Hepatitis

Hepatitis

Hepatitis (plural: hepatitides) is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar (ἧπαρ), the root being hepat- (ἡπατ-), meaning liver, and suffix -itis, meaning "inflammation" (c. 1727). The condition can be self-limiting (healing on its own) or can progress to fibrosis (scarring) and cirrhosis.

Hepatitis may occur with limited or no symptoms, but often leads to jaundice, anorexia (poor appetite) and malaise. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. Worldwide hepatitis viruses are the most common cause of the condition, but hepatitis can be caused by other infections, toxic substances (notably alcohol, certain medications, some industrial organic solvents and plants), and autoimmune diseases.

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Signs and symptoms

Acute

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 (jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice, tender hepatomegaly (swelling of the liver), lymphadenopathy (enlarged lymph nodes, in 5%), and splenomegaly (enlargement of the spleen. Acute viral hepatitis is more likely to be asymptomatic in children. Symptomatic individuals may present after a convalescent stage of 7 to 10 days, with the total illness lasting weeks.

A small proportion of people with acute hepatitis progress to acute liver failure, in which the liver is unable to remove harmful substances from the blood (leading to confusion and coma due to hepatic encephalopathy) and produce blood proteins (leading to peripheral edema and bleeding). This may become life-threatening and occasionally requires a liver transplant.

Chronic

Chronic hepatitis may cause nonspecific symptoms such as malaise, tiredness and weakness, and often leads to no symptoms at all. It is commonly identified on blood tests performed either for screening or to evaluate nonspecific symptoms. The presence of jaundice indicates advanced liver damage. On physical examination there may be enlargement of the liver.

Extensive damage to and scarring of liver (i.e. cirrhosis) leads to weight loss, easy bruising and bleeding, peripheral edema (swelling of the legs) and accumulation of ascites (fluid in the abdomen). Eventually, cirrhosis may lead to various complications: esophageal varices (enlarged veins in the wall of the esophagus that can cause life-threatening bleeding), hepatic encephalopathy (confusion and coma) and hepatorenal syndrome (kidney dysfunction).

Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis.

Causes .

Viral hepatitis is the most common cause of hepatitis worldwide. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses hepatitis A, hepatitis B, hepatitis C, hepatitis D (which requires hepatitis B to cause disease), and hepatitis E. Other common causes of non-viral hepatitis include toxic and drug-induced, alcoholic, autoimmune, fatty liver, and metabolic disorders. Less commonly some bacterial, parasitic, fungal, mycobacterial and protozoal infections can cause hepatitis. Additionally, certain complications of pregnancy and decreased blood flow to the liver can induce hepatitis. Cholestasis (obstruction of bile flow) due to hepatocellular dysfunction, biliary tract obstruction, or biliary atresia can result in liver damage and hepatitis.

Alcoholic hepatitis

Excessive alcohol consumption is a significant cause of hepatitis and liver damage (cirrhosis). Alcoholic hepatitis usually develops over years-long exposure to alcohol. Alcohol intake in excess of 80 grams of alcohol a day in men and 40 grams a day in women is associated with development of alcoholic hepatitis. Alcoholic hepatitis can vary from mild asymptomatic disease to severe liver inflammation and liver failure. Symptoms and physical exam findings are similar to other causes of hepatitis. Laboratory findings are significant for elevated transaminases, usually with elevation of aspartate transaminase (AST) in a 2 to 1 ratio to alanine transaminase (ALT).

Alcoholic hepatitis may lead to cirrhosis and is more common in patients with long-term alcohol consumption and those infected with hepatitis C. Patients who drink alcohol to excess are also more often than others found to have hepatitis C. The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis.

Toxic and drug-induced hepatitis

A large number of medications and other chemical agents can cause hepatitis. In the United States acetaminophen, antibiotics, and central nervous system medications are among the most common causes of drug-induced hepatitis. Herbal remedies and dietary supplements may also cause hepatitis, and these are the most common causes of drug-induced hepatitis in Korea. Risk factors for drug-induced hepatitis include: increasing age, female sex, and previous drug-induced hepatitis. Genetic variability is increasingly understood as a key predisposing risk factor to drug-induced hepatitis.

Toxins and medications can cause liver injury through a variety of mechanisms, including direct cell damage, disrupting cell metabolism, and inducing structural changes. Some medications, like acetaminophen, cause predictable dose-related liver damage, whereas others cause idiosyncratic reactions that vary among individuals.

Exposure to other hepatotoxins can occur accidentally or intentionally through ingestion, inhalation, and skin absorption. Occupational exposure may occur in many work fields and can present acutely or insidiously. Mushroom poisoning is a common toxic exposure that may result in hepatitis.

Autoimmune

Autoimmune hepatitis is a chronic disease caused by an abnormal immune response against liver cells. The disease is thought to have a genetic predisposition as it is associated with certain human leukocyte antigens. The symptoms of autoimmune hepatitis are similar to other hepatitides and may have a fluctuating course from mild to very severe. Women with the disease may have abnormal menstruation or become amenorrheic. The disease occurs in people of all ages but most commonly in young women. Many people with autoimmune hepatitis have other autoimmune diseases.

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the occurrence of fatty liver in people who have little or no history of alcohol use. In the early stage there are usually no symptoms, as the disease progresses symptoms typical of chronic hepatitis may develop. NAFLD is associated with metabolic syndrome, obesity, diabetes and hyperlipidemia. Severe NAFLD leads to inflammation, fibrosis, and cirrhosis, a state referred to as non-alcoholic steatohepatitis (NASH). Diagnosis requires excluding other causes of hepatitis, including excessive alcohol intake. While imaging can show fatty liver, only liver biopsy can demonstrate inflammation and fibrosis characteristic of NASH. NASH is recognized as the third most common cause of liver disease in the United States.

Ischemic hepatitis

Injury to liver cells due to insufficient blood or oxygen results in ischemic hepatitis (or shock liver). The condition is most often associated with heart failure but can also be caused by shock or sepsis. Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT). The condition usually resolves if the underlying cause is treated successfully. Ischemic hepatitis rarely causes permanent liver damage.

Giant cell hepatitis

Giant cell hepatitis is a rare form of hepatitis that predominantly occurs in newborns and children. Diagnosis is made on the basis of the presence of multinucleated hepatocyte giant cells on liver biopsy. The cause of giant cell hepatitis is unknown but the condition is associated with viral infection, autoimmune disorders, and drug toxicity.

