and reliable tests to screen for the virus were not available until 1992.
Therefore, those who received blood or blood products prior to the implementation of screening the blood supply for HCV may have been exposed to the virus.
Blood products include clotting factors (taken by hemophiliacs), immunoglobulin, Rhogam, platelets, and plasma.
In 2001, the Centers for Disease Control and Prevention reported that the risk of HCV infection from a unit of transfused blood in the United States is less than one per million transfused units.
Iatrogenic medical or dental exposure
People can be exposed to HCV via inadequately or improperly sterilized medical or dental equipment. Equipment that may harbor contaminated blood if improperly sterilized includes needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air guns, etc.
Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero.
Occupational exposure to blood
Medical and dental personnel, first responders (e.g., firefighters, paramedics, emergency medical technicians, law enforcement officers), and military combat personnel can be exposed to HCV through accidental exposure to blood through accidental needlesticks or blood spatter to the eyes or open wounds.
Universal precautions to protect against such accidental exposures significantly reduce the risk of exposure to HCV.
Recreational exposure to blood
Contact sports and other activities, such as "slam dancing" that may result in accidental blood-to-blood exposure are potential sources of exposure to HCV.
Sexual exposure
Sexual transmission of HCV is considered to be rare. Studies show the risk of sexual transmission in heterosexual, monogamous relationships is extremely rare or even null.
The CDC does not recommend the use of condoms between long-term monogamous discordant couples (where one partner is positive and the other is negative).
However, because of the high prevalence of hepatitis C, this small risk may translate into a non-trivial number of cases transmitted by sexual routes.
Vaginal penetrative sex is believed to have a lower risk of transmission than sexual practices that involve higher levels of trauma to anogenital mucosa (anal penetrative sex, fisting, use of sex toys).
Body piercings and tattoos
Tattooing dyes, ink pots, stylets and piercing implements can transmit HCV-infected blood from one person to another if proper sterilization techniques are not followed.
Tattoos or piercings performed before the mid 1980s, "underground," or non-professionally are of particular concern since sterile techniques in such settings may have been or be insufficient to prevent disease.
Despite these risks, it is rare for tattoos to be directly associated with HCV infection and the U.S. Centers for Disease Control and Prevention's position on this subject states that, "no data exist in the United States indicating that persons with exposures to tattooing alone are at increased risk for HCV infection.
Shared personal care items
Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or pedicuring equipment can easily be contaminated with blood.
Sharing such items can potentially lead to exposure to HCV.
Appropriate caution should be taken regarding any medical condition which results in bleeding such as canker sores, cold sores, and immediately after flossing.
HCV is not spread through casual contact such as hugging, kissing, or sharing eating or cooking utensils.
Vertical transmission
Vertical transmission refers to the transmission of a communicable disease from an infected mother to her child during the birth process.
Mother-to-child transmission of hepatitis C has been well described, but occurs relatively infrequently.
Transmission occurs only among women who are HCV RNA positive at the time of delivery; the risk of transmission in this setting is approximately 6 out of 100.
Among women who are both HCV and HIV positive at the time of delivery, the risk of transmitting HCV is increased to approximately 25 out of 100.
The risk of vertical transmission of HCV does not appear to be associated with method of delivery or breastfeeding.
Diagnosis
The diagnosis of "hepatitis C" is rarely made during the acute phase of the disease because the majority of people infected experience no symptoms during this phase of the disease.
Those who do experience acute phase symptoms are rarely ill enough to seek medical attention.
The diagnosis of chronic phase hepatitis C is also challenging due to the absence or lack of specificity of symptoms until advanced liver disease develops, which may not occur until decades into the disease.
Chronic hepatitis C may be suspected on the basis of the medical history (particularly if there is any history of IV drug abuse or inhaled substance usage such as cocaine), a history of piercings or tattoos, unexplained symptoms, or abnormal liver enzymes or liver function tests found during routine blood testing.
Occasionally, hepatitis C is diagnosed as a result of targeted screening such as blood donation (blood donors are screened for numerous blood-borne diseases including hepatitis C) or contact tracing.
Hepatitis C testing begins with serological blood tests used to detect antibodies to HCV. Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in >90% within 5 months after exposure, and in >97% by 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to the hepatitis C virus, but may miss patients who have not yet developed antibodies (seroconversion), or have an insufficient level of antibodies to detect.
Rarely, people infected with HCV never develop antibodies to the virus and therefore, never test positive using HCV antibody screening.
Because of this possibility, RNA testing (see nucleic acid testing methods below) should be considered when antibody testing is negative but suspicion of hepatitis C is high (e.g. because of elevated transaminases in someone with risk factors for hepatitis C).
Anti-HCV antibodies indicate exposure to the virus, but cannot determine if ongoing infection is present.
All persons with positive anti-HCV antibody tests must undergo additional testing for the presence of the hepatitis C virus itself to determine whether current infection is present.
The presence of the virus is tested for using molecular nucleic acid testing methods such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), or branched DNA (b-DNA). All HCV nucleic acid molecular tests have the capacity to detect not only whether the virus is present, but also to measure the amount of virus present in the blood (the HCV viral load).
The HCV viral load is an important factor in determining the probability of response to interferon-based therapy, but does not indicate disease severity nor the likelihood of disease progression.
In people with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length and potential response to interferon-based therapy.
Treatment
There is a very small chance of clearing the virus spontaneously in chronic HCV carriers (0.5 to 0.74% per year), however, the majority of patients with chronic hepatitis C will not clear it without treatment.
Current treatment is a combination of pegylated interferon alpha (brand names Pegasys and PEG-Intron) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on genotype.
Indications for treatment include patients with proven hepatitis C virus infection and persistent abnormal liver function tests. Sustained cure rates (sustained viral response) of 75% or better occur in people with genotypes HCV 2 and 3 in 24 weeks of treatment,[21] about 50% in those with genotype 1 with 48 weeks of treatment and 65% for those with genotype 4 in 48 weeks of treatment.
About 80% of hepatitis C patients in the United States have genotype 1. Genotype 4 is more common in the Middle East and Africa. Should treatment with pegylated interferon + ribavirin not return a 2-log viral reduction or complete clearance of RNA (termed early virological response) after 12 weeks for genotype 1, the chance of treatment success is less than 1%. Early virological response is typically not tested for in non-genotype 1 patients, as the chances of attaining it are greater than 90%.
The mechanism of action is not entirely clear, because even patients who appear to have had a sustained virological response still have actively replicating virus in their liver and peripheral blood mononuclear cells.
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. Physicians considering shorter durations of treatment (e.g., 24 weeks) should do so within the context of a clinical trial.
Treatment during the acute infection phase has much higher success rates (greater than 90%) with a shorter duration of treatment; however, this must be balanced against the 15-40% chance of spontaneous clearance without treatment (see Acute Hepatitis C section above).
Those with low initial viral loads respond much better to treatment than those with higher viral loads (greater than 400,000 IU/mL).
Current combination therapy is usually supervised by physicians in the fields of gastroenterology, hepatology or infectious disease.
The treatment may be physically demanding, particularly for those with a prior history of drug or alcohol abuse.
It can qualify for temporary disability in some cases.
A substantial proportion of patients will experience a panoply of side effects ranging from a 'flu-like' syndrome (the most common, experienced for a few days after the weekly injection of interferon) to severe adverse events including anemia, cardiovascular events and psychiatric problems such as suicide or suicidal ideation.
The latter are exacerbated by the general physiological stress experienced by the patient.
Current guidelines strongly recommend that hepatitis C patients be vaccinated for hepatitis A and B if they have not yet been exposed to these viruses, as infection with a second virus could worsen their liver disease.
Alcoholic beverage consumption accelerates HCV associated fibrosis and cirrhosis, and makes liver cancer more likely; insulin resistance and metabolic syndrome may similarly worsen the hepatic prognosis.
There is also evidence that smoking increases the fibrosis (scarring) rate.
During pregnancy and breastfeeding
If a woman who is pregnant has risk factors for hepatitis C, she should be tested for antibodies against HCV. About 4% infants born to HCV infected women become infected.
There is no treatment that can prevent this from happening.
There is a high chance of the baby ridding the HCV in the first 12 months.
In a mother that also has HIV, the rate of transmission can be as high as 19%.
There are currently no data to determine whether antiviral therapy reduces perinatal transmission.
Ribavirin and interferons are contraindicated during pregnancy.
However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant.
HCV antibodies from the mother may persist in infants until 15 months of age.
If an early diagnosis is desired, testing for HCV RNA can be performed between the ages of 2 and 6 months, with a repeat test done independent of the first test result.
If a later diagnosis is preferred, an anti-HCV test can performed after 15 months of age.
Most infants infected with HCV at the time of birth have no symptoms and do well during childhood.
There is no evidence that breast-feeding spreads HCV. To be cautious, an infected mother should avoid breastfeeding if her nipples are cracked and bleeding.
Alternative therapies
Several alternative therapies aim to maintain liver functionality, rather than treat the virus itself, thereby slowing the course of the disease to retain quality of life.
As an example, extract of Silybum marianum and Sho-saiko-to are sold for their HCV related effects; the first is said to provide some generic help to hepatic functions, and the second claims to aid in liver health and provide some antiviral effects.
There has never been any verifiable histologic or virologic benefit demonstrated with any of the alternative therapies.
Experimental treatments
The drug viramidine, which is a prodrug of ribavirin that has better targeting for the liver, and therefore may be more effective against hepatitis C for a given tolerated dose, is in phase III experimental trials against hepatitis C.
It will be used in conjunction with interferons, in the same manner as ribavirin.
However, this drug is not expected to be active against ribavirin-resistant strains, and the use of the drug against infections which have already failed ribavirin/interferon treatment, is unproven.
There are new drugs under development like the protease inhibitors (including VX 950) and polymerase inhibitors (such as NM 283), but development of some of these is still in the early phase. VX 950, also known as Telaprevir is currently in Phase 3 Trials.
One protease inhibitor, BILN 2061, had to be discontinued due to safety problems early in the clinical testing.
Some more modern new drugs that provide some support in treating HCV are Albuferon, Zadaxin, and DAPY.
Antisense phosphorothioate oligos have been targeted to hepatitis C.
Antisense Morpholino oligos have shown promise in preclinical studies
however, they were found to cause a limited viral load reduction.
Immunoglobulins against the hepatitis C virus exist and newer types are under development. Thus far, their roles have been unclear as they have not been shown to help in clearing chronic infection or in the prevention of infection with acute exposures (e.g. needlesticks).
They do have a limited role in transplant patients.
In addition to the standard treatment with interferon and ribavirin, some studies have shown higher success rates when the antiviral drug amantadine (Symmetrel) is added to the regimen.
Sometimes called "triple therapy", it involves the addition of 100 mg of amantadine twice a day.
Studies indicate that this may be especially helpful for "nonresponders" - patients who have not been successful in previous treatments using interferon and ribavirin only.
Currently, amantadine is not approved for treatment of Hepatitis C, and studies are ongoing to determine when it is most likely to benefit the patient.
Epidemiology
Hepatitis C infects nearly 200 million people worldwide and 4 million in the United States.
