Siddha cure for Jaundice - Aravindh Health Centre - Home
Jaundice
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Definition And Explanation
Jaundice (also known as icterus; from the Greek word icteric) is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae (whites of the eyes), and other mucous membranes caused by hyperbilirubinemia (increased levels of bilirubin in the blood).
The term jaundice also have an origin from the French word jaune, meaning yellow.
People with jaundice have a problem with their liver, which stops it from removing dead red blood cells properly.
These blood cells contain a chemical called bilirubin. The yellow colour of the skin and mucous membranes happens because of an increase in the bile pigment, bilirubin, in the blood.
This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid.
Concentration of bilirubin in blood plasma does not normally exceed 1 mg/dL (>17µmol/L).
A concentration higher than 1.8 mg/dL (>30µmol/L) leads to jaundