Approximately 11,000-15,000 persons die from chronic liver disease annually nationwide and viral hepatitis is a serious global health problem especially in developing countries affecting millions of and children adults. In the United States, viral hepatitis became a major public health problem with an estimated 113,000 new infections in 2005. Although multiple viral pathogens cause hepatitis, especially three - hepatitis A, B and C- are responsible for majority of cases. Although hepatitis D and E are not as commonly diagnosed but these two are also important. All of these viruses cause acute, or short-term viral hepatitis but the hepatitis B and C viruses can also cause chronic or long-term hepatitis. Approximately 1.4 million cases of hepatitis A virus (HAV) infection are reported annually. It has been estimated that 3% of the world's population has been infected with HCV of which 170 million people are chronically infected, and an additional 3 to 4 million people are infected each year. Infections of HBV and HCV are the most prevalent and their aftermaths are serious. The most common cause of liver fibrosis and cirrhosis is long term chronic infection with one or both of these viruses, leading to liver failure and hepatocellular carcinoma (HCC). Hepatitis D virus (HDV) is a subviral satellite that needs the presence of another virus for replication i.e. HBV. More serious complications are developed in HDV coinfection with HBV which include a greater likelihood of liver failure and a mortality rate as high as 20%. Hepatitis E virus (HEV) is found predominantly in regions with poor sanitation and inadequate hygienic conditions. Another virus, G, is associated with hepatitis but has not been shown to cause serious clinical disease. There have even been some reports of a seventh virus, F but these reports are not confirmed, and health experts do not accept it as a unique virus. Although all forms of viral hepatitis have common symptoms, but each also has its own special features.
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Hepatitis is the liver inflammation. Toxins, chemicals including alcohol in excessive quantity, autoimmune diseases in which immune system damage healthy tissues in the body and microorganisms, particularly viruses are associated with hepatitis.
PHASES OF HEPATITIS
1. Acute Phase: It is the initial short term stage of the disease that begins with the entry of virus into the body and continues for up to 6 months.These infections are self-limited. All forms (A to E) have an acute phase. The most common symptoms are malaise or fatigue, low-grade fever, jaundice, joint pain and nausea and vomiting. Acute viral hepatitis can be divided into four phases:
Incubation Phase: This phase begins with the initial infection and continues until the onset of symptoms. In this phase, virus reproduces rapidly and the infected person may be highly contagious and this is a dangerous period for others because the infected person does not know about the infection and cannot take precautions to avoid passing it on.
Prodromal Phase: This phase starts with the onset of symptoms. A low grade fever, which may be followed within days by anorexia, malaise and nausea and vomiting. Smoker often loses their desire to smoke. The blood levels of some proteins (ALT) which are made by liver rise.
Icteric Phase: This phase may begin 3 to 10 days after first symptoms appear. Changes in the color of urine, stools, skin and sclera are seen. Jaundice itself is at its worst about 1 to 2 weeks after the starts of this phase and then fades over a period of 4-8 weeks.
Recovery Phase: This phase typically lasts 4 to 8 weeks but can last up to 6 months. During this phase, liver enlargement (hepatomegaly) occurs and liver may be tender to the touch, so that a person may feel discomfort just below the right ribs with slight pressure. Finally all symptoms disappear and person returns to normal health with immunity to future infections by the same kind of virus.
Complications of acute Phase include:
Fulminant hepatitis is most often associated with hepatitis B (1% of cases), but may also develop with hepatitides A and C. Death can occur within 2 weeks of onset. Liver cells are destroyed very rapidly and liver size decreases dramatically and this condition is known as acute yellow atrophy. The liver stops to provide essential functions for the rest of the body. The toxic substances build up in the blood and enter the brain and cause hepatic encephalopathy. The pressure of fluids in the brain builds up which causes physical damage to brain cells directly and reduces blood flow to the brain. And thus additional brain cell damage takes place. Death may occur due to lack of oxygen. The toxic substances may also promote kidney failure that is always fatal.
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2. Chronic Phase: A continuing lifelong infection that begins after six months of infection without recovery. Hepatitis viruses B, C, and D are known to cause chronic hepatitis; the others do not (chronic hepatitis caused by HCV is most likely lead to death). It can develop when a person's immune system is unable to eliminate the invading virus. Symptoms are same as in acute phase and may first appear, continue, or disappear. Some people infected with hepatitis don't show any symptoms until late in the chronic phase (20 or more years after infection). Three Phases of Chronic Phase are:
Replicative Phase: In this phase the virus reproduces itself actively and infects healthy hepatocytes. This phase may last several years, resulting in a large amount of virus in the blood (viremia), thus the disease is most contagious during this phase.