There are about 35,000 to 185,000 new cases a year in the United States.
It is currently a leading cause of cirrhosis, a common cause of hepatocellular carcinoma, and as a result of these conditions it is the leading reason for liver transplantation in the United States.
Co-infection with HIV is common and rates among HIV positive populations are higher. 10,000-20,000 deaths a year in the United States are from HCV; expectations are that this mortality rate will increase, as those who were infected by transfusion before HCV testing become apparent.
A survey conducted in California showed prevalence of up to 34% among prison inmates; 82% of subjects diagnosed with hepatitis C have previously been in jail, and transmission while in prison is well described.
Prevalence is higher in some countries in Africa and Asia.
Egypt has the highest seroprevalence for HCV, up to 20% in some areas.
There is a hypothesis that the high prevalence is linked to a now-discontinued mass-treatment campaign for schistosomiasis, which is endemic in that country.
Regardless of how the epidemic started, a high rate of HCV transmission continues in Egypt, both iatrogenically and within the community and household.
Co-infection with HIV
Approximately 350,000, or 35% of patients in the USA infected with HIV are also infected with the hepatitis C virus, mainly because both viruses are blood-borne and present in similar populations.
In other countries co-infection is less common, and this is possibly related to differing drug policies.[citation needed] HCV is the leading cause of chronic liver disease in the USA.
It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure.
This is not to say treatment is not an option for those living with co-infection.
Prevention
The following guidelines will prevent infection with the hepatitis C virus, which is spread by blood:
* Avoid sharing drug needles or any other drug paraphernalia including works for injection or bills or straws
* Avoid unsanitary tattoo methods
* Avoid unsanitary body piercing methods
* Avoid unsanitary acupuncture
* Avoid needlestick injury
* Avoid sharing personal items such as toothbrushes, razors, and nail clippers.
* Use latex condoms correctly and every time you have sex if not in a long-term monogamous relationship
Proponents of harm reduction believe that strategies such as the provision of new needles and syringes, and education about safer drug injection procedures, greatly decreases the risk of hepatitis C spreading between injecting drug users.
No vaccine protects against contracting hepatitis C, or helps to treat it. Vaccines are under development and some have shown encouraging results.
History
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 that 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 CDC, utilized a novel molecular cloning approach to identify the unknown organism.
In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April of 1989, the discovery of the virus, re-named hepatitis C virus (HCV), was published in two articles in the journal Science.
Chiron filed for several patents on the virus and its diagnosis.
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 co-inventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court.
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.
In 2004 Chiron held 100 patents in 20 countries related to hepatitis C and had successfully sued many companies for infringement.
Scientists and competitors have complained that the company hinders the fight against hepatitis C by demanding too much money for its technology.
Most people have few, if any symptoms after the initial infection, yet the virus persists in the liver in about 85% of those infected.
Persistent infection can be treated with medication, peginterferon and ribavirin being the standard-of-care therapy.
Only 51% are cured overall.
Those who develop cirrhosis or liver cancer may require a liver transplant, and the virus universally recurs after transplantation.
An estimated 270-300 million people worldwide are infected with hepatitis C.
Hepatitis C is a strictly human disease.
It cannot be contracted from or given to any animal.
Chimpanzees are able to carry the disease for lab work, but the animals do not get sick.
The inability to perform animal testing has severely limited attempts to study and cure the disease in a nonhuman in vivo environment.
No vaccine against hepatitis C is available.
The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proved conclusively in 1989.
It is one of five known hepatitis viruses: A, B, C, D, and E.
Signs and symptoms
Acute
Acute hepatitis C refers to the first 6 months after infection with HCV.
Between 60% to 70% of people infected develop no symptoms during the acute phase.
In the minority of patients who experience acute phase symptoms, they are generally mild and nonspecific, and rarely lead to a specific diagnosis of hepatitis C.
Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms.
The hepatitis C virus is usually detectable in the blood within one to three weeks after infection by PCR, and antibodies to the virus are generally detectable within 3 to 15 weeks.
Up to 50% of persons infected with HCV clear the virus from their bodies during the acute phase as shown by normalization in liver enzymes (alanine transaminase (ALT) & aspartate transaminase (AST)), as well as plasma HCV-RNA clearance (this is known as spontaneous viral clearance).
The remaining 60-85% of patients infected with HCV develop chronic hepatitis C, i.e., infection lasting more than 6 months.
Previous practice was to not treat acute infections to see if the person would spontaneously clear; recent studies have shown that treatment during the acute phase of genotype 1 infections has a greater than 90% success rate with half the treatment time required for chronic infections.
Chronic
Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months.
Clinically, it is often asymptomatic (without symptoms) and it is mostly discovered accidentally.
The natural course of chronic hepatitis C varies considerably from one person to another. Although almost all people infected with HCV have evidence of inflammation on liver biopsy the rate of progression of liver scarring (fibrosis) shows significant variability among individuals. Accurate estimates of the risk over time are difficult to establish because of the limited time that tests for this virus have been available.
Recent data suggest that among untreated patients, roughly one-third progress to liver cirrhosis in less than 20 years. Another third progress to cirrhosis within 30 years.
The remainder of patients appear to progress so slowly that they are unlikely to develop cirrhosis within their lifetimes.
In contrast the NIH consensus guidelines state that the risk of progression to cirrhosis over a 20-year period is 3-20 percent.
Factors that have been reported to influence the rate of HCV disease progression include age (increasing age associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV coinfection (associated with a markedly increased rate of disease progression), and fatty liver (the presence of fat in liver cells has been associated with an increased rate of disease progression).
Symptoms specifically suggestive of liver disease are typically absent until substantial scarring of the liver has occurred. However, hepatitis C is a systemic disease and patients may experience a wide spectrum of clinical manifestations ranging from an absence of symptoms to a more symptomatic illness prior to the development of advanced liver disease. Generalized signs and symptoms associated with chronic hepatitis C include fatigue, flu-like symptoms, joint pains, itching, sleep disturbances, appetite changes, nausea, and depression.
Once chronic hepatitis C has progressed to cirrhosis, signs and symptoms may appear that are generally caused by either decreased liver function or increased pressure in the liver circulation, a condition known as portal hypertension.
Possible signs and symptoms of liver cirrhosis include ascites (accumulation of fluid in the abdomen), bruising and bleeding tendency, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy.
Hepatic encephalopathy is due to the accumulation of ammonia and other substances normally cleared by a healthy liver.
Liver enzyme tests show variable elevation of ALT and AST.
Periodically they might show normal results.
Usually prothrombin and albumin results are normal, but may become abnormal, once cirrhosis has developed.
The level of elevation of liver tests do not correlate well with the amount of liver injury on biopsy.
Viral genotype and viral load also do not correlate with the amount of liver injury.
Liver biopsy is the best test to determine the amount of scarring and inflammation.
Radiographic studies such as ultrasound or CT scan do not always show liver injury until it is fairly advanced.
Chronic hepatitis C, more than other forms of hepatitis, can be associated with extrahepatic manifestations associated with the presence of HCV such as porphyria cutanea tarda, cryoglobulinemia (a form of small-vessel vasculitis) and glomerulonephritis (inflammation of the kidney), specifically membranoproliferative glomerulonephritis (MPGN).
Hepatitis C is also rarely associated with sicca syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus and with B-cell lymphoproliferative disorders.
Virology
The Hepatitis C virus (HCV) is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus. It is the only known member of the hepacivirus genus in the family Flaviviridae. There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.).
The hepatitis C virus (HCV) is transmitted by blood-to-blood contact.
In developed countries, it is estimated that 90% of persons with chronic HCV infection were infected through transfusion of unscreened blood or blood products or via injecting drug use or sexual exposure.
In developing countries, the primary sources of HCV infection are unsterilized injection equipment and infusion of inadequately screened blood and blood products. There has not been a documented transfusion-related case of hepatitis C in the United States for over a decade as the blood supply is vigorously screened with both EIA and PCR technologies.
Although injection drug use is the most common routes of HCV infection, any practice, activity, or situation that involves blood-to-blood exposure can potentially be a source of HCV infection.
The virus may be sexually transmitted, although this is rare, and usually only occurs when an STD that causes open sores and bleeding is also present and makes blood contact more likely.
Transmission
Several activities and practices were initially identified as potential sources of exposure to the hepatitis C virus. More recent studies question this route of transmission.
Currently it is felt to be a means of rare transmission of hepatitis C infection.
Injection drug use
Those who currently use or have used drug injection as their delivery route for drugs are at increased risk for getting hepatitis C because they may be sharing needles or other drug paraphernalia (includes cookers, cotton, spoons, water, etc.), which may be contaminated with HCV-infected blood. An estimated 60% to 80% of intravenous recreational drug users in the United States have been infected with HCV.
Harm reduction strategies are encouraged in many countries to reduce the spread of hepatitis C, through education, provision of clean needles and syringes, and safer injecting techniques.
For reasons that are not clear transmission by this route currently appears to be declining in the US.
Blood products
Blood transfusion, blood products, or organ transplantation prior to implementation of HCV screening (in the U.S., this would refer to procedures prior to 1992) is a decreasing risk factor for hepatitis C.
The virus was first isolated in 1989 and reliable tests to screen for the virus were not available until 1992.
Therefore, those who received blood or blood products prior to the implementation of screening the blood supply for HCV may have been exposed to the virus.
Blood products include clotting factors (taken by hemophiliacs), immunoglobulin, Rhogam, platelets, and plasma.
In 2001, the Centers for Disease Control and Prevention reported that the risk of HCV infection from a unit of transfused blood in the United States is less than one per million transfused units.
Iatrogenic medical or dental exposure
People can be exposed to HCV via inadequately or improperly sterilized medical or dental equipment. Equipment that may harbor contaminated blood if improperly sterilized includes needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air guns, etc.
Scrupulous use of appropriate sterilization techniques and proper disposal of used equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero.
Occupational exposure to blood
Medical and dental personnel, first responders (e.g., firefighters, paramedics, emergency medical technicians, law enforcement officers), and military combat personnel can be exposed to HCV through accidental exposure to blood through accidental needlesticks or blood spatter to the eyes or open wounds.
Universal precautions to protect against such accidental exposures significantly reduce the risk of exposure to HCV.
Recreational exposure to blood
Contact sports and other activities, such as "slam dancing" that may result in accidental blood-to-blood exposure are potential sources of exposure to HCV.
Sexual exposure
Sexual transmission of HCV is considered to be rare. Studies show the risk of sexual transmission in heterosexual, monogamous relationships is extremely rare or even null.
The CDC does not recommend the use of condoms between long-term monogamous discordant couples (where one partner is positive and the other is negative).
However, because of the high prevalence of hepatitis C, this small risk may translate into a non-trivial number of cases transmitted by sexual routes.
Vaginal penetrative sex is believed to have a lower risk of transmission than sexual practices that involve higher levels of trauma to anogenital mucosa (anal penetrative sex, fisting, use of sex toys).
Body piercings and tattoos
Tattooing dyes, ink pots, stylets and piercing implements can transmit HCV-infected blood from one person to another if proper sterilization techniques are not followed.