Diagnosis

Diagnosis is made by assessing an individual's symptoms, physical exam, and medical history, in conjunction with blood tests, liver biopsy, and imaging. Blood testing includes blood chemistry, liver enzymes, and serology. Abnormalities in blood chemistry and enzyme results may be indicative of certain etiologies or stages of hepatitis. Imaging can identify steatosis of the liver but liver biopsy is required to demonstrate fibrosis and cirrhosis. A biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications caused by liver biopsy.

Viral hepatitis

Serologic testing may be used to evaluate for viral hepatitis.

Hepatitis A

Marker	Detection Time	Description	Significance
Faecal HAV	2–4 weeks or 28days	-	Early detection
Ig M anti HAV	4–12 weeks	Enzyme immunoassay for antibodies	During Acute Illness
Ig G anti HAV	5 weeks - persistent	Enzyme immunoassay for antibodies	Old infection or Reinfection

Hepatitis C
Marker	Detection Time	Description	Significance	Note
HCV-RNA	1–3 weeks or 21 days	PCR	Demonstrates presence or absence of virus	Results may be intermittent during course of infection. Negative result is not indicative of absence.
anti-HCV	5–6 weeks	Enzyme Immunoassay for antibodies	Demonstrates past or present infection	High false positive in those with autoimmune disorders and populations with low virus prevalence.
ALT	5–6 weeks	-	Peak in ALT coincides with peak in anti-HCV	Fluctuating ALT levels is an indication of active liver disease.

Hepatitis B

Hepatitis B is an infectious inflammatory illness of the liver caused by the hepatitis B virus (HBV) that affects hominoidea, including humans. 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 population has been infected at one point in their lives, including 350 million who are chronic carriers.

The virus is transmitted by exposure to infectious blood or body fluids such as semen and vaginal fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic carriers. Perinatal infection is a major route of infection in endemic (mainly developing) countries. Other risk factors for developing HBV infection include working in a healthcare setting, transfusions, dialysis, acupuncture, tattooing, sharing razors or toothbrushes with an infected person, travel in countries where it is endemic, and residence in an institution. However, hepatitis B viruses cannot be spread by holding hands, sharing eating utensils or drinking glasses, kissing, hugging, coughing, sneezing, or breastfeeding.

The acute illness causes liver inflammation, vomiting, jaundice, and, rarely, death. Chronic hepatitis B may eventually cause cirrhosis and liver cancer—a disease with poor response to all but a few current therapies. The infection is preventable by vaccination.

Hepatitis B virus is a hepadnavirus—hepa from hepatotropic (attracted to the liver) and dna because it is a DNA virus—and it has a circular genome of partially double-stranded DNA. The viruses replicate through an RNA intermediate form by reverse transcription, which in practice relates them to retroviruses. Although replication takes place in the liver, the virus spreads to the blood where viral proteins and antibodies against them are found in infected people. The hepatitis B virus is 50 to 100 times more infectious than HIV.

Signs and 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, and 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 people may have more severe liver disease (fulminant hepatic failure), and may die as a result. The infection may be entirely asymptomatic and may go unrecognized.

Chronic infection with hepatitis B virus either may be 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). Across Europe hepatitis B and C cause approximately 50% hepatocellular carcinomas. 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).

Symptoms outside of the liver are present in 1–10% of HBV-infected people and include serum-sickness–like syndrome, acute necrotizing vasculitis (polyarteritis nodosa), membranous glomerulonephritis, and papular acrodermatitis of childhood (Gianotti–Crosti syndrome). The serum-sickness–like syndrome occurs in the setting of acute hepatitis B, often preceding the onset of jaundice. The clinical features are fever, skin rash, and polyarteritis. The symptoms often subside shortly after the onset of jaundice, but can persist throughout the duration of acute hepatitis B. About 30–50% of people with acute necrotizing vasculitis (polyarteritis nodosa) are HBV carriers. HBV-associated nephropathy has been described in adults but is more common in children. Membranous glomerulonephritis is the most common form. Other immune-mediated hematological disorders, such as essential mixed cryoglobulinemia and aplastic anemia.

Virology

Structure

The structure of hepatitis B virus

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. These virions are 30-42 nm in diameter. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity. The outer envelope contains embedded proteins that are involved in viral binding of, and entry into, susceptible cells. The virus is one of the smallest enveloped animal viruses, and the 42 nM virions, which are capable of infecting hepatocytes, are referred to as "Dane particles". In addition to the Dane particles, filamentous and spherical bodies lacking a core can be found in the serum of infected individuals. 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 but it is associated with the development of liver cancer. It stimulates genes that promote cell growth and inactivates growth regulating molecules.

Replication

The life cycle of hepatitis B virus is complex. Hepatitis B is one of a few known pararetroviruses: non-retroviruses that still use reverse transcription in their replication process. The virus gains entry into the cell by binding to NTCP on the surface and being endocytosed. 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 that 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 (the DNA polymerase) synthesizes DNA via its reverse transcriptase activity.

Serotypes and genotypes:

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.

Genotypes differ by at least 8% of their sequence and were first reported in 1988 when six were initially described (A-F). Two further types have since been described (G and H). Most genotypes are now divided into subgenotypes with distinct properties.

Distribution of genotypes

Genotype A is most commonly found in the Americas, Africa, India and Western Europe. It is divided into subgenotypes. Of these subgenotype A1 is further subdivided into an Asian and an African clade.

Genotype B is most commonly found in Asia and the United States. Genotype B1 dominates in Japan, B2 in China and Vietnam while B3 confined to Indonesia. B4 is confined to Vietnam. All these strains specify the serotype ayw1. B5 is most common in the Philippines.

Genotype C is most common in Asia and the United States. Subgenotype C1 is common in Japan, Korea and China. C2 is common in China, South-East Asia and Bangladesh and C3 in Oceania. All these strains specify the serotype adr. C4 specifying ayw3 is found in Aborigines from Australia.

Genotype D is most commonly found in Southern Europe, India and the United States and has been divided into 8 subtypes (D1–D8). In Turkey genotype D is also the most common type. A pattern of defined geographical distribution is less evident with D1–D4 where these subgenotypes are widely spread within Europe, Africa and Asia. This may be due to their divergence having occurred before that of genotypes B and C. D4 appears to be the oldest split and is still the dominating subgenotype of D in Oceania.