Seroconversion Phase: The immune system attacks and destroys about 10% of infected hepatocytes each year. In this phase less viremia is found.
Nonreplicative Phase: The virus ceases reproducing and viremia is minimal.
Complications of Chronic Phase include:
The first serious complication, 10 or more years after infection, is cirrhosis. A second serious complication, which usually develops more slowly and appears later than cirrhosis, is hepatocellular carcinoma. In the first place, the inflammation reactive to liver cell injury may damage the liver cells and the latter injury may be caused by the immunologic component of the inflammation if an auto-aggressive mechanism in liver disease should eventually be established. Later the fibroblastic component of the inflammation causes hepatocellular injury, and thus cirrhosis develops.
TESTING FOR VIRUSES
Radioimmunoassay and Immunofluorescence
ELISA: A simple ELISA test may not be sensitive enough to detect some viruses, such as the HCV thus a second generation enzyme immunoassay, EIA-2 that was developed in 1992 is much more sensitive than ELISA.
Another test, known as a Recombinant Immunoblot Assay, was developed to check for false-positive results with the EIA-2.
Polymerase Chain Reaction (PCR): It is expensive to perform and cannot used as routinely as other methods. FDA has approved it only to screen active infections of some viruses, such as hepatitis C virus.
PATHOLOGY OF VIRAL HEPATITIS
Liver biopsy has considered the most reliable method and the most diagnostic tool for viral hepatitis. The pathology of viral hepatitis plays a significant role in diagnosis and prognosis of disease. Morphologic features in viral hepatitis include:
Hepatocellular alterations; A characteristic variation of both nuclei and cytoplasm of the hepatocyte occurs, basically involves neighbouring cells and is not restricted to any lobular zone. These variations occur due to a combination of regressive or catabolic processes and of mitotic division of intact and also damaged cells in response to the loss of function of damaged or necrotic cells. The regressive changes include shattering of the endoplasmic reticulum with detachment of the polysomes which leads to a disturbance of the hepatocellular secretion of proteins such as albumin and coagulation factors due to suppression of structural proteins formation. Mitochondrial alterations are late. Reduction and alteration of microvilli of the cell membrane which are directed towards the perisinusoidal and pericellular spaces occur and these changes are associated with varying water and glycogen content in neighbouring cells, some of which appear ballooned. Autophagosomes develop by lysosomes result cytoplasmic degeneration. Mitochondria and other organelles are broken and this process terminates in lipofuscin pigment which is prominent in viral hepatitis.
Cell death: Hepatocytolysis takes place due to the rupture of cell membrane blebs.
Cholestasis: Visible stagnation of bile which is due to an alteration of hepatocytic bile acid metabolism associated with elevation of all biliary substances including alkaline phosphatase. Hepatocytes may become dedifferentiated around the bile plugs but increased in number to represent acinar structures. The hyperbilirubinemia may be the result of increased haemolysis or of a selective disturbance of the secretion of organic anions, not including bile acids, and thus is an acquired Dubin-Johnson syndrome.
Intralobular inflammatory reaction: The accumulation of inflammatory cells is most probably a reaction to damage or death of liver cells. The proliferated sinusoidal macrophages (Kupffer cells) may contain recognizable fragments of hepatocytes, acidophilic bodies, lipofuscin, bile plugs, and also glycogen which are most numerous components of the inflammation. The intermixing of them with lymphocytes, large lymphoid cells, plasma cells and few fibroblasts, depends upon the duration of the disease.
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Portal inflammatory reaction: Other inflammatory cells, particularly lymphocytes, are more frequent in the portal tracts and eosinophils may also be seen. Granulomas are rare. The inflammatory exudate may spread into the peripheral zone of the parenchyma, the limiting plate may be destroyed and peripheral hepatocytes may become necrotic (piecemeal necrosis).
Lesions of biliary passages: Bile ductules surrounded by inflammatory exudates proliferate and bile ductular epithelium may become necrotic.
Vascular changes: Only hepatic veins are involved, that show two characteristic changes: (a) an edematous acellular thickening of the wall, and (b) an endophlebitis with adherence of fibrin and cells to the proliferated endothelial lining.
If the hepatitis is severe (as in case of hepatitis A and B) or remains for a long time (as in case of hepatitis B and C), hardened fibers may develop in the liver and this condition is called fibrosis. Over time, hardened scar tissue replace more and more normal liver tissue which may obstruct the normal blood flow through the liver and seriously damage to its structure and function inability and this leads to cirrhosis. In this condition, blood can back up into the intestines and the spleen that may increase pressure in these organs which further leads to portal hypertension - include bleeding and accumulation of fluid in the abdomen (ascites). The production of bile can also be reduced. Liver is not able to remove toxins from the bloodstream that may cause mental confusion and even coma (encephalopathy).