Tattoos or piercings performed before the mid 1980s, "underground," or non-professionally are of particular concern since sterile techniques in such settings may have been or be insufficient to prevent disease.
Despite these risks, it is rare for tattoos to be directly associated with HCV infection and the U.S. Centers for Disease Control and Prevention's position on this subject states that, "no data exist in the United States indicating that persons with exposures to tattooing alone are at increased risk for HCV infection.
Shared personal care items
Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or pedicuring equipment can easily be contaminated with blood.
Sharing such items can potentially lead to exposure to HCV.
Appropriate caution should be taken regarding any medical condition which results in bleeding such as canker sores, cold sores, and immediately after flossing.
HCV is not spread through casual contact such as hugging, kissing, or sharing eating or cooking utensils.
Vertical transmission
Vertical transmission refers to the transmission of a communicable disease from an infected mother to her child during the birth process.
Mother-to-child transmission of hepatitis C has been well described, but occurs relatively infrequently.
Transmission occurs only among women who are HCV RNA positive at the time of delivery; the risk of transmission in this setting is approximately 6 out of 100.
Among women who are both HCV and HIV positive at the time of delivery, the risk of transmitting HCV is increased to approximately 25 out of 100.
The risk of vertical transmission of HCV does not appear to be associated with method of delivery or breastfeeding.
Diagnosis
The diagnosis of "hepatitis C" is rarely made during the acute phase of the disease because the majority of people infected experience no symptoms during this phase of the disease.
Those who do experience acute phase symptoms are rarely ill enough to seek medical attention.
The diagnosis of chronic phase hepatitis C is also challenging due to the absence or lack of specificity of symptoms until advanced liver disease develops, which may not occur until decades into the disease.
Chronic hepatitis C may be suspected on the basis of the medical history (particularly if there is any history of IV drug abuse or inhaled substance usage such as cocaine), a history of piercings or tattoos, unexplained symptoms, or abnormal liver enzymes or liver function tests found during routine blood testing.
Occasionally, hepatitis C is diagnosed as a result of targeted screening such as blood donation (blood donors are screened for numerous blood-borne diseases including hepatitis C) or contact tracing.
Hepatitis C testing begins with serological blood tests used to detect antibodies to HCV. Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in >90% within 5 months after exposure, and in >97% by 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to the hepatitis C virus, but may miss patients who have not yet developed antibodies (seroconversion), or have an insufficient level of antibodies to detect.
Rarely, people infected with HCV never develop antibodies to the virus and therefore, never test positive using HCV antibody screening.
Because of this possibility, RNA testing (see nucleic acid testing methods below) should be considered when antibody testing is negative but suspicion of hepatitis C is high (e.g. because of elevated transaminases in someone with risk factors for hepatitis C).
Anti-HCV antibodies indicate exposure to the virus, but cannot determine if ongoing infection is present.
All persons with positive anti-HCV antibody tests must undergo additional testing for the presence of the hepatitis C virus itself to determine whether current infection is present.
The presence of the virus is tested for using molecular nucleic acid testing methods such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), or branched DNA (b-DNA). All HCV nucleic acid molecular tests have the capacity to detect not only whether the virus is present, but also to measure the amount of virus present in the blood (the HCV viral load).
The HCV viral load is an important factor in determining the probability of response to interferon-based therapy, but does not indicate disease severity nor the likelihood of disease progression.
In people with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length and potential response to interferon-based therapy.
Treatment
There is a very small chance of clearing the virus spontaneously in chronic HCV carriers (0.5 to 0.74% per year), however, the majority of patients with chronic hepatitis C will not clear it without treatment.
Current treatment is a combination of pegylated interferon alpha (brand names Pegasys and PEG-Intron) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on genotype.
Indications for treatment include patients with proven hepatitis C virus infection and persistent abnormal liver function tests. Sustained cure rates (sustained viral response) of 75% or better occur in people with genotypes HCV 2 and 3 in 24 weeks of treatment,[21] about 50% in those with genotype 1 with 48 weeks of treatment and 65% for those with genotype 4 in 48 weeks of treatment.
About 80% of hepatitis C patients in the United States have genotype 1. Genotype 4 is more common in the Middle East and Africa. Should treatment with pegylated interferon + ribavirin not return a 2-log viral reduction or complete clearance of RNA (termed early virological response) after 12 weeks for genotype 1, the chance of treatment success is less than 1%. Early virological response is typically not tested for in non-genotype 1 patients, as the chances of attaining it are greater than 90%.
The mechanism of action is not entirely clear, because even patients who appear to have had a sustained virological response still have actively replicating virus in their liver and peripheral blood mononuclear cells.
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. Physicians considering shorter durations of treatment (e.g., 24 weeks) should do so within the context of a clinical trial.
Treatment during the acute infection phase has much higher success rates (greater than 90%) with a shorter duration of treatment; however, this must be balanced against the 15-40% chance of spontaneous clearance without treatment (see Acute Hepatitis C section above).
Those with low initial viral loads respond much better to treatment than those with higher viral loads (greater than 400,000 IU/mL).
Current combination therapy is usually supervised by physicians in the fields of gastroenterology, hepatology or infectious disease.
The treatment may be physically demanding, particularly for those with a prior history of drug or alcohol abuse.
It can qualify for temporary disability in some cases.
A substantial proportion of patients will experience a panoply of side effects ranging from a 'flu-like' syndrome (the most common, experienced for a few days after the weekly injection of interferon) to severe adverse events including anemia, cardiovascular events and psychiatric problems such as suicide or suicidal ideation.
The latter are exacerbated by the general physiological stress experienced by the patient.
Current guidelines strongly recommend that hepatitis C patients be vaccinated for hepatitis A and B if they have not yet been exposed to these viruses, as infection with a second virus could worsen their liver disease.
Alcoholic beverage consumption accelerates HCV associated fibrosis and cirrhosis, and makes liver cancer more likely; insulin resistance and metabolic syndrome may similarly worsen the hepatic prognosis.
There is also evidence that smoking increases the fibrosis (scarring) rate.
During pregnancy and breastfeeding
If a woman who is pregnant has risk factors for hepatitis C, she should be tested for antibodies against HCV. About 4% infants born to HCV infected women become infected.
There is no treatment that can prevent this from happening.
There is a high chance of the baby ridding the HCV in the first 12 months.
In a mother that also has HIV, the rate of transmission can be as high as 19%.
There are currently no data to determine whether antiviral therapy reduces perinatal transmission.
Ribavirin and interferons are contraindicated during pregnancy.
However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant.
HCV antibodies from the mother may persist in infants until 15 months of age.
If an early diagnosis is desired, testing for HCV RNA can be performed between the ages of 2 and 6 months, with a repeat test done independent of the first test result.
If a later diagnosis is preferred, an anti-HCV test can performed after 15 months of age.
Most infants infected with HCV at the time of birth have no symptoms and do well during childhood.
There is no evidence that breast-feeding spreads HCV. To be cautious, an infected mother should avoid breastfeeding if her nipples are cracked and bleeding.
Alternative therapies
Several alternative therapies aim to maintain liver functionality, rather than treat the virus itself, thereby slowing the course of the disease to retain quality of life.
As an example, extract of Silybum marianum and Sho-saiko-to are sold for their HCV related effects; the first is said to provide some generic help to hepatic functions, and the second claims to aid in liver health and provide some antiviral effects.
There has never been any verifiable histologic or virologic benefit demonstrated with any of the alternative therapies.
Experimental treatments
The drug viramidine, which is a prodrug of ribavirin that has better targeting for the liver, and therefore may be more effective against hepatitis C for a given tolerated dose, is in phase III experimental trials against hepatitis C.
It will be used in conjunction with interferons, in the same manner as ribavirin.
However, this drug is not expected to be active against ribavirin-resistant strains, and the use of the drug against infections which have already failed ribavirin/interferon treatment, is unproven.
There are new drugs under development like the protease inhibitors (including VX 950) and polymerase inhibitors (such as NM 283), but development of some of these is still in the early phase. VX 950, also known as Telaprevir is currently in Phase 3 Trials.
One protease inhibitor, BILN 2061, had to be discontinued due to safety problems early in the clinical testing.
Some more modern new drugs that provide some support in treating HCV are Albuferon, Zadaxin, and DAPY.
Antisense phosphorothioate oligos have been targeted to hepatitis C.
Antisense Morpholino oligos have shown promise in preclinical studies
however, they were found to cause a limited viral load reduction.
Immunoglobulins against the hepatitis C virus exist and newer types are under development. Thus far, their roles have been unclear as they have not been shown to help in clearing chronic infection or in the prevention of infection with acute exposures (e.g. needlesticks).
They do have a limited role in transplant patients.
In addition to the standard treatment with interferon and ribavirin, some studies have shown higher success rates when the antiviral drug amantadine (Symmetrel) is added to the regimen.
Sometimes called "triple therapy", it involves the addition of 100 mg of amantadine twice a day.
Studies indicate that this may be especially helpful for "nonresponders" - patients who have not been successful in previous treatments using interferon and ribavirin only.
Currently, amantadine is not approved for treatment of Hepatitis C, and studies are ongoing to determine when it is most likely to benefit the patient.
Epidemiology
Hepatitis C infects nearly 200 million people worldwide and 4 million in the United States.
There are about 35,000 to 185,000 new cases a year in the United States.
It is currently a leading cause of cirrhosis, a common cause of hepatocellular carcinoma, and as a result of these conditions it is the leading reason for liver transplantation in the United States.
Co-infection with HIV is common and rates among HIV positive populations are higher. 10,000-20,000 deaths a year in the United States are from HCV; expectations are that this mortality rate will increase, as those who were infected by transfusion before HCV testing become apparent.
A survey conducted in California showed prevalence of up to 34% among prison inmates; 82% of subjects diagnosed with hepatitis C have previously been in jail, and transmission while in prison is well described.
Prevalence is higher in some countries in Africa and Asia.
Egypt has the highest seroprevalence for HCV, up to 20% in some areas.
There is a hypothesis that the high prevalence is linked to a now-discontinued mass-treatment campaign for schistosomiasis, which is endemic in that country.
Regardless of how the epidemic started, a high rate of HCV transmission continues in Egypt, both iatrogenically and within the community and household.
Co-infection with HIV
Approximately 350,000, or 35% of patients in the USA infected with HIV are also infected with the hepatitis C virus, mainly because both viruses are blood-borne and present in similar populations.
In other countries co-infection is less common, and this is possibly related to differing drug policies.[citation needed] HCV is the leading cause of chronic liver disease in the USA.
It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure.
This is not to say treatment is not an option for those living with co-infection.
Prevention
The following guidelines will prevent infection with the hepatitis C virus, which is spread by blood:
* Avoid sharing drug needles or any other drug paraphernalia including works for injection or bills or straws
* Avoid unsanitary tattoo methods
* Avoid unsanitary body piercing methods
* Avoid unsanitary acupuncture
* Avoid needlestick injury
* Avoid sharing personal items such as toothbrushes, razors, and nail clippers.