Type E is most commonly found in West and Southern Africa.

Type F is most commonly found in Central and South America and has been divided into two subgroups (F1 and F2).

Genotype G has an insertion of 36 nucleotides in the core gene and is found in France and the United States.

Type H is most commonly found in Central and South America and California in United States.

Africa has five genotypes (A-E). Of these the predominant genotypes are A in Kenya, B and D in Egypt, D in Tunisia, A-D in South Africa and E in Nigeria. Genotype H is probably split off from genotype F within the New World.

Evolution

A Bayesian analysis of the genotypes suggests that the rate of evolution of the core protein gene is 1.127 (95% credible interval 0.925-1.329) substitutions per site per year.

The most recent common ancestor of genotypes A, B, D evolved in 1895 (95% confidence interval 1819-1959), 1829 (95% confidence interval 1690-1935) and 1880 (95% confidence interval 1783-1948) respectively.

Mechanisms

Pathogenesis

Hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells, known as hepatocytes. A functional receptor is NTCP. There is evidence that the receptor in the closely related duck hepatitis B virus is carboxypeptidase D. The virions bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis. HBV-preS-specific receptors are expressed primarily 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, in particular virus-specific cytotoxic T lymphocytes(CTLs), contributes to most of the liver injury associated with HBV infection. CTLs eliminate HBV infection by killing infected cells and producing antiviral cytokines, which are then used to purge HBV from viable hepatocytes. 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.

Transmission

Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include sexual contact, blood transfusions and transfusion with other human blood products, re-use of contaminated needles and syringes, and vertical transmission from mother to child (MTCT) 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. And Shi et al. showed that breastfeeding after proper immunoprophylaxis did not contribute to MTCT of HBV.

Diagnosis

The tests, called assays, for detection of hepatitis B virus infection involve serum or blood tests that detect either viral antigens (proteins produced by the virus) or antibodies produced by the host. Interpretation of these assays is complex.

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. Therefore most hepatitis B diagnostic panels contain HBsAg and total anti-HBc (both IgM and IgG).

Shortly after the appearance of the HBsAg, another antigen called 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.[56] 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). The time between the removal of the HBsAg and the appearance of anti-HBs is called the window period. A person negative for HBsAg but positive for anti-HBs either has 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 (ALT) levels and inflammation of the liver, as revealed by biopsy. Carriers who have seroconverted to HBeAg negative status, in particular 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.

PCR tests have been developed to detect and measure the amount of HBV DNA, called the viral load, in clinical specimens. These tests are used to assess a person's infection status and to monitor treatment. Individuals with high viral loads, characteristically have ground glass hepatocytes on biopsy.

Prevention

Vaccines for the prevention of hepatitis B have been routinely used since the early 1980s. The first vaccines contained inactivated HBsAg that was derived from human plasma of hepatitis B virus carriers. Modern vaccines contain HBsAg from yeast or mammalian cell cultures using recombinant DNA technology and have no risk of transmitting hepatitis B virus. Most vaccines are given in three doses over a course of months. A protective response to the vaccine is defined as an anti-HBs antibody concentration of at least10 mIU/ml in the recipient's serum. The vaccine is more effective in children and 95 per cent of those vaccinated have protective levels of antibody. This drops to around 90% at forty years of age and to around 75 percent in those over sixty. The protection afforded by vaccination is long lasting even after antibody levels fall below 10 mIU/ml. Vaccination at birth is recommended for all infants of HBV infected mothers. A combination of hepatitis B immunoglobulin and an accelerated course of HBV vaccine prevents perinatal HBV transmission in around 90% of cases.

In assisted reproductive technology, The Practice Committee of the American Society for Reproductive Medicine advises that sperm washing is not necessary for males with hepatitis B to prevent transmission, unless the female partner has not been effectively vaccinated. In females with hepatitis B, the risk of vertical transmission during IVF is no different from the risk in spontaneous conception.

Treatment

The hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously. Early antiviral treatment may be required in fewer than 1% of people, 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. Treatment lasts from six months to a year, depending on medication and genotype.

Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. As of 2008, 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 alpha-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 person's heredity. The treatment reduces viral replication in the liver, thereby reducing the viral load (the amount of virus particles as measured in the blood). Response to treatment differs between the genotypes. Interferon treatment may produce an e antigen seroconversion rate of 37% in genotype A but only a 6% seroconversion in type D. Genotype B has similar seroconversion rates to type A while type C seroconverts only in 15% of cases. Sustained e antigen loss after treatment is ~45% in types A and B but only 25–30% in types C and D.

Prognosis

Hepatitis B virus infection may be either 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, this drops to 30% for younger children, and 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 (HDV) can occur only with a concomitant hepatitis B infection, because HDV uses the HBV 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.

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 following alcohol or drug use, or in people with impaired immunity. HBV goes through cycles of replication and non-replication. Approximately 50% of overt carriers experience acute reactivation. Males with baseline ALT of 200 UL/L are three times more likely to develop a reactivation than people with lower levels. Although reactivation can occur spontaneously, people who undergo chemotherapy have a higher risk. Immunosuppressive drugs favor increased HBV replication while inhibiting cytotoxic T cell function in the liver. The risk of reactivation varies depending on the serological profile; those with detectable HBsAg in their blood are at the greatest risk, but those with only antibodies to the core antigen are also at risk. The presence of antibodies to the surface antigen, which are considered to be a marker of immunity, does not preclude reactivation. Treatment with prophylactic antiviral drugs can prevent the serious morbidity associated with HBV disease reactivation.

Epidemiology

In 2004, an estimated 350 million individuals were infected worldwide. National and regional prevalence ranges from over 10% in Asia to under 0.5% in the United States and northern Europe. Routes of infection include vertical transmission (such as through childbirth), early life horizontal transmission (bites, lesions, and sanitary habits), and adult horizontal transmission (sexual contact, intravenous drug use).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, injection drug abuse and unprotected sex are the primary methods, although other factors may also 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% with 10-15% prevalence in Africa/Far East. As of 2010, China has 120 million infected people, followed by India and Indonesia with 40 million and 12 million, respectively. According to World Health Organization (WHO), an estimated 600,000 people die every year related to the infection.