In 1973, hepatitis A virus was identified by Dr. Feinstone. Four of the seven genotypes of HAV affect humans (genotypes I and III are the most common), but only one serotype exists. As it is belongs to the family of picornaviruses, it is among the smallest of viruses (25 to 35 nanometers in diameter). It has capsid - an icosahedron (20-sided)-shaped, made up of 60 capsomers, which are composed of 4 different proteins. Nucleic acid is single-stranded RNA. It has no envelope.
The average HAV incubation time is 28 days, but it may vary from 15 to 45 days.
It is an acute form of hepatitis and there is no chronic infection and HAV infection induces lifelong immunity. Relapses occur in some HAV infected people after 6-9 months. About one in 100 people infected with HAV may come across with Fulminant infection that very rarely may progress to liver failure and death.
Eating fresh foods or using eating utensils that have been handled by a carrier or washed with Faeces-contaminated water.
Visitors from developed countries going to developing countries are at a very high risk for infection unless they have been immunized.
Touching a diaper changing table that has not been well cleaned or changing the diaper of an infected infant.
Sex with a carrier.
Transmission of HAV is typically through faecal-oral route.
Babies and young children having hepatitis B infection do not show noticeable symptoms while adolescents and adults experience symptoms.
Symptoms of hepatitis A can include:
Yellowing of the skin, fever and whites of the eyes, dark urine and/or pale stool (jaundice)
Diarrhoea, nausea and vomiting
Feeling sick and tired(fatigue)
Pain in the upper-right abdomen, weight loss and loss of appetite
HAV infection can also cause increase in enzymes that are produced by the liver above normal levels in the bloodstream.
Diagnosis: Hepatitis A can be diagnosed by a blood test that looks for two types of antibodies to the virus. IgM antibodies which are produced 5-10 days before symptoms begin and usually disappear within six months are first seen. IgG antibodies are also seen, that replace IgM antibodies and provide protection against future HAV infection. Thus acute infection is diagnosed by the detection of HAV-IgM in serum and past Infection i.e. immunity is determined by the detection of HAV-IgG.
Treatment: Proper bed rest should be taken and it is suggested to drink plenty of fluids, especially in diarrhoea or vomiting. OTC pain relievers, such as ibuprofen, helps to manage some of the hepatitis A symptoms but before using them consult the healthcare provider.
If someone in household has been diagnosed with hepatitis A -get an injection of immune globulin (gamma globulin).
Vaccination: It is the best way to prevent hepatitis A and Havrix and VAQTA are two HAV vaccines. Both of these vaccines are injected twice, usually six months apart.
Twinrix is a combination vaccine for HAV and HBV. Four inactivated vaccines (HavrixÂ®, VaqtaÂ®, EpaxalÂ®, and AvaximÂ®) are presently commercially. The protective effect of inactivated hepatitis A vaccine (HealiveÂ®) against hepatitis A is 100%.
Avoid water that could be contaminated with faecal material.
Avoid not properly cooked or raw shellfish.
Always wash hands properly after using the toilet, changing a diaper and before cooking and having meal.
Use a latex barrier such as a dental dam for oral-analsex.
HBV is a partially DNA-containing virus of the Hepadnaviridae family, 42 nm in diameter, discovered by Dr. Baruch blumberg in 1963, having icosahedral capsid, DNA-dependent Polymerase, Spherical envelope. It is a blood borne virus that leave the blood and enter other body fluids such as semen, saliva, tears, sweat and vaginal fluids. HBV cannot survive in intestine very well as attacked and destroyed by the bacteria that normally live there.
Mode of transmission: Sexual, parenteral (Blood and blood products, Contaminated needle), perinatal (mother to child during delivery and labor).
The incubation period for HBV is 60 days, and it may vary from 28 to 160 days.
Hepatitis B virus is a noncytopathic which means that it does not directly damage liver cells. Instead, it is the response of immune system's aggressive to the virus that usually results in inflammation and damage to the liver.
Hepatitis B virus causes acute hepatitis but unlike hepatitis A, hepatitis B may become a chronic infection. This indicates that the immune system is not capable of removing virus within six months after infection. This increases the risk of liver damage and hepatocellular carcinoma.
Transfusion recipients, Needle-sharing among intravenous drug abusers, hemodialysis patients and staff and hemophiliac patients are at high risk.