* Use latex condoms correctly and every time you have sex if not in a long-term monogamous relationship
Proponents of harm reduction believe that strategies such as the provision of new needles and syringes, and education about safer drug injection procedures, greatly decreases the risk of hepatitis C spreading between injecting drug users.
No vaccine protects against contracting hepatitis C, or helps to treat it. Vaccines are under development and some have shown encouraging results.
History
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 that 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 CDC, utilized a novel molecular cloning approach to identify the unknown organism.
In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April of 1989, the discovery of the virus, re-named hepatitis C virus (HCV), was published in two articles in the journal Science.
Chiron filed for several patents on the virus and its diagnosis.
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 co-inventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court.
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.
In 2004 Chiron held 100 patents in 20 countries related to hepatitis C and had successfully sued many companies for infringement.
Scientists and competitors have complained that the company hinders the fight against hepatitis C by demanding too much money for its technology.
HEPATITIS B
Hepatitis B is a disease caused by HBV hepatitis B virus which infects the liver of hominoidae, including humans, and causes an inflammation called hepatitis.
Originally known as "serum hepatitis", the disease has caused epidemics in parts of Asia and Africa, and it is endemic in China.
About a third of the world's population, more than 2 billion people, have been infected with the hepatitis B virus.
This includes 350 million chronic carriers of the virus.
Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood.
The acute illness causes liver inflammation, vomiting, jaundice and—rarely—death. Chronic hepatitis B may eventually cause liver cirrhosis and liver cancer—a fatal disease with very poor response to current chemotherapy.
The infection is preventable by vaccination.
Hepatitis B virus is an hepadnavirus—hepa from hepatotrophic and dna because it is a DNA virus—and it has a circular genome composed of partially double-stranded DNA.
The viruses replicate through an RNA intermediate form by reverse transcription, and in this respect they are similar to retroviruses.
Although replication takes place in the liver, the virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people.
Blood tests for these proteins and antibodies are used to diagnose the infection.
Virology
Hepatitis B virus (HBV) is a member of the Hepadnavirus family.
The virus particle, (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein.
The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity.
The outer envelope contains embedded proteins which are involved in viral binding of, and entry into, susceptible cells.
The virus is one of the smallest enveloped animal viruses with a virion diameter of 42nm, but pleomorphic forms exist, including filamentous and spherical bodies lacking a core.
These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus.
Genome
The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double-stranded. One end of the full length strand is linked to the viral DNA polymerase.
The genome is 3020-3320 nucleotides long (for the full length strand) and 1700-2800 nucleotides long (for the short length strand).
The negative-sense, (non-coding), is complementary to the viral mRNA.
The viral DNA is found in the nucleus soon after infection of the cell. The partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a protein molecule from the (-) sense strand and a short sequence of RNA from the (+) sense strand.
Non-coding bases are removed from the ends of the (-)sense strand and the ends are rejoined.
There are four known genes encoded by the genome called C, X, P, and S.
The core protein is coded for by gene C (HBcAg), and its start codon is preceded by an upstream in-frame AUG start codon from which the pre-core protein is produced.
HBeAg is produced by proteolytic processing of the pre-core protein.
The DNA polymerase is encoded by gene P. Gene S is the gene that codes for the surface antigen (HBsAg).
The HBsAg gene is one long open reading frame but contains three in frame "start" (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large, middle, and small (pre-S1 + pre-S2 + S, pre-S2 + S, or S) are produced.
The function of the protein coded for by gene X is not fully understood.[13]
Replication
The life cycle of Hepatitis B virus is complex. Hepatitis B is one of a few known non-retroviral viruses which use reverse transcription as a part of its replication process.
The virus gains entry into the cell by binding to an unknown receptor on the surface of the cell and enters it by endocytosis.
Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host proteins called chaperones.
The partially double stranded viral DNA is then made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of four viral mRNAs. The largest mRNA, (which is longer than the viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral DNA polymerase.
These four viral transcripts undergo additional processing and go on to form progeny virions which are released from the cell or returned to the nucleus and re-cycled to produce even more copies.
The long mRNA is then transported back to the cytoplasm where the virion P protein synthesizes DNA via its reverse transcriptase activity.
Serotypes
The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome.
The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus.
Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment and possibly vaccination.
Pathogenesis
Cirrhosis of the liver and liver cancer may ensue from Hepatitis B.
The hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells, known as hepatocytes.
The receptor is not yet known, though there is evidence that the receptor in the closely related duck hepatitis B virus is carboxypeptidase D.
HBV virions (DANE particle) bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis.
PreS and IgA receptors are accused of this interaction.
HBV-preS specific receptors are primarily expressed on hepatocytes; however, viral DNA and proteins have also been detected in extrahepatic sites, suggesting that cellular receptors for HBV may also exist on extrahepatic cells.
During HBV infection, the host immune response causes both hepatocellular damage and viral clearance.
Although the innate immune response does not play a significant role in these processes, the adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to most of the liver injury associated with HBV infection.
By killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, CTLs eliminate the virus.[19] Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver.
Epidemiology
The primary method of transmission reflects the prevalence of chronic HBV infection in a given area.
In low prevalence areas such as the continental United States and Western Europe, where less than 2% of the population is chronically infected, injection drug abuse and unprotected sex are the primary methods, although other factors may be important.
In moderate prevalence areas, which include Eastern Europe, Russia, and Japan, where 2-7% of the population is chronically infected, the disease is predominantly spread among children.
In high prevalence areas such as China and South East Asia, transmission during childbirth is most common, although in other areas of high endemicity such as Africa, transmission during childhood is a significant factor.
The prevalence of chronic HBV infection in areas of high endemicity is at least 8%.
Transmission
Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood.
Possible forms of transmission include (but are not limited to) unprotected sexual contact, blood transfusions, re-use of contaminated needles & syringes, and vertical transmission from mother to child during childbirth.
Without intervention, a mother who is positive for HBsAg confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for HBeAg.
HBV can be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV.
However, at least 30% of reported hepatitis B among adults cannot be associated with an identifiable risk factor.
Medical aspects
Several vaccines have been developed for the prevention of hepatitis B virus infection.
These rely on the use of one of the viral envelope proteins (hepatitis B surface antigen or HBsAg).
The vaccine was originally prepared from plasma obtained from patients who had long-standing hepatitis B virus infection.
However, currently, these are more often made using recombinant DNA technology, though plasma-derived vaccines continue to be used; the two types of vaccines are equally effective and safe.
Following vaccination Hepatitis B Surface antigen may be detected in serum for several days; this is known as vaccine antigenaemia.
Vaccine is generally administered in either a two, three, or four dose schedules; and can be received by infants to adults. It provides protection for 85-90% of individuals, and lasts for 23 years.
Unlike Hepatitis A, Hepatitis B does not generally spread through water and food.
Instead, it is transmitted through body fluids, from which prevention is taken to avoid: unprotected sexual contact, blood transfusions, re-use of contaminated needles and syringes, and vertical transmission during child birth.
Infants may be vaccinated at birth.
Symptoms
Acute infection with hepatitis B virus is associated with acute viral hepatitis - an illness that begins with general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever, dark urine, and then progresses to development of jaundice.
It has been noted that itchy skin has been an indication as a possible symptom of all hepatitis virus types.
The illness lasts for a few weeks and then gradually improves in most affected people.
A few patients may have more severe liver disease (fulminant hepatic failure), and may die as a result of it.
The infection may be entirely asymptomatic and may go unrecognized.
Chronic infection with Hepatitis B virus may be either asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), leading to cirrhosis over a period of several years.
This type of infection dramatically increases the incidence of hepatocellular carcinoma (liver cancer). Chronic carriers are encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and liver cancer.
Hepatitis B virus has been linked to the development of Membranous glomerulonephritis (MGN).
Diagnosis
The hepatitis B surface antigen (HBsAg) is most frequently used to screen for the presence of this infection.
It is the first detectable viral antigen to appear during infection.
However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host.
The infectious virion contains an inner "core particle" enclosing viral genome.
The icosahedral core particle is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or HBcAg.
During this 'window' in which the host remains infected but is successfully clearing the virus, IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be the only serological evidence of disease.
Shortly after the appearance of the HBsAg, another antigen named as the hepatitis B e antigen (HBeAg) will appear.
Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the hepatitis B virus do not produce the 'e' antigen, so this rule does not always hold true.
During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (anti-HBe) will arise immediately afterwards.
This conversion is usually associated with a dramatic decline in viral replication.
If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by IgG antibodies to the hepatitis B surface antigen and core antigen, (anti-HBs and anti HBc IgG). A person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously.
Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers.
Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase levels and inflammation of the liver, as revealed by biopsy.
Carriers who have seroconverted to HBeAg negative status, particularly those who acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others.
More recently, PCR tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens.
These tests are called viral loads and are used to assess a person's infection status and to monitor treatment.
Prognosis
Hepatitis B virus infection may either be acute (self-limiting) or chronic (long-standing).
Persons with self-limiting infection clear the infection spontaneously within weeks to months.
Children are less likely than adults to clear the infection.
More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus.
However, only 5% of newborns that acquire the infection from their mother at birth will clear the infection. This population has a 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma.
Of those infected between the age of one to six, 70% will clear the infection.
Hepatitis D infection can only occur with a concomitant infection with Hepatitis B virus because the Hepatitis D virus uses the Hepatitis B virus surface antigen to form a capsid.
Co-infection with hepatitis D increases the risk of liver cirrhosis and liver cancer.
Polyarteritis nodosa is more common in people with hepatitis B infection.
Treatment
Acute hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously.
Early antiviral treatment may only be required in fewer than 1% of patients, whose infection takes a very aggressive course ("fulminant hepatitis") or who are immunocompromised.
On the other hand, treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer.
Chronically infected individuals with persistently elevated serum alanine aminotransferase, a marker of liver damage, and HBV DNA levels are candidates for therapy.
Although none of the available drugs can clear the infection, they can stop the virus from replicating, and minimize liver damage such as cirrhosis and liver cancer.
Currently, there are seven medications licensed for treatment of hepatitis B infection in the United States.
These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude) and the two immune system modulators interferon alpha-2a and pegylated interferon alfa-2a (Pegasys). The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting pegylated interferon, which is injected only once weekly.
However, some individuals are much more likely to respond than others and this might be because of the genotype of the infecting virus or the patient's heredity.
The treatment works by reducing the viral load, (the amount of virus particles as measured in the blood), which in turn reduces viral replication in the liver.
Infants born to mothers known to carry hepatitis B can be treated with antibodies to the hepatitis B virus (hepatitis B immune globulin or HBIg).
When given with the vaccine within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This treatment allows a mother to safely breastfeed her child.
Reactivation
Hepatitis B virus DNA persists in the body after infection and in some people the disease recurs.
Although rare, reactivation is seen most often in people with impaired immunity.
Hepatitis B goes through cycles of replication and non-replication.
Approximately 50% of patients experience acute reactivation.
Male patients with baseline ALT of 200 UL/L are three times more likely to develop a reactivation than patients with lower levels.
Patients who undergo chemotherapy are at risk for HBV reactivation.