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 1966 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.

Society and culture

World Hepatitis Day, observed July 28, aims to raise global awareness of hepatitis B and hepatitis C and encourage prevention, diagnosis and treatment. It has been led by the World Hepatitis Alliance since 2007 and in May 2010, it got global endorsement from the World Health Organization.

Hepatitis C

Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure, liver cancer or life-threatening esophageal and gastric varices.

HCV is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions. An estimated 150–200 million people worldwide are infected with hepatitis C. The existence of hepatitis C (originally identifiable only as a type of non-A non-B hepatitis) was postulated in the 1970s and proven in 1989. Hepatitis C infects only humans and chimpanzees.

The virus persists in the liver in about 85% of those infected. This persistent infection can be treated with medication: the standard therapy is a combination of peginterferon and ribavirin, with either boceprevir or telaprevir added in some cases. Overall, 50–80% of people treated are cured. Those who develop cirrhosis or liver cancer may require a liver transplant. Hepatitis C is the leading reason for liver transplantation, though the virus usually recurs after transplantation. No vaccine against hepatitis C is available.

Signs and symptoms

Acute infection

Hepatitis C infection causes acute symptoms in 15% of cases. Symptoms are generally mild and vague, including a decreased appetite, fatigue, nausea, muscle or joint pains, and weight loss and rarely does acute liver failure result. Most cases of acute infection are not associated with jaundice. The infection resolves spontaneously in 10-50% of cases, which occurs more frequently in individuals who are young and female.

Chronic infection

About 80% of those exposed to the virus develop a chronic infection. This is defined as the presence of detectable viral replication for at least six months. Most experience minimal or no symptoms during the initial few decades of the infection. Chronic hepatitis C can be associated with fatigue and mild cognitive problems. Chronic infection after several years may cause cirrhosis or liver cancer. The liver enzymes are normal in 7-53%. Late relapses after apparent cure have been reported, but these can be difficult to distinguish from reinfection.

Fatty changes to the liver occur in about half of those infected and are usually present before cirrhosis develops. Usually (80% of the time) this change affects less than a third of the liver. Worldwide hepatitis C is the cause of 27% of cirrhosis cases and 25% of hepatocellular carcinoma. About 10–30% of those infected develop cirrhosis over 30 years. Cirrhosis is more common in those also infected with hepatitis B, schistosoma, or HIV, in alcoholics and in those of male gender. In those with hepatitis C, excess alcohol increases the risk of developing cirrhosis 100-fold. Those who develop cirrhosis have a 20-fold greater risk of hepatocellular carcinoma. This transformation occurs at a rate of 1–3% per year.Being infected with hepatits B in additional to hepatitis C increases this risk further.

Liver cirrhosis may lead to portal hypertension, ascites (accumulation of fluid in the abdomen), easy bruising or bleeding, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. Ascites occurs at some stage in more than half of those who have a chronic infection.

Extrahepatic complications

The most common problem due to hepatitis C but not involving the liver is mixed cryoglobulinemia (usually the type II form) - an inflammation of small and medium-sized blood vessels. Hepatitis C is also associated with Sjögren's syndrome (an autoimmune disorder); thrombocytopenia; lichen planus; porphyria cutanea tarda; necrolytic acral erythema; insulin resistance; diabetes mellitus; diabetic nephropathy; autoimmune thyroiditis and B-cell lymphoproliferative disorders. Thrombocytopenia is estimated to occur in 0.16% to 45.4% of people with chronic hepatitis C. 20-30% of people infected have rheumatoid factor - a type of antibody. Possible associations include Hyde's prurigo nodularis and membranoproliferative glomerulonephritis. Cardiomyopathy with associated arrhythmias has also been reported. A variety of central nervous system disorders have been reported. Chronic infection seems to be associated with an increased risk of pancreatic cancer.

Occult infection

Persons who have been infected with hepatitis C may appear to clear the virus but remain infected. The virus is not detectable with conventional testing but can be found with ultra-sensitive tests. The original method of detection was by demonstrating the viral genome within liver biopsies, but newer methods include an antibody test for the virus' core protein and the detection of the viral genome after first concentrating the viral particles by ultracentrifugation. A form of infection with persistently moderately elevated serum liver enzymes but without antibodies to hepatitis C has also been reported. This form is known as cryptogenic occult infection.

Several clinical pictures have been associated with this type of infection. It may be found in people with anti-hepatitis-C antibodies but with normal serum levels of liver enzymes; in antibody-negative people with ongoing elevated liver enzymes of unknown cause; in healthy populations without evidence of liver disease; and in groups at risk for HCV infection including those on haemodialysis or family members of people with occult HCV. The clinical relevance of this form of infection is under investigation. The consequences of occult infection appear to be less severe than with chronic infection but can vary from minimal to hepatocellular carcinoma.

The rate of occult infection in those apparently cured is controversial but appears to be low. 40% of those with hepatitis but with both negative hepatitis C serology and the absence of detectable viral genome in the serum have hepatitis C virus in the liver on biopsy. How commonly this occurs in children is unknown.

Virology

The hepatitis C virus (HCV) is a small, enveloped, single-stranded, positive-sense RNA virus. It is a member of the Hepacivirus genus in the family Flaviviridae. There are seven major genotypes of HCV, which are known as genotypes one to seven. The genotypes are divided into several subtypes with the number of subtypes depending on the genotype. In the United States, about 70% of cases are caused by genotype 1, 20% by genotype 2 and about 1% by each of the other genotypes. Genotype 1 is also the most common in South America and Europe.

The half life of the virus particles in the serum is around 3 hours and may be as short as 45 minutes. In an infected person, about 1012 virus particles are produced each day. In addition to replicating in the liver the virus can multiply in lymphocytes.

Transmission

The primary route of transmission in the developed world is intravenous drug use (IDU), while in the developing world the main methods are blood transfusions and unsafe medical procedures. The cause of transmission remains unknown in 20% of cases; however, many of these are believed to be accounted for by IDU.

Intravenous drug use

IDU is a major risk factor for hepatitis C in many parts of the world. Of 77 countries reviewed, 25 (including the United States) were found to have prevalences of hepatitis C in the intravenous drug user population of between 60% and 80%. Twelve countries had rates greater than 80%. It is believed that ten million intravenous drug users are infected with hepatitis C; China (1.6 million), the United States (1.5 million), and Russia (1.3 million) have the highest absolute totals. Occurrence of hepatitis C among prison inmates in the United States is 10 to 20 times that of the occurrence observed in the general population; this has been attributed to high-risk behavior in prisons such as IDU and tattooing with nonsterile equipment.