Sex with an infected person
Accidental touching of infected body fluids and then touching the eyes, mouth, or broken skin.
Accidental scalpel cuts or needle punctures are serious occupational hazards for health-care workers.
Deliberate puncture using improperly cleaned needles, such as in tattooing and acupuncture.
Tools used in nail salons and barbershops may be contaminated.
Sharing of toiletry articles such as razor blades, razors, toothbrushes, fingernail files, or nail clippers with family members.
Symptoms: Symptoms are same as of HAV infection. Some people who show symptoms of acute hepatitis B feel sick and tired (fatigue). Symptoms of chronic hepatitis B may be similar to acute hepatitis B but they are usually mild to moderate in intensity and come and go.
Diagnosis: Hepatitis B is first diagnosed by a blood test in which certain antigens and antibodies are examined. Initial blood tests for diagnosis of HBV infection look for one antigen - HBsAg (the hepatitis B surface antigen) and two antibodies - anti-HBc (antibodies to the HBV core antigen) and anti-HBs (antibodies to the HBV surface antigen). There are two types of anti-HBc antibodies: IgM antibodies and IgG antibodies.
HBeAg and anti-HBe: anti-HBe is the antibodies to HBV envelope antigen. If HBeAg is detected in a blood sample, this indicates that the virus is still highly active in the liver and there are chances of its transmission to others while if anti-HBe is positive and HBeAg is negative, this indicates that the virus is inactive.
Interpretation of hepatitis B markers
+ early, then -
+ early, then -
+ early, then -
HBV Viral Load: Viral load testing is done if HBV is in the process of reproduction in the liver. If an HBV viral load > 100,000 copies/ml that means that the virus is highly active in the liver and has the ability to cause liver damage. If a viral load < 100,000 copies/ml, especially when HBeAg is negative and anti-HBe is positive, suggests that the immune system controls virus.
Liver Enzyme Tests: Using a liver enzyme test the levels of liver enzymes - alanine aminotransferase (ALT) and aspartamine aminotransferase (AST) - are measured because elevated enzyme levels is an indicator of improper functioning of liver.
Alpha-fetoprotein (AFP): Cancerous liver cells produce AFP because risk of liver cancer increases in case of people with chronic hepatitis B.
Ultrasound: Many liver experts also suggest ultrasound or "echo" machine for the diagnosis of HCC chronically infected people.
Treatment: FDA approved drugs for managing chronic hepatitis B are:
Year approved by the FDA
Mechanism of action
0.5 mg once daily on an empty stomach, increased to 1.0 mg
Baraclude (Nucleoside analogs) inhibit DNA synthesis in HBV infected cells, reducing viral load.
Epivir-HBV, Zeffix, or Heptodin
one tablet of 100mg once daily orally
Lamivudine is an antiviral agent.
One tablet of 10 mg once daily orally.
A nucleotide analog of adenosine monophosphate first phosphorylates to active form which then competes with the natural substrate deoxyadenisine triphosphate, also causes DNA chain termination after its incorporation into viral DNA and thus inhibits HBV DNA polymerase (reverse transcriptase) activity.
Given in Patients >18years, recommended dose is 5 millions international units, self injected, subcutaneously for 16 weeks
Antiviral and immunomodulatory actions (enhance T-cell helper activity and cause maturation of B-lymphocytes and also inhibits the T cell suppressors), HBV DNA lost and seroconversion of HBeAg to anti-HBe.
Injected once a week usually for six months to a year.
Pegasys, (PEG-Intron) a drug which contains microscopic particles of polyethylene glycol which are linked to an interferon molecule. It is more efficacious than standard interferon-alfa.
600 mg taken orally, once daily
Tyzeka, an unmodified ß-L enantiomer of thymidine that competes with the natural substrate, thymidine 5'-triphosphate and thus inhibits HBV DNA polymerase (reverse transcriptase). It causes DNA chain termination after incorporation into viral DNA, resulting in inhibition of HBV replication.
300 mg taken orally, once daily, without regard to food
Tenofovir diphosphate, an oral nucleotide analogue competes with the natural substrate deoxyadenosine 5'-triphosphate and thus inhibits the HBV polymerase activity.
ACTVE IMMUNIZATION - Licensed in 1982; now recombinant [Recombivax HB (Merck) 0, 1 and 6 months and Engerix-B (Smith Kline) 0, 1 and 2 months], before plasma derived. A 10-year booster injection has been recommended.
PASSIVE IMMUNIZATION - hepatitis B immune globulin (HBIG), is given simultaneously with HBV vaccine into opposite deltoid muscles (or for newborns, into opposite thigh muscles).