The current view are that immunosuppressive drugs favor increased HBV replication while inhibiting cytotoxic T cell function in the liver.
History
The earliest record of an epidemic caused by Hepatitis B virus was made by Lurman in 1885.
An outbreak of smallpox occurred in Bremen in 1883 and 1,289 shipyard employees were vaccinated with lymph from other people. After several weeks, and up to eight months later, 191 of the vaccinated workers became ill with jaundice and were diagnosed as suffering from serum hepatitis.
Other employees who had been inoculated with different batches of lymph remained healthy.
Lurman's paper, now regarded as a classical example of an epidemiological study, proved that contaminated lymph was the source of the outbreak.
Later, numerous similar outbreaks were reported following the introduction, in 1909, of hypodermic needles that were used, and more importantly reused, for administering Salvarsan for the treatment of syphilis.
The virus was not discovered until 1965 when Baruch Blumberg, then working at the National Institutes of Health (NIH), discovered the Australia antigen (later known to be Hepatitis B surface antigen, or HBsAg) in the blood of Australian aboriginal people.
Although a virus had been suspected since the research published by MacCallum in 1947, D.S. Dane and others discovered the virus particle in 1970 by electron microscopy.
By the early 1980s the genome of the virus had been sequenced, and the first vaccines were being tested.
Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV).
The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis) which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer.
Originally known as "serum hepatitis", the disease has caused epidemics in parts of Asia and Africa, and it is endemic in China.
About a third of the world's population, more than 2 billion people, have been infected with the hepatitis B virus.
This includes 350 million chronic carriers of the virus.
Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood.
The acute illness causes liver inflammation, vomiting, jaundice and—rarely—death. Chronic hepatitis B may eventually cause liver cirrhosis and liver cancer—a fatal disease with very poor response to current chemotherapy.
The infection is preventable by vaccination.
Hepatitis B virus is an hepadnavirus—hepa from hepatotrophic and dna because it is a DNA virus—and it has a circular genome composed of partially double-stranded DNA.
The viruses replicate through an RNA intermediate form by reverse transcription, and in this respect they are similar to retroviruses.
Although replication takes place in the liver, the virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people.
Blood tests for these proteins and antibodies are used to diagnose the infection.
Virology
Hepatitis B virus (HBV) is a member of the Hepadnavirus family.
The virus particle, (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein.
The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity.
The outer envelope contains embedded proteins which are involved in viral binding of, and entry into, susceptible cells.
The virus is one of the smallest enveloped animal viruses with a virion diameter of 42nm, but pleomorphic forms exist, including filamentous and spherical bodies lacking a core.
These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus.
Genome
The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double-stranded. One end of the full length strand is linked to the viral DNA polymerase.
The genome is 3020-3320 nucleotides long (for the full length strand) and 1700-2800 nucleotides long (for the short length strand).
The negative-sense, (non-coding), is complementary to the viral mRNA.
The viral DNA is found in the nucleus soon after infection of the cell. The partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a protein molecule from the (-) sense strand and a short sequence of RNA from the (+) sense strand.
Non-coding bases are removed from the ends of the (-)sense strand and the ends are rejoined.
There are four known genes encoded by the genome called C, X, P, and S.
The core protein is coded for by gene C (HBcAg), and its start codon is preceded by an upstream in-frame AUG start codon from which the pre-core protein is produced.
HBeAg is produced by proteolytic processing of the pre-core protein.
The DNA polymerase is encoded by gene P. Gene S is the gene that codes for the surface antigen (HBsAg).
The HBsAg gene is one long open reading frame but contains three in frame "start" (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large, middle, and small (pre-S1 + pre-S2 + S, pre-S2 + S, or S) are produced.
The function of the protein coded for by gene X is not fully understood.[13]
Replication
The life cycle of Hepatitis B virus is complex. Hepatitis B is one of a few known non-retroviral viruses which use reverse transcription as a part of its replication process.
The virus gains entry into the cell by binding to an unknown receptor on the surface of the cell and enters it by endocytosis.
Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host proteins called chaperones.
The partially double stranded viral DNA is then made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of four viral mRNAs. The largest mRNA, (which is longer than the viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral DNA polymerase.
These four viral transcripts undergo additional processing and go on to form progeny virions which are released from the cell or returned to the nucleus and re-cycled to produce even more copies.
The long mRNA is then transported back to the cytoplasm where the virion P protein synthesizes DNA via its reverse transcriptase activity.
Serotypes
The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome.
The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus.
Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment and possibly vaccination.
Pathogenesis
Cirrhosis of the liver and liver cancer may ensue from Hepatitis B.
The hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells, known as hepatocytes.
The receptor is not yet known, though there is evidence that the receptor in the closely related duck hepatitis B virus is carboxypeptidase D.
HBV virions (DANE particle) bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis.
PreS and IgA receptors are accused of this interaction.
HBV-preS specific receptors are primarily expressed on hepatocytes; however, viral DNA and proteins have also been detected in extrahepatic sites, suggesting that cellular receptors for HBV may also exist on extrahepatic cells.
During HBV infection, the host immune response causes both hepatocellular damage and viral clearance.
Although the innate immune response does not play a significant role in these processes, the adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to most of the liver injury associated with HBV infection.
By killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, CTLs eliminate the virus.[19] Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver.
Epidemiology
The primary method of transmission reflects the prevalence of chronic HBV infection in a given area.
In low prevalence areas such as the continental United States and Western Europe, where less than 2% of the population is chronically infected, injection drug abuse and unprotected sex are the primary methods, although other factors may be important.
In moderate prevalence areas, which include Eastern Europe, Russia, and Japan, where 2-7% of the population is chronically infected, the disease is predominantly spread among children.
In high prevalence areas such as China and South East Asia, transmission during childbirth is most common, although in other areas of high endemicity such as Africa, transmission during childhood is a significant factor.
The prevalence of chronic HBV infection in areas of high endemicity is at least 8%.
Transmission
Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood.
Possible forms of transmission include (but are not limited to) unprotected sexual contact, blood transfusions, re-use of contaminated needles & syringes, and vertical transmission from mother to child during childbirth.
Without intervention, a mother who is positive for HBsAg confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for HBeAg.
HBV can be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV.
However, at least 30% of reported hepatitis B among adults cannot be associated with an identifiable risk factor.
Medical aspects
Several vaccines have been developed for the prevention of hepatitis B virus infection.
These rely on the use of one of the viral envelope proteins (hepatitis B surface antigen or HBsAg).
The vaccine was originally prepared from plasma obtained from patients who had long-standing hepatitis B virus infection.
However, currently, these are more often made using recombinant DNA technology, though plasma-derived vaccines continue to be used; the two types of vaccines are equally effective and safe.
Following vaccination Hepatitis B Surface antigen may be detected in serum for several days; this is known as vaccine antigenaemia.
Vaccine is generally administered in either a two, three, or four dose schedules; and can be received by infants to adults. It provides protection for 85-90% of individuals, and lasts for 23 years.
Unlike Hepatitis A, Hepatitis B does not generally spread through water and food.
Instead, it is transmitted through body fluids, from which prevention is taken to avoid: unprotected sexual contact, blood transfusions, re-use of contaminated needles and syringes, and vertical transmission during child birth.
Infants may be vaccinated at birth.
Symptoms
Acute infection with hepatitis B virus is associated with acute viral hepatitis - an illness that begins with general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever, dark urine, and then progresses to development of jaundice.
It has been noted that itchy skin has been an indication as a possible symptom of all hepatitis virus types.
The illness lasts for a few weeks and then gradually improves in most affected people.
A few patients may have more severe liver disease (fulminant hepatic failure), and may die as a result of it.
The infection may be entirely asymptomatic and may go unrecognized.
Chronic infection with Hepatitis B virus may be either asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), leading to cirrhosis over a period of several years.
This type of infection dramatically increases the incidence of hepatocellular carcinoma (liver cancer). Chronic carriers are encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and liver cancer.
Hepatitis B virus has been linked to the development of Membranous glomerulonephritis (MGN).
Diagnosis
The hepatitis B surface antigen (HBsAg) is most frequently used to screen for the presence of this infection.
It is the first detectable viral antigen to appear during infection.
However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host.
The infectious virion contains an inner "core particle" enclosing viral genome.
The icosahedral core particle is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or HBcAg.
During this 'window' in which the host remains infected but is successfully clearing the virus, IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be the only serological evidence of disease.
Shortly after the appearance of the HBsAg, another antigen named as the hepatitis B e antigen (HBeAg) will appear.
Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the hepatitis B virus do not produce the 'e' antigen, so this rule does not always hold true.
During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (anti-HBe) will arise immediately afterwards.
This conversion is usually associated with a dramatic decline in viral replication.
If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by IgG antibodies to the hepatitis B surface antigen and core antigen, (anti-HBs and anti HBc IgG). A person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously.
Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers.
Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase levels and inflammation of the liver, as revealed by biopsy.
Carriers who have seroconverted to HBeAg negative status, particularly those who acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others.
More recently, PCR tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens.
These tests are called viral loads and are used to assess a person's infection status and to monitor treatment.
Prognosis
Hepatitis B virus infection may either be acute (self-limiting) or chronic (long-standing).
Persons with self-limiting infection clear the infection spontaneously within weeks to months.
Children are less likely than adults to clear the infection.
More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus.
However, only 5% of newborns that acquire the infection from their mother at birth will clear the infection. This population has a 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma.
Of those infected between the age of one to six, 70% will clear the infection.
Hepatitis D infection can only occur with a concomitant infection with Hepatitis B virus because the Hepatitis D virus uses the Hepatitis B virus surface antigen to form a capsid.
Co-infection with hepatitis D increases the risk of liver cirrhosis and liver cancer.
Polyarteritis nodosa is more common in people with hepatitis B infection.
Treatment
Acute hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously.
Early antiviral treatment may only be required in fewer than 1% of patients, whose infection takes a very aggressive course ("fulminant hepatitis") or who are immunocompromised.
On the other hand, treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer.
Chronically infected individuals with persistently elevated serum alanine aminotransferase, a marker of liver damage, and HBV DNA levels are candidates for therapy.
Although none of the available drugs can clear the infection, they can stop the virus from replicating, and minimize liver damage such as cirrhosis and liver cancer.
Currently, there are seven medications licensed for treatment of hepatitis B infection in the United States.
These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude) and the two immune system modulators interferon alpha-2a and pegylated interferon alfa-2a (Pegasys). The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting pegylated interferon, which is injected only once weekly.
However, some individuals are much more likely to respond than others and this might be because of the genotype of the infecting virus or the patient's heredity.
The treatment works by reducing the viral load, (the amount of virus particles as measured in the blood), which in turn reduces viral replication in the liver.
Infants born to mothers known to carry hepatitis B can be treated with antibodies to the hepatitis B virus (hepatitis B immune globulin or HBIg).
When given with the vaccine within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This treatment allows a mother to safely breastfeed her child.
Reactivation
Hepatitis B virus DNA persists in the body after infection and in some people the disease recurs.