Healthcare exposure

Blood transfusion, transfusion of blood products, or organ transplants without HCV screening carry significant risks of infection. The United States instituted universal screening in 1992 and Canada instituted universal screening in 1990. This decreased the risk from one in 200 units to between one in 10,000 to one in 10,000,000 per unit of blood. This low risk remains as there is a period of about 11–70 days between the potential blood donor's acquiring hepatitis C and the blood's testing positive depending on the method. Some countries do not screen for hepatitis C due to the cost.

Those who have experienced a needle stick injury from someone who was HCV positive have about a 1.8% chance of subsequently contracting the disease themselves. The risk is greater if the needle in question is hollow and the puncture wound is deep. There is a risk from mucosal exposures to blood; but this risk is low, and there is no risk if blood exposure occurs on intact skin.

Hospital equipment has also been documented as a method of transmission of hepatitis C, including reuse of needles and syringes; multiple-use medication vials; infusion bags; and improperly sterilized surgical equipment, among others. Limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities are known to be the primary cause of the spread of HCV in Egypt, the country with highest rate of infection in the world.

Sexual intercourse

Whether hepatitis C can be transmitted through sexual activity is controversial. While there is an association between high-risk sexual activity and hepatitis C, it is not known whether transmission of the disease is due to drug use that has not been admitted to or sex (as risk factors). The majority of evidence supports there being no risk for monogamous heterosexual couples. Sexual practices that involve higher levels of trauma to the anogenital mucosa, such as anal penetrative sex, or that occur when there is a concurrent sexually transmitted infection, including HIV or genital ulceration, do present a risk. The United States government recommends condom use to prevent hepatitis C transmission in only those with multiple partners.

Body modification

Tattooing is associated with two to threefold increased risk of hepatitis C. This can be due to either improperly sterilized equipment or contamination of the dyes being used. Tattoos or piercings performed either before the mid-1980s, "underground," or nonprofessionally are of particular concern, since sterile techniques in such settings may be lacking. The risk also appears to be greater for larger tattoos. It is estimated that nearly half of prison inmates share unsterilized tattooing equipment. It is rare for tattoos in a licensed facility to be directly associated with HCV infection.

Shared personal items

Personal-care items such as razors, toothbrushes, and manicuring or pedicuring equipment can be contaminated with blood. Sharing such items can potentially lead to exposure to HCV. Appropriate caution should be taken regarding any medical condition that results in bleeding, such as cuts and sores. HCV is not spread through casual contact, such as hugging, kissing, or sharing eating or cooking utensils. Neither is it transmitted through food or water.

Vertical transmission

Vertical transmission of hepatitis C from an infected mother to her child occurs in less than 10% of pregnancies. There are no measures that alter this risk. It is not clear when during pregnancy transmission occurs, but it may occur both during gestation and at delivery. A long labor is associated with a greater risk of transmission. There is no evidence that breast-feeding spreads HCV; however, to be cautious, an infected mother is advised to avoid breastfeeding if her nipples are cracked and bleeding, or her viral loads are high.

Diagnosis

There are a number of diagnostic tests for hepatitis C, including HCV antibody enzyme immunoassay or ELISA, recombinant immunoblot assay, and quantitative HCV RNA polymerase chain reaction (PCR). HCV RNA can be detected by PCR typically one to two weeks after infection, while antibodies can take substantially longer to form and thus be detected.

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months based on the presence of its RNA. Chronic infections are typically asymptomatic during the first few decades, and thus are most commonly discovered following the investigation of elevated liver enzyme levels or during a routine screening of high-risk individuals. Testing is not able to distinguish between acute and chronic infections. Diagnosis in the infant is difficult as maternal antibodies may persist for up to 18 months.

Serology

Hepatitis C testing typically begins with blood testing to detect the presence of antibodies to the HCV, using an enzyme immunoassay. If this test is positive, a confirmatory test is then performed to verify the immunoassay and to determine the viral load. A recombinant immunoblot assay is used to verify the immunoassay and the viral load is determined by a HCV RNA polymerase chain reaction. If there are no RNA and the immunoblot is positive, it means that the person tested had a previous infection but cleared it either with treatment or spontaneously; if the immunoblot is negative, it means that the immunoassay was wrong. It takes about 6–8 weeks following infection before the immunoassay will test positive. A number of tests are available as point of care testing which means that results are available within 30 minutes.

Liver enzymes are variable during the initial part of the infection and on average begin to rise at seven weeks after infection. The elevation of liver enzymes does not closely follow disease severity.

Biopsy

Liver biopsies are used to determine the degree of liver damage present; however, there are risks from the procedure. The typical changes seen are lymphocytes within the parenchyma, lymphoid follicles in portal triad, and changes to the bile ducts. There are a number of blood tests available that try to determine the degree of hepatic fibrosis and alleviate the need for biopsy.

Screening

It is believed that only 5–50% of those infected in the United States and Canada are aware of their status. Testing is recommended in those at high risk, which includes injection drug users, those who have received blood transfusions before 1992, those who have been in jail, those on long term hemodialysis, and those with tattoos. Screening is also recommended in those with elevated liver enzymes, as this is frequently the only sign of chronic hepatitis. Routine screening is not currently recommended in the United States. In 2012, the U.S. Centers for Disease Control and Prevention (CDC) added a recommendation for a single screening test for those born between 1945 and 1965.

Prevention

As of 2011, no vaccine protects against contracting hepatitis C. However, there are a number under development and some have shown encouraging results. A combination of harm reduction strategies, such as the provision of new needles and syringes and treatment of substance use, decrease the risk of hepatitis C in intravenous drug users by about 75%. The screening of blood donors is important at a national level, as is adhering to universal precautions within healthcare facilities. In countries where there is an insufficient supply of sterile syringes, medications should be given orally rather than via injection (when possible).

Treatment

HCV induces chronic infection in 50–80% of infected persons. Approximately 40–80% of these clear with treatment. In rare cases, infection can clear without treatment. Those with chronic hepatitis C are advised to avoid alcohol and medications toxic to the liver, and to be vaccinated for hepatitis A and hepatitis B. Ultrasound surveillance for hepatocellular carcinoma is recommended in those with accompanying cirrhosis.