Hepatitis C virus is a Flavivirus, identified as a unique virus by Bredan Arena in 1987. It is a blood borne, enveloped ss-RNA spherical virus with an icosahedral capsid, 40-60 nm in diameter.
At least 6 genotypes and multiple sub-genotypes are present. Genotypes 1a and 1b common in US and is associated with the more severe forms of the disease. 12 months of treatment is required in case of Type 1 infection; all other types require only 6 months.
Viral RNA encodes a polyprotein which is broken down by cell enzymes into 10 smaller structural and regulatory proteins including Core proteins and two envelope proteins.
RNA-polymerase (HCV enzyme required for replication of viral RNA) has a defect i.e. unable to detect errors during synthesis of new RNA.
Chronic hepatitis C virus (HCV) infection is a major cause of liver disease that ultimately causes cirrhosis, and HCC.
Transmission: HCV is transmitted by blood to blood contact and also the injection drug use is a major risk factor .HCV can also be transmitted through high-risk sexual activity. Transmission risk is increased by high levels of viremia at delivery. Other risk factors include:
Receipt of unscreened blood, blood products, tissue, or organs
Tattooing, ear piercing, body piercing or acupuncture under nonsterile conditions
Children born to an Hepatitis C infected mother
Occupational exposure to infected blood
Infection with HIV
Sharing toothbrushes, razors, and nail-grooming equipment
Symptoms: Symptoms usually become worse if HCV infection leads to serious liver damage and/or cirrhosis.
HCV Antibody Testing
HCV Viral Load Testing: Low if < 2 million copies/ml (600,000-800,000 IU/ml)
High if > 2 million copies/ml (600,000-800,000 IU/ml)
Liver Enzyme Tests
Combination therapy is now the preferred HCV treatment.
Hepatitis C FDA-Approved Combination Therapy
PegasysHYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#pegasys" (HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#pegasys"peginterferon alfa-2a) HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#pegasys"+ Copegus (ribavirin)
PegIntron HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#peg"(HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#peg"peginterferon alfa-2b) HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#peg"+ Rebetol (ribavirin)
Roferon A HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#rof"(HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#rof"Standard interferon alfa-2a) HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#rof"+ Ribavirin (ribavirin)
Intron A HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#rebetron"(HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#rebetron"Standard Interferon alfa-2b) HYPERLINK "http://www.hivandhepatitis.com/hep_c/hepc_news_comb.html#rebetron"+ Rebetol (ribavirin)
Ribavirin is taken orally twice a day (800-1200mg a day). It is a synthetic antiviral nucleoside analogue that works with interferon but not on its own, taken orally, interferes with proper reproduction of the viral RNA and thus inhibits viral growth, Side effect- haemolytic anaemia.
Natural compounds block HCV infection. Quercetin inhibits the synthesis of cellular proteins (heat shock protein 70 and 40) that are important for viral infection. Because quercetin targets cellular proteins rather than viral proteins, there are less chances of developing viral resistance.
There is no vaccine against HCV
Dr. Mario Rizzetto identified HDV, in Italy. It is a blood borne, small 1.7Kb single stranded circular RNA virus of genus, Deltaviridae, having Delta antigen (internal core protein), and no virion polymerase.
Requires HBV (as a helper virus) outer coating called surface antigen - to synthesize its own outer protein coat to encapsulate its genetic core and thus cannot reproduce without the help of HBV, thus called a subviral satellite of HBV.
Transmission occurs via percutanous exposures (injecting drug use) or permucosal exposures.
Diagnosis can be done by the presence of high titered antibodies to HDV (anti-HDV) in a patient with serologic evidence of HBV infection (HBsAg or IgM anti-HBc positive).
Treatment: There is no vaccine for HDV, but there is an effective vaccine for HBV and in order to prevent HDV-HBV co-infection, the HBV vaccine or Hepatitis B Immune Globulin can be used.
First identified Mikhail Balayan in 1983. It has not been classified, but it has structural similarities to the family of caliciviruses, 32-34 nm in diameter, Non-enveloped, spherical and nucleocapsid encloses ss-RNA virus.
Incubation period is 40 days and it may vary from 15-60 days.
Transmission through faecal-oral route and seen in low socioeconomic conditions.
Pregnant women are more susceptible, especially during their third trimester: 20% risk of developing fulminant hepatitis, a high risk of premature delivery and a 33% chance that the baby will die.
A prototype vaccine devised and tested in China has proven 100% effective in preventing hepatitis E. HEV 239, is a recombinant vaccine, given over a six-month period, afforded patients full immunity from the disease up to a year after the final inoculation, without prompting any serious side effects.