Although rare, reactivation is seen most often in people with impaired immunity.
Hepatitis B goes through cycles of replication and non-replication.
Approximately 50% of patients experience acute reactivation.
Male patients with baseline ALT of 200 UL/L are three times more likely to develop a reactivation than patients with lower levels.
Patients who undergo chemotherapy are at risk for HBV reactivation.
The current view are that immunosuppressive drugs favor increased HBV replication while inhibiting cytotoxic T cell function in the liver.
History
The earliest record of an epidemic caused by Hepatitis B virus was made by Lurman in 1885.
An outbreak of smallpox occurred in Bremen in 1883 and 1,289 shipyard employees were vaccinated with lymph from other people. After several weeks, and up to eight months later, 191 of the vaccinated workers became ill with jaundice and were diagnosed as suffering from serum hepatitis.
Other employees who had been inoculated with different batches of lymph remained healthy.
Lurman's paper, now regarded as a classical example of an epidemiological study, proved that contaminated lymph was the source of the outbreak.
Later, numerous similar outbreaks were reported following the introduction, in 1909, of hypodermic needles that were used, and more importantly reused, for administering Salvarsan for the treatment of syphilis.
The virus was not discovered until 1965 when Baruch Blumberg, then working at the National Institutes of Health (NIH), discovered the Australia antigen (later known to be Hepatitis B surface antigen, or HBsAg) in the blood of Australian aboriginal people.
Although a virus had been suspected since the research published by MacCallum in 1947, D.S. Dane and others discovered the virus particle in 1970 by electron microscopy.
By the early 1980s the genome of the virus had been sequenced, and the first vaccines were being tested.
Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV).
The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis) which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer.
HEPATITIS A
Hepatitis A
Hepatitis A (formerly known as infectious hepatitis) is an acute infectious disease of the liver caused by the hepatitis A virus (HAV)
It is most commonly transmitted by the fecal-oral route via contaminated food or drinking water. Every year, approximately 10 million people worldwide are infected with the virus.
The time between infection and the appearance of the symptoms, (the incubation period), is between two and six weeks and the average incubation period is 28 days.
In developing countries, and in regions with poor hygiene standards, the incidence of infection with this virus is high and the illness is usually contracted in early childhood.
HAV has also been found in samples taken to study ocean water quality.
Hepatitis A infection causes no clinical signs and symptoms in over 90% of these children and since the infection confers lifelong immunity, the disease is of no special significance to the indigenous population. In Europe, the United States and other industrialized countries, on the other hand, the infection is contracted primarily by susceptible young adults, most of whom are infected with the virus during trips to countries with a high incidence of the disease.
Hepatitis A does not have a chronic stage and does not cause permanent liver damage.
Following infection, the immune system makes antibodies against HAV that confer immunity against future infection.
The disease can be prevented by vaccination and hepatitis A vaccine has been proven effective in controlling outbreaks worldwide.
Virology
The Hepatitis virus (HAV) is a Picornavirus; it is non-enveloped and contains a single-stranded RNA packaged in a protein shell. There is only one type of the virus.
Pathogenesis
Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine.
The blood carries the virus to its target, the liver, and multiplies within hepatocytes and Kupffer cells (i.e., liver macrophages). There is no apparent virus-mediated cytotoxicity, and liver pathology is likely immune-mediated.
Virions are secreted into the bile and released in stool.
HAV is excreted in large quantities approximately 11 days prior to appearance of symptoms or anti-HAV IgM antibodies in the blood.
The incubation period is 15-50 days, and mortality is less than 0.5%.
Epidemiology
HAV is found in the feces of infected persons and those who are at higher risk include travelers to developing countries where there is a higher incidence rate, and those having sexual contact or drug use with infected persons.
There were 30,000 cases of Hepatitis A reported to the CDC in the U.S. in 1997. The agency estimates that there were as many as 270,000 cases each year from 1980 through 2000.
Transmission
The virus spreads by the fecal-oral route and infections often occur in conditions of poor sanitation and overcrowding.
Hepatitis A can be transmitted by the parenteral route but very rarely by blood and blood products.
Food-borne outbreaks are not uncommon, and ingestion of shellfish cultivated in polluted water is associated with a high risk of infection.
Approximately 40% of all acute viral hepatitis is caused by HAV.
Infected individuals are infectious prior to onset of symptoms, roughly 10 days following infection.
The virus is resistant to detergent, acid (pH 1), solvents (e.g., ether, chloroform), drying, and temperatures up to 60oC. It can survive for months in fresh and salt water.
Common-source (e.g., water, restaurant) outbreaks are typical.
Infection is common in children in developing countries, reaching 100% incidence, but following infection there is life-long immunity.
HAV can be inactivated by: chlorine treatment (drinking water), formalin (0.35%, 37oC, 72 hours), peracetic acid (2%, 4 hours), beta-propiolactone (0.25%, 1 hour), and UV radiation (2 μW/cm2/min).
Cases
The most widespread hepatitis A outbreak in the United States afflicted at least 640 people (killing four) in north-eastern Ohio and south-western Pennsylvania in late 2003.
The outbreak was blamed on tainted green onions at a restaurant in Monaca, Pennsylvania. In 1988, 300,000 people in Shanghai, China were infected with HAV after eating clams from a contaminated river.[14]
Prevention
Hepatitis A can be prevented by vaccination, good hygiene and sanitation.[1][15] Hepatitis A is also one of the main reasons not to surf or go in the ocean after rains in coastal areas that are known to have bad runoff.
The vaccine protects against HAV in more than 95% of cases for 10 years. It contains inactivated Hepatitis A virus providing active immunity against a future infection.
The vaccine was first phased in 1996 for children in high-risk areas, and in 1999 it was spread to areas with elevating levels of infection.
The vaccine is given in two doses in the muscle of the upper arm.
The first dose provides protection two to four weeks after initial vaccination; the second booster dose, given six to twelve months later, provides protection for up to twenty years.
Symptoms
Early symptoms of hepatitis A infection can be mistaken for influenza, but some sufferers, especially children, exhibit no symptoms at all.
Symptoms typically appear 2 to 6 weeks, (the incubation period ), after the initial infection.
Symptoms can return over the following 6-9 months which include:
* Fatigue
* Fever
* Abdominal pain
* Nausea
* Diarrhea
* Appetite loss
* Depression
* Jaundice, a yellowing of the skin or whites of the eyes
* Sharp pains in the right-upper quadrant of the abdomen
* Weight loss
* Itching
Diagnosis
Serum IgG, IgM and ALT following Hepatitis A virus infection
Although HAV is excreted in the feces towards the end of the incubation period, specific diagnosis is made by the detection of HAV-specific IgM antibodies in the blood.
IgM antibody is only present in the blood following an acute hepatitis A infection.
It is detectable from one to two weeks after the initial infection and persists for up to 14 weeks.
The presence of IgG antibody in the blood means that the acute stage of the illness is past and the person is immune to further infection.
IgG antibody to HAV is also found in the blood following vaccination and tests for immunity to the virus are based on the detection of this antibody.
During the acute stage of the infection, the liver enzyme alanine transferase (ALT) is present in the blood at levels much higher than is normal.
The enzyme comes from the liver cells that have been damaged by the virus.
Hepatitis A virus is present in the blood, (viremia), and feces of infected people up to two weeks before clinical illness develops.
Prognosis
The United States Centers for Disease Control and Prevention (CDC) in 1991 reported a low mortality rate for hepatitis A of 4 deaths per 1000 cases for the general population but a higher rate of 17.5 per 1000, in those aged 50 and over.
Death usually occurs when the patient contracts Hepatitis A while already suffering from another form of Hepatitis, such as Hepatitis B or Hepatitis C or AIDS.
Young children who are infected with hepatitis A typically have a milder form of the disease, usually lasting from 1-3 weeks, whereas adults tend to experience a much more severe form of the disease.
Treatment
There is no specific treatment for hepatitis A.
Sufferers are advised to rest, avoid fatty foods and alcohol (these may be poorly tolerated for some additional months during the recovery phase and cause minor relapses), eat a well-balanced diet, and stay hydrated. Approximately 15% of people diagnosed with hepatitis A may experience one or more symptomatic relapse(s) for up to 24 months after contracting this disease.
Hepatitis A (formerly known as infectious hepatitis) is an acute infectious disease of the liver caused by the hepatitis A virus (HAV)
It is most commonly transmitted by the fecal-oral route via contaminated food or drinking water. Every year, approximately 10 million people worldwide are infected with the virus.
The time between infection and the appearance of the symptoms, (the incubation period), is between two and six weeks and the average incubation period is 28 days.
In developing countries, and in regions with poor hygiene standards, the incidence of infection with this virus is high and the illness is usually contracted in early childhood.
HAV has also been found in samples taken to study ocean water quality.
Hepatitis A infection causes no clinical signs and symptoms in over 90% of these children and since the infection confers lifelong immunity, the disease is of no special significance to the indigenous population. In Europe, the United States and other industrialized countries, on the other hand, the infection is contracted primarily by susceptible young adults, most of whom are infected with the virus during trips to countries with a high incidence of the disease.
Hepatitis A does not have a chronic stage and does not cause permanent liver damage.
Following infection, the immune system makes antibodies against HAV that confer immunity against future infection.
The disease can be prevented by vaccination and hepatitis A vaccine has been proven effective in controlling outbreaks worldwide.
Virology
The Hepatitis virus (HAV) is a Picornavirus; it is non-enveloped and contains a single-stranded RNA packaged in a protein shell. There is only one type of the virus.
Pathogenesis
Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine.
The blood carries the virus to its target, the liver, and multiplies within hepatocytes and Kupffer cells (i.e., liver macrophages). There is no apparent virus-mediated cytotoxicity, and liver pathology is likely immune-mediated.
Virions are secreted into the bile and released in stool.
HAV is excreted in large quantities approximately 11 days prior to appearance of symptoms or anti-HAV IgM antibodies in the blood.
The incubation period is 15-50 days, and mortality is less than 0.5%.
Epidemiology
HAV is found in the feces of infected persons and those who are at higher risk include travelers to developing countries where there is a higher incidence rate, and those having sexual contact or drug use with infected persons.
There were 30,000 cases of Hepatitis A reported to the CDC in the U.S. in 1997. The agency estimates that there were as many as 270,000 cases each year from 1980 through 2000.
Transmission
The virus spreads by the fecal-oral route and infections often occur in conditions of poor sanitation and overcrowding.
Hepatitis A can be transmitted by the parenteral route but very rarely by blood and blood products.
Food-borne outbreaks are not uncommon, and ingestion of shellfish cultivated in polluted water is associated with a high risk of infection.
Approximately 40% of all acute viral hepatitis is caused by HAV.
Infected individuals are infectious prior to onset of symptoms, roughly 10 days following infection.
The virus is resistant to detergent, acid (pH 1), solvents (e.g., ether, chloroform), drying, and temperatures up to 60oC. It can survive for months in fresh and salt water.
Common-source (e.g., water, restaurant) outbreaks are typical.
Infection is common in children in developing countries, reaching 100% incidence, but following infection there is life-long immunity.