Medications

In general, treatment is recommended for those with proven HCV infection liver abnormalities; As of 2010, treatments consist of a combination of pegylated interferon alpha and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on HCV genotype. This results cure rates of between 70–80% for genotype 2 and 3, and 45 to 70% for other genotypes. When combined with ribavirin, pegylated interferon-alpha-2a may be superior to pegylated interferon-alpha-2b, though the evidence is not strong. Another agent, sofosbuvir, when combined with ribavirin, shows improved response rates in the 95% range for genotype 2. This benefit is somewhat offset by a greater rate of adverse effects.

Combining either boceprevir or telaprevir with ribavirin and peginterferon alfa improves antiviral response for hepatitis C genotype 1. Adverse effects with treatment are common, with half of people getting flu like symptoms and a third experiencing emotional problems. Treatment during the first six months is more effective than once hepatitis C has become chronic. If someone develops a new infection and it has not cleared after eight to twelve weeks, 24 weeks of pegylated interferon is recommended. In people with thalassemia, ribavirin appears to be useful but increases the need for transfusions.

Surgery

Cirrhosis due to hepatitis C is a common reason for liver transplantionthough the virus usually (80–90% of cases) recurs afterwards. Infection of the graft leads to 10–30% of people developing cirrhosis within five years. Treatment with pegylated interferon and ribavirin post transplant decreases the risk of recurrence to 70%.

Alternative medicine

Several alternative therapies are claimed by their proponents to be helpful for hepatitis C including milk thistle, ginseng, and colloidal silver. However, no alternative therapy has been shown to improve outcomes in hepatitis C, and no evidence exists that alternative therapies have any effect on the virus at all.

Prognosis

The responses to treatment is measured by sustained viral response and vary by HCV C genotype. A sustained response occurs in about 40-50% in people with HCV genotype 1 given 48 weeks of treatment. A sustained response is seen in 70-80% of people with HCV genotypes 2 and 3 with 24 weeks of treatment. A sustained response occurs about 65% in those with genotype 4 after 48 weeks of treatment. The evidence for treatment in genotype 6 disease is sparse and what evidence there is supports 48 weeks of treatment at the same doses used for genotype 1 disease. Successful treatment decreases the future risk of hepatocellular carcinoma by 75%.

Epidemiology

It is estimated that 150–200 million people, or ~3% of the world's population, are living with chronic hepatitis C. About 3–4 million people are infected per year, and more than 350,000 people die yearly from hepatitis C-related diseases. During 2010 it is estimated that 16,000 people died from acute infections while 196,000 deaths occurred from liver cancer secondary to the infection. Rates have increased substantially in the 20th century due to a combination of intravenous drug abuse and reused but poorly sterilized medical equipment.

Rates are high (>3.5% population infected) in Central and East Asia, North Africa and the Middle East, they are intermediate (1.5%-3.5%) in South and Southeast Asia, sub-Saharan Africa, Andean, Central and Southern Latin America, Caribbean, Oceania, Australasia and Central, Eastern and Western Europe; and they are low (<1.5%) in Asia Pacific, Tropical Latin America and North America.

Among those chronically infected, the risk of cirrhosis after 20 years varies between studies but has been estimated at ~10%-15% for men and ~1-5% for women. The reason for this difference is not known. Once cirrhosis is established, the rate of developing hepatocellular carcinoma is ~1%-4% per year. Rates of new infections have decreased in the Western world since the 1990s due to improved screening of blood before transfusion.

In the United States, about 2% of people have hepatitis C, with the number of new cases per year stabilized at 17,000 since 2007. The number of deaths from hepatitis C has increased to 15,800 in 2008 and by 2007 had overtaken HIV/AIDS as a cause of death in the USA. This mortality rate is expected to increase, as those infected by transfusion before HCV testing become apparent. In Europe the percentage of people with chronic infections has been estimated to be between 0.13 and 3.26%.

The total number of people with this infection is higher in some countries in Africa and Asia. Countries with particularly high rates of infection include Egypt (22%), Pakistan (4.8%) and China (3.2%). It is believed that the high prevalence in Egypt is linked to a now-discontinued mass-treatment campaign for schistosomiasis, using improperly sterilized glass syringes.

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 how most post-transfusion hepatitis cases were not due to hepatitis A or B viruses. Despite this discovery, international research efforts to identify the virus, initially called non-A, non-B hepatitis (NANBH), failed for the next decade. In 1987, Michael Houghton, Qui-Lim Choo, and George Kuo at Chiron Corporation, collaborating with Dr. D.W. Bradley at the Centers for Disease Control and Prevention, used a novel molecular cloning approach to identify the unknown organism and develop a diagnostic test. In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH specimens. In April 1989, the discovery of HCV was published in two articles in the journal Science. The discovery led to significant improvements in diagnosis and improved antiviral treatment. 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."

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 coinventor, and receive damages and royalty income. He dropped the suit in 1998 after losing before an appeals court.

Society and culture

World Hepatitis Day, held on July 28, is coordinated by the World Hepatitis Alliance. The economic costs of hepatitis C are significant both to the individual and to society. In the United States the average lifetime cost of the disease was estimated at 33,407 USD in 2003 with the cost of a liver transplant as of 2011 costing approximately 200,000 USD. In Canada the cost of a course of antiviral treatment is as high as 30,000 CAD in 2003, while the United States costs are between 9,200 and 17,600 in 1998 USD. In many areas of the world, people are unable to afford treatment with antivirals as they either lack insurance coverage or the insurance they have will not pay for antivirals.

Research

As of 2011, there are about one hundred medications in development for hepatitis C. These include vaccines to treat hepatitis, immunomodulators, and cyclophilin inhibitors, among others. These potential new treatments have come about due to a better understanding of the hepatitis C virus.

An enormous barrier to find robust treatment to hepatitis C is due to the lack of a suitable animal model. Despite moderate successes, current research highlights the need for thorough pre-clinical testing in mammalian systems such as mouse, particularly for the development of vaccines in poorer communities. Currently, chimpanzees remain the available in vivo system to study, yet their utilization is curbed by ethical concerns and regulatory restrictions. While scientists have made exhaustive use of human cell culture systems such as hepatocytes, questions have been raised about their accuracy in reflecting the body's response to infection.