HAV can be inactivated by: chlorine treatment (drinking water), formalin (0.35%, 37oC, 72 hours), peracetic acid (2%, 4 hours), beta-propiolactone (0.25%, 1 hour), and UV radiation (2 μW/cm2/min).
Cases
The most widespread hepatitis A outbreak in the United States afflicted at least 640 people (killing four) in north-eastern Ohio and south-western Pennsylvania in late 2003.
The outbreak was blamed on tainted green onions at a restaurant in Monaca, Pennsylvania. In 1988, 300,000 people in Shanghai, China were infected with HAV after eating clams from a contaminated river.[14]
Prevention
Hepatitis A can be prevented by vaccination, good hygiene and sanitation.[1][15] Hepatitis A is also one of the main reasons not to surf or go in the ocean after rains in coastal areas that are known to have bad runoff.
The vaccine protects against HAV in more than 95% of cases for 10 years. It contains inactivated Hepatitis A virus providing active immunity against a future infection.
The vaccine was first phased in 1996 for children in high-risk areas, and in 1999 it was spread to areas with elevating levels of infection.
The vaccine is given in two doses in the muscle of the upper arm.
The first dose provides protection two to four weeks after initial vaccination; the second booster dose, given six to twelve months later, provides protection for up to twenty years.
Symptoms
Early symptoms of hepatitis A infection can be mistaken for influenza, but some sufferers, especially children, exhibit no symptoms at all.
Symptoms typically appear 2 to 6 weeks, (the incubation period ), after the initial infection.
Symptoms can return over the following 6-9 months which include:
* Fatigue
* Fever
* Abdominal pain
* Nausea
* Diarrhea
* Appetite loss
* Depression
* Jaundice, a yellowing of the skin or whites of the eyes
* Sharp pains in the right-upper quadrant of the abdomen
* Weight loss
* Itching
Diagnosis
Serum IgG, IgM and ALT following Hepatitis A virus infection
Although HAV is excreted in the feces towards the end of the incubation period, specific diagnosis is made by the detection of HAV-specific IgM antibodies in the blood.
IgM antibody is only present in the blood following an acute hepatitis A infection.
It is detectable from one to two weeks after the initial infection and persists for up to 14 weeks.
The presence of IgG antibody in the blood means that the acute stage of the illness is past and the person is immune to further infection.
IgG antibody to HAV is also found in the blood following vaccination and tests for immunity to the virus are based on the detection of this antibody.
During the acute stage of the infection, the liver enzyme alanine transferase (ALT) is present in the blood at levels much higher than is normal.
The enzyme comes from the liver cells that have been damaged by the virus.
Hepatitis A virus is present in the blood, (viremia), and feces of infected people up to two weeks before clinical illness develops.
Prognosis
The United States Centers for Disease Control and Prevention (CDC) in 1991 reported a low mortality rate for hepatitis A of 4 deaths per 1000 cases for the general population but a higher rate of 17.5 per 1000, in those aged 50 and over.
Death usually occurs when the patient contracts Hepatitis A while already suffering from another form of Hepatitis, such as Hepatitis B or Hepatitis C or AIDS.
Young children who are infected with hepatitis A typically have a milder form of the disease, usually lasting from 1-3 weeks, whereas adults tend to experience a much more severe form of the disease.
Treatment
There is no specific treatment for hepatitis A.
Sufferers are advised to rest, avoid fatty foods and alcohol (these may be poorly tolerated for some additional months during the recovery phase and cause minor relapses), eat a well-balanced diet, and stay hydrated. Approximately 15% of people diagnosed with hepatitis A may experience one or more symptomatic relapse(s) for up to 24 months after contracting this disease.
HEPATITIS
Hepatitis
Hepatitis (plural hepatitides) implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar (ἧπαρ), the root being hepat- (ἡπατ-), meaning liver, and suffix -itis, meaning "inflammation" (c. 1727)[1]. The condition can be self-limiting, healing on its own, or can progress to scarring of the liver. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. A group of viruses known as the hepatitis viruses cause most cases of liver damage worldwide. Hepatitis can also be due to toxins (notably alcohol), other infections or from autoimmune process. It may run a subclinical course when the affected person may not feel ill. The patient becomes unwell and symptomatic when the disease impairs liver functions that include, among other things, removal of harmful substances, regulation of blood composition, and production of bile to help digestion.
Causes
Acute
* Viral hepatitis: Hepatitis A through E (more than 95% of viral cause), Herpes simplex, Cytomegalovirus, Epstein-Barr, yellow fever virus, adenoviruses.
* Non viral infection: toxoplasma, Leptospira, Q fever,[2] rocky mountain spotted fever[3]
* Alcohol
* Toxins: Amanita toxin in mushrooms, carbon tetrachloride, asafetida
* Drugs: Paracetamol, amoxycillin, antituberculosis medicines, minocycline and many others (see longer list below).
* Ischemic hepatitis (circulatory insufficiency)
* Pregnancy
* Auto immune conditions, e.g., Systemic Lupus Erythematosus (SLE)
* Metabolic diseases, e.g., Wilson's disease
Chronic
* Viral hepatitis: Hepatitis B with or without hepatitis D, hepatitis C (neither hepatitis A nor hepatitis E causes chronic hepatitis)
* Autoimmune: Autoimmune hepatitis
* Alcohol
* Drugs: methyldopa, nitrofurantoin, isoniazid, ketoconazole
* Non-alcoholic steatohepatitis
* Heredity: Wilson's disease, alpha 1-antitrypsin deficiency
* Primary biliary cirrhosis and primary sclerosing cholangitis occasionally mimic chronic hepatitis[4]
Symptoms
Acute
Clinically, the course of acute hepatitis varies widely from mild symptoms requiring no treatment to fulminant hepatic failure needing liver transplantation. Acute viral hepatitis is more likely to be asymptomatic in younger people. Symptomatic individuals may present after convalescent stage of 7 to 10 days, with the total illness lasting 2 to 6 weeks.[4]
Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice (33%) and tender hepatomegaly (10%). There can be occasional lymphadenopathy (5%) or splenomegaly (5%).[5]
Chronic
Majority of patients will remain asymptomatic or mildly symptomatic, abnormal blood tests being the only manifestation. Features may be related to the extent of liver damage or the cause of hepatitis. Many experience return of symptoms related to acute hepatitis. Jaundice can be a late feature and may indicate extensive damage. Other features include abdominal fullness from enlarged liver or spleen, low grade fever and fluid retention (ascites). Extensive damage and scarring of liver (i.e., cirrhosis) leads to weight loss, easy bruising and bleeding tendencies. Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis.[6]
Findings on clinical examination are usually those of cirrhosis or are related to aetiology.
Types
Viral
Most cases of acute hepatitis are due to viral infections:
* Hepatitis A
* Hepatitis B
* Hepatitis C
* Hepatitis B with D
* Hepatitis E
* Hepatitis F virus (existence unknown)
* Hepatitis G, or GBV-C
* In addition to the hepatitis viruses (please note that the hepatitis viruses are not all related), other viruses can also cause hepatitis, including cytomegalovirus, Epstein-Barr virus, yellow fever, etc.
Other viral infections can cause hepatitis (inflammation of the liver):
* Mumps virus
* Rubella virus
* Cytomegalovirus
* Epstein-Barr virus
* Other herpes viruses
Alcoholic hepatitis
Ethanol, mostly in alcoholic beverages, is a significant cause of hepatitis. Usually alcoholic hepatitis comes after a period of increased alcohol consumption. Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen ascites, and modest elevation of liver blood tests. Alcoholic hepatitis can vary from mild with only liver test elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and liver failure. Severe cases are characterized by either obtundation (dulled consciousness) or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both categories is 50% within 30 days of onset.
Alcoholic hepatitis is distinct from cirrhosis caused by long term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Patients who drink alcohol to excess are also more often than others found to have hepatitis C.[citation needed] The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis.
Drug induced
A large number of drugs can cause hepatitis:[7]
* Allopurinol
* Amitriptyline (antidepressant)
* Amiodarone (antiarrhythmic)
* Atomoxetine [8]
* Azathioprine[9]
* Halothane (a specific type of anesthetic gas)
* Hormonal contraceptives
* Ibuprofen and indomethacin (NSAIDs)
* Isoniazid (INH), rifampicin, and pyrazinamide (tuberculosis-specific antibiotics)
* Ketoconazole (antifungal)
* Loratadine (antihistamine)
* Methotrexate (immune suppressant)
* Methyldopa (antihypertensive)
* Minocycline (tetracycline antibiotic)
* Nifedipine (antihypertensive)
* Nitrofurantoin (antibiotic)
* Paracetamol (acetaminophen in the United States) can cause hepatitis when taken in an overdose. The severity of liver damage may be limited by prompt administration of acetylcysteine.
* Phenytoin and valproic acid (antiepileptics)
* Troglitazone (antidiabetic, withdrawn in 2000 for causing hepatitis)
* Zidovudine (antiretroviral i.e., against HIV)
* Some herbs and nutritional supplements[10]
The clinical course of drug-induced hepatitis is quite variable, depending on the drug and the patient's tendency to react to the drug. For example, halothane hepatitis can range from mild to fatal as can INH-induced hepatitis. Hormonal contraception can cause structural changes in the liver. Amiodarone hepatitis can be untreatable since the long half life of the drug (up to 60 days) means that there is no effective way to stop exposure to the drug. Statins can cause elevations of liver function blood tests normally without indicating an underlying hepatitis. Lastly, human variability is such that any drug can be a cause of hepatitis.
Toxins
Other Toxins can cause hepatitis:
* Amatoxin-containing mushrooms, including the Death Cap (Amanita phalloides), the Destroying Angel (Amanita ocreata), and some species of Galerina. A portion of a single mushroom can be enough to be lethal (10 mg or less of α-amanitin).
* White phosphorus, an industrial toxin and war chemical.
* Carbon tetrachloride ("tetra", a dry cleaning agent), chloroform, and trichloroethylene, all chlorinated hydrocarbons, cause steatohepatitis (hepatitis with fatty liver).
* Cylindrospermopsin, a toxin from the cyanobacterium Cylindrospermopsis raciborskii and other cyanobacteria.
Metabolic disorders
Some metabolic disorders cause different forms of hepatitis. Hemochromatosis (due to iron accumulation) and Wilson's disease (copper accumulation) can cause liver inflammation and necrosis.
Non-alcoholic steatohepatitis (NASH) is effectively a consequence of metabolic syndrome.
Obstructive
"Obstructive jaundice" is the term used to describe jaundice due to obstruction of the bile duct (by gallstones or external obstruction by cancer). If longstanding, it leads to destruction and inflammation of liver tissue.
Autoimmune
Anomalous presentation of human leukocyte antigen (HLA) class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection; causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis.
Alpha 1-antitrypsin deficiency
In severe cases of alpha 1-antitrypsin deficiency (A1AD), the accumulated protein in the endoplasmic reticulum causes liver cell damage and inflammation.
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is the occurrence of fatty liver in people who have no history of alcohol use. It is most commonly associated with obesity (80% of all obese people have fatty liver). It is more common in women. Severe NAFLD leads to inflammation, a state referred to as non-alcoholic steatohepatitis (NASH), which on biopsy of the liver resembles alcoholic hepatitis (with fat droplets and inflammatory cells, but usually no Mallory bodies).
The diagnosis depends on medical history, physical exam, blood tests, radiological imaging and sometimes a liver biopsy. The initial evaluation to identify the presence of fatty infiltration of the liver is medical imaging, including such ultrasound, computed tomography (CT), or magnetic resonance (MRI). However, imaging cannot readily identify inflammation in the liver. Therefore, the differentiation between steatosis and NASH often requires a liver biopsy. It can also be difficult to distinguish NASH from alcoholic hepatitis when the patient has a history of alcohol consumption. Sometimes in such cases a trial of abstinence from alcohol along with follow-up blood tests and a repeated liver biopsy are required.
NASH is becoming recognized as the most important cause of liver disease second only to hepatitis C in numbers of patients going on to cirrhosis.[citation needed]
Ischemic hepatitis
Ischemic hepatitis is caused by decreased circulation to the liver cells. Usually this is due to decreased blood pressure (or shock), leading to the equivalent term "shock liver". Patients with ischemic hepatitis are usually very ill due to the underlying cause of shock. Rarely, ischemic hepatitis can be caused by local problems with the blood vessels that supply oxygen to the liver (such as thrombosis, or clotting of the hepatic artery which partially supplies blood to liver cells). Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT), which may exceed 1000 U/L. The elevation in these blood tests is usually transient (lasting 7 to 10 days). It is rare that liver function will be affected by ischemic hepatitis.
Hepatitis (plural hepatitides) implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar (ἧπαρ), the root being hepat- (ἡπατ-), meaning liver, and suffix -itis, meaning "inflammation" (c. 1727)[1]. The condition can be self-limiting, healing on its own, or can progress to scarring of the liver. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. A group of viruses known as the hepatitis viruses cause most cases of liver damage worldwide. Hepatitis can also be due to toxins (notably alcohol), other infections or from autoimmune process. It may run a subclinical course when the affected person may not feel ill. The patient becomes unwell and symptomatic when the disease impairs liver functions that include, among other things, removal of harmful substances, regulation of blood composition, and production of bile to help digestion.
Causes
Acute
* Viral hepatitis: Hepatitis A through E (more than 95% of viral cause), Herpes simplex, Cytomegalovirus, Epstein-Barr, yellow fever virus, adenoviruses.
* Non viral infection: toxoplasma, Leptospira, Q fever,[2] rocky mountain spotted fever[3]
* Alcohol
* Toxins: Amanita toxin in mushrooms, carbon tetrachloride, asafetida
* Drugs: Paracetamol, amoxycillin, antituberculosis medicines, minocycline and many others (see longer list below).
* Ischemic hepatitis (circulatory insufficiency)
* Pregnancy
* Auto immune conditions, e.g., Systemic Lupus Erythematosus (SLE)
* Metabolic diseases, e.g., Wilson's disease
Chronic
* Viral hepatitis: Hepatitis B with or without hepatitis D, hepatitis C (neither hepatitis A nor hepatitis E causes chronic hepatitis)
* Autoimmune: Autoimmune hepatitis
* Alcohol
* Drugs: methyldopa, nitrofurantoin, isoniazid, ketoconazole
* Non-alcoholic steatohepatitis
* Heredity: Wilson's disease, alpha 1-antitrypsin deficiency
* Primary biliary cirrhosis and primary sclerosing cholangitis occasionally mimic chronic hepatitis[4]
Symptoms
Acute
Clinically, the course of acute hepatitis varies widely from mild symptoms requiring no treatment to fulminant hepatic failure needing liver transplantation. Acute viral hepatitis is more likely to be asymptomatic in younger people. Symptomatic individuals may present after convalescent stage of 7 to 10 days, with the total illness lasting 2 to 6 weeks.[4]
Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice (33%) and tender hepatomegaly (10%). There can be occasional lymphadenopathy (5%) or splenomegaly (5%).[5]
Chronic
Majority of patients will remain asymptomatic or mildly symptomatic, abnormal blood tests being the only manifestation. Features may be related to the extent of liver damage or the cause of hepatitis. Many experience return of symptoms related to acute hepatitis. Jaundice can be a late feature and may indicate extensive damage. Other features include abdominal fullness from enlarged liver or spleen, low grade fever and fluid retention (ascites). Extensive damage and scarring of liver (i.e., cirrhosis) leads to weight loss, easy bruising and bleeding tendencies. Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis.[6]
Findings on clinical examination are usually those of cirrhosis or are related to aetiology.
Types
Viral
Most cases of acute hepatitis are due to viral infections:
* Hepatitis A
* Hepatitis B
* Hepatitis C
* Hepatitis B with D
* Hepatitis E
* Hepatitis F virus (existence unknown)
* Hepatitis G, or GBV-C
* In addition to the hepatitis viruses (please note that the hepatitis viruses are not all related), other viruses can also cause hepatitis, including cytomegalovirus, Epstein-Barr virus, yellow fever, etc.
Other viral infections can cause hepatitis (inflammation of the liver):
* Mumps virus
* Rubella virus
* Cytomegalovirus
* Epstein-Barr virus
* Other herpes viruses
Alcoholic hepatitis
Ethanol, mostly in alcoholic beverages, is a significant cause of hepatitis. Usually alcoholic hepatitis comes after a period of increased alcohol consumption. Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen ascites, and modest elevation of liver blood tests. Alcoholic hepatitis can vary from mild with only liver test elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and liver failure. Severe cases are characterized by either obtundation (dulled consciousness) or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both categories is 50% within 30 days of onset.
Alcoholic hepatitis is distinct from cirrhosis caused by long term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Patients who drink alcohol to excess are also more often than others found to have hepatitis C.[citation needed] The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis.
Drug induced
A large number of drugs can cause hepatitis:[7]
* Allopurinol
* Amitriptyline (antidepressant)
* Amiodarone (antiarrhythmic)
* Atomoxetine [8]
* Azathioprine[9]
* Halothane (a specific type of anesthetic gas)
* Hormonal contraceptives
* Ibuprofen and indomethacin (NSAIDs)
* Isoniazid (INH), rifampicin, and pyrazinamide (tuberculosis-specific antibiotics)
* Ketoconazole (antifungal)
* Loratadine (antihistamine)
* Methotrexate (immune suppressant)
* Methyldopa (antihypertensive)
* Minocycline (tetracycline antibiotic)
* Nifedipine (antihypertensive)
* Nitrofurantoin (antibiotic)
* Paracetamol (acetaminophen in the United States) can cause hepatitis when taken in an overdose. The severity of liver damage may be limited by prompt administration of acetylcysteine.
* Phenytoin and valproic acid (antiepileptics)
* Troglitazone (antidiabetic, withdrawn in 2000 for causing hepatitis)
* Zidovudine (antiretroviral i.e., against HIV)
* Some herbs and nutritional supplements[10]
The clinical course of drug-induced hepatitis is quite variable, depending on the drug and the patient's tendency to react to the drug. For example, halothane hepatitis can range from mild to fatal as can INH-induced hepatitis. Hormonal contraception can cause structural changes in the liver. Amiodarone hepatitis can be untreatable since the long half life of the drug (up to 60 days) means that there is no effective way to stop exposure to the drug. Statins can cause elevations of liver function blood tests normally without indicating an underlying hepatitis. Lastly, human variability is such that any drug can be a cause of hepatitis.
Toxins
Other Toxins can cause hepatitis:
* Amatoxin-containing mushrooms, including the Death Cap (Amanita phalloides), the Destroying Angel (Amanita ocreata), and some species of Galerina. A portion of a single mushroom can be enough to be lethal (10 mg or less of α-amanitin).
* White phosphorus, an industrial toxin and war chemical.
* Carbon tetrachloride ("tetra", a dry cleaning agent), chloroform, and trichloroethylene, all chlorinated hydrocarbons, cause steatohepatitis (hepatitis with fatty liver).
* Cylindrospermopsin, a toxin from the cyanobacterium Cylindrospermopsis raciborskii and other cyanobacteria.
Metabolic disorders
Some metabolic disorders cause different forms of hepatitis. Hemochromatosis (due to iron accumulation) and Wilson's disease (copper accumulation) can cause liver inflammation and necrosis.
Non-alcoholic steatohepatitis (NASH) is effectively a consequence of metabolic syndrome.
Obstructive
"Obstructive jaundice" is the term used to describe jaundice due to obstruction of the bile duct (by gallstones or external obstruction by cancer). If longstanding, it leads to destruction and inflammation of liver tissue.
Autoimmune
Anomalous presentation of human leukocyte antigen (HLA) class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection; causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis.
Alpha 1-antitrypsin deficiency
In severe cases of alpha 1-antitrypsin deficiency (A1AD), the accumulated protein in the endoplasmic reticulum causes liver cell damage and inflammation.
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is the occurrence of fatty liver in people who have no history of alcohol use. It is most commonly associated with obesity (80% of all obese people have fatty liver). It is more common in women. Severe NAFLD leads to inflammation, a state referred to as non-alcoholic steatohepatitis (NASH), which on biopsy of the liver resembles alcoholic hepatitis (with fat droplets and inflammatory cells, but usually no Mallory bodies).
The diagnosis depends on medical history, physical exam, blood tests, radiological imaging and sometimes a liver biopsy. The initial evaluation to identify the presence of fatty infiltration of the liver is medical imaging, including such ultrasound, computed tomography (CT), or magnetic resonance (MRI). However, imaging cannot readily identify inflammation in the liver. Therefore, the differentiation between steatosis and NASH often requires a liver biopsy. It can also be difficult to distinguish NASH from alcoholic hepatitis when the patient has a history of alcohol consumption. Sometimes in such cases a trial of abstinence from alcohol along with follow-up blood tests and a repeated liver biopsy are required.
NASH is becoming recognized as the most important cause of liver disease second only to hepatitis C in numbers of patients going on to cirrhosis.[citation needed]
Ischemic hepatitis
Ischemic hepatitis is caused by decreased circulation to the liver cells. Usually this is due to decreased blood pressure (or shock), leading to the equivalent term "shock liver". Patients with ischemic hepatitis are usually very ill due to the underlying cause of shock. Rarely, ischemic hepatitis can be caused by local problems with the blood vessels that supply oxygen to the liver (such as thrombosis, or clotting of the hepatic artery which partially supplies blood to liver cells). Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT), which may exceed 1000 U/L. The elevation in these blood tests is usually transient (lasting 7 to 10 days). It is rare that liver function will be affected by ischemic hepatitis.
Monday, July 6, 2009
LIVER FUNCTIONS
The liver is an organ in living beings, including humans.
It plays a major role in metabolism and has a number of functions in the body including
glycogen storage,
plasma protein synthesis,
drug detoxification.
This organ also is the largest gland in the human body. It produces bile, which is important in digestion.
It performs and regulates a wide variety of high-volume biochemical reactions requiring specialized tissues
Wednesday, June 3, 2009
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