Chimpanzees

Along with humans, chimpanzees are the only permissive hosts to hepatitis C infection. This tropism is not entirely understood, yet historically, these animals have provided enormous use for the characterization of several hepatitis viruses, and thus far remain the only animal model with complete immunocompetence for HCV infection, and remain an important aspect of evaluating preclinical strengths of potential vaccines. A notable example is the demonstration that transcribed RNA from cDNA clone of hepatitis C was infectious. Unfortunately, the use of apes in medical research is banned in several countries, making the use of an alternative mammalian model for hepatitis C research even more necessary.

Mice

An enormous part of current hepatitis research is to reproduce infections in alternative mammalian models. A strategy is to introduce liver tissues from humans into mice, a technique known as xenotransplantation. This is done by generating chimeric mice, and exposing the mice HCV infection. This engineering process is known to create humanized mice, and provide enormous opportunities to study hepatitis C within the 3D architectural design of the liver and evaluating antiviral compounds. Alternatively, generating inbred mice with susceptibility to HCV would drastically simplify the process of studying mouse models.

In recent years, scientists have made advancements towards understanding why mouse cells do not permit the entry of HCV, in an attempt to elucidate as to why hepatitis C remains elusive to study in alternative mammalian models. In 2009, researchers identified human OCLN as the factor which allows viral entry into both mouse and human cells.

Special populations

Children and pregnancy

Compared with adults, infection in children is much less well understood. Worldwide the prevalence of hepatitis C virus infection in pregnant women and children has been estimated to 1-8% and 0.05-5% respectively.The vertical transmission rate has been estimated to be 3-5% and there is a high rate of spontaneous clearance (25-50%) in the children. Higher rates have been reported for both vertical transmission (18%, 6-36% and 41%). and prevalence in children (15%).

In developed countries transmission around the time of birth is now the leading cause of HCV infection. In the absence of virus in the mother's blood transmission seems to be rare. Factors associated with an increased rate of infection include membrane rupture of longer than 6 hours before delivery and procedures exposing the infant to maternal blood. Cesarean sections are not recommended. Breast feeding is considered safe if the nipples are not damaged. Infection around the time of birth in one child does not increase the risk in a subsequent pregnancy. All genotypes appear to have the same risk of transmission.

HCV infection is frequently found in children who have previously been presumed to have non-A, non-B hepatitis and cryptogenic liver disease. The presentation in childhood may be asymptomatic or with elevated liver function tests. While infection is commonly asymptomatic both cirrhosis with liver failure and hepatocellular carcinoma may occur in childhood.

Immunosuppressed

The prevalence of hepatitis C in immunosuppressed hosts is higher than the normal population particularly in those with human immunodeficiency virus infection, recipients of organ transplants and those with hypogammaglobulinemia. Infection in these hosts is associated with an unusually rapid progression to cirrhosis.

Differential diagnosis

Several diseases can present with signs, symptoms, and/or liver function test abnormalities similar to hepatitis. In severe cases of alpha 1-antitrypsin deficiency (A1AD), excess protein in liver cells causes and inflammation and cirrhosis. Some metabolic disorders cause damage to the liver through a variety of mechanisms. In hemochromatosis and Wilson's disease toxic accumulation of dietary minerals results in inflammation and cirrhosis.

Pathology

The liver, like all organs, responds to injury in a limited number of ways and a number of patterns have been identified. Liver biopsies are rarely performed for acute hepatitis and because of this the histology of chronic hepatitis is better known than that of acute hepatitis.

Acute

In acute hepatitis the lesions (areas of abnormal tissue) predominantly contain diffuse sinusoidal and portal mononuclear infiltrates (lymphocytes, plasma cells, Kupffer cells) and swollen hepatocytes. Acidophilic cells (Councilman bodies) are common. Hepatocyte regeneration and cholestasis (canalicular bile plugs) typically are present. Bridging hepatic necrosis (areas of necrosis connecting two or more portal tracts) may also occur. There may be some lobular disarray. Although aggregates of lymphocytes in portal zones may occur these are usually neither common nor prominent. The normal architecture is preserved. There is no evidence of fibrosis or cirrhosis (fibrosis plus regenerative nodules). In severe cases prominent hepatocellular necrosis around the central vein (zone 3) may be seen.

In submassive necrosis – a rare presentation of acute hepatitis – there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease. Two distinct patterns of necrosis have been recognised: (1) zonal coagulative necrosis or (2) panlobular (nonzonal) necrosis. Numerous macrophages and lymphocytes are present. Necrosis and inflammation of the biliary tree occurs. Hyperplasia of the surviving biliary tract cells may be present. Stromal haemorrhage is common.

The histology may show some correlation with the cause:

Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia.

Zone 2 (midzonal) – rare – is seen in yellow fever.

Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure or chloroform ingestion. Drugs such as acetaminophen may be metabolized in zone 1 to toxic compounds that cause necrosis in zone 3.

Where patients have recovered from this condition, biopsies commonly show multiacinar regenerative nodules (previously known as adenomatous hyperplasia).

Massive hepatic necrosis is also known and is usually rapidly fatal. The pathology resembles that of submassive necrosis but is more markered in both degree and extent.

Chronic

Chronic hepatitis has been better studied and several conditions have been described.

Chronic hepatitis with piecemeal (periportal) necrosis (or interface hepatitis) with or without fibrosis (formerly chronic active hepatitis) is any case of hepatitis occurring for more than 6 months with portal based inflammation, fibrosis, disruption of the terminal plate, and piecemeal necrosis. This term has now been replaced by the diagnosis of 'chronic hepatitis'.

Chronic hepatitis without piecemeal necrosis (formerly called chronic persistent hepatitis) has no significant periportal necrosis or regeneration with a fairly dense mononuclear portal infiltrate. Councilman bodies are frequently seen within the lobule. Instead it includes persistent parenchymal focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal infiltrates.

The older terms have been deprecated because the conditions are now understood as being able to alter over time so that what might have been regarded as a relatively benign lesion could still progress to cirrhosis. The simpler term chronic hepatitis is now preferred in association with the causative agent (when known) and a grade based on the degree of inflammation, piecemeal or bridging necrosis (interface hepatitis) and the stage of fibrosis. Several grading systems have been proposed but none have been adopted universally.

Cirrhosis is a diffuse process characterized by regenerative nodules that are separated from one another by bands of fibrosis. It is the end stage for many chronic liver diseases. The pathophysiological process that results in cirrhosis is as follows: hepatocytes are lost through a gradual process of hepatocellular injury and inflammation. This injury stimulates a regenerative response in the remaining hepatocytes. The fibrotic scars limit the extent to which the normal architecture can be reestablished as the scars isolate groups of hepatocytes. This results in nodules formation. Angiogenisis (new vessel formation) accompanies scar production which results in the formation of abnormal channels between the central hepatic veins and the portal vessels. This in turn causes shunting of blood around the regenerating parenchyma. Normal vascular structures including the sinusoidal channels may be obliterated by fibrotic tissue leading to portal hypertension. The overall reduction in hepatocyte mass, in conjunction with the portal blood shunting, prevents the liver from accomplishing its usual functions – the filtering of blood from the gastrointestinal tract and serum protein production. These changes give rise to the clinical manifestations of cirrhosis.

Specific cases

Most of the causes of hepatitis cannot be distinguished on the basis of the pathology but some do have particular features that are suggestive of a particular diagnosis.

The presence of micronodular cirrhosis, Mallory bodies and fatty change within a single biopsy are highly suggestive of alcoholic injury. Perivenular, pericellular fibrosis (known as 'chicken wire fibrosis' because of its appearance on trichrome or van Gieson stains) with partial or complete obliteration of the central vein is also very suggestive of alcohol abuse.

Cardiac, ischemic and venous outflow obstruction all cause similar patterns. The sinusoids are often dilated and filled with erythrocytes. The liver cell plates may be compressed. Coagulative necrosis of the hepatocytes can occur around the central vein. Hemosiderin and lipochrome laden macrophages and inflammatory cells may be found. At the edge of the fibrotic zone cholestasis may be present. The portal tracts are rarely significantly involved until late in the course.

Biliary tract disease including primary biliary cirrhosis, sclerosing cholangitis, inflammatory changes associated with idiopathic inflammatory bowel disease and duct obstruction have similar histology in their early stages. Although these diseases tend to primarily involve the biliary tract they may also be associated with chronic inflammation within the liver and difficult to distinguish on histological grounds alone. The fibrotic changes associated with these disease principally involve the portal tracts with cholangiole proliferation, portal tract inflammation with neutrophils surrounding the cholangioles, disruption of the terminal plate by mononuclear inflammatory cells and occasional hepatocyte necrosis. The central veins are either not involved in the fibrotic process or become involved only late in the course of the disease. Consequently the central–portal relationships are minimally distorted. Where cirrhosis is present it tends to be in the form of a portal–portal bridging fibrosis.

Hepatitis E causes different histological patterns that depend on the host's background. In immunocompetent patients the typical pattern is of severe intralobular necrosis and acute cholangitis in the portal tract with numerous neutrophils. This normally resolves without sequelae. Disease is more severe in those with preexisting liver disease such as cirrhosis. In the immunocompromised patients chronic infection may result with rapid progression to cirrhosis. The histology is similar to that found in hepatitis C virus with dense lymphocytic portal infiltrate, constant piecemeal necrosis and fibrosis.

World Hepatitis Day

World Hepatitis Day, observed on July 28 every year, aims to raise global awareness of hepatitis B and hepatitis C and encourage prevention, diagnosis and treatment. One of only four disease awareness days recognised by the World Health Organization (WHO), it is co-ordinated by the WHO and the World Hepatitis Alliance.

Approximately 500 million people worldwide are living with either hepatitis B or hepatitis C. If left untreated and unmanaged, hepatitis B or C can lead to advanced liver scarring (cirrhosis) and other complications, including liver cancer or liver failure. While many people worry more about contracting AIDS than hepatitis, the reality is that every year 1.5 million people worldwide die from either hepatitis B or C faster than they would from HIV/AIDS.

Hepatitis groups, patients and advocates worldwide take part in events on 28 July to mark the occasion. Notably in 2012, a Guinness World Record was created when 12,588 people from 20 countries did the Three Wise Monkeys actions on World Hepatitis Day to signify the willful ignorance of the disease.

History

The inaugural International Hepatitis C Awareness day, coordinated by various European and Middle Eastern Patient Groups, took place October 1, 2004, however many patient groups continued to mark 'hepatitis day' on disparate dates. For this reason in 2008, the World Hepatitis Alliance in collaboration with patient groups declared May 19 the first global World Hepatitis Day.

Following the adoption of a viral hepatitis resolution during the 63rd World Health Assembly in May 2010, World Hepatitis Day was given global endorsement as the primary focus for national and international awareness-raising efforts and the date was changed to July 28 (in honour of Nobel Laureate Prof. Baruch Samuel Blumberg, discoverer of the hepatitis B virus, who celebrates his birthday on that date). The resolution resolves that:"28 July shall be designated as World Hepatitis Day in order to provide an opportunity for education and greater understanding of viral hepatitis as a global public health problem, and to stimulate the strengthening of preventive and control measures of this disease in Member States;"

World Hepatitis Day is now recognised in over 100 countries each year through events such as free screenings, poster campaigns, demonstrations, concerts, talk shows, flash mobs and vaccination drives, amongst many others. Each year a wrap up report is published by the WHO and the World Hepatitis Alliance detailing all the events across the world.

Focus

World Hepatitis Day provides an opportunity to focus on specific actions such as: Strengthening prevention, screening and control of viral hepatitis and its related diseases; Increasing hepatitis B vaccine coverage and integration into national immunization programmes; and coordinating a global response to hepatitis to increase access to treatment.

Participants in World Hepatitis Day aim to raise awareness of viral hepatitis, the viruses A, B, C, D and E can cause acute and chronic infection and inflammation of the liver leading to cirrhosis and liver cancer. These viruses constitute a major global health risk with an estimated 350 million people being chronically infected with hepatitis B and an estimated 170 million people being chronically infected with hepatitis C.

Approximately 500 million people worldwide are living with either hepatitis B or hepatitis C., including liver cancer or liver failure. While many people worry more about contracting AIDS than hepatitis, the reality is that every year 1.5 million people worldwide die from either hepatitis B or C faster than they would from HIV/AIDS.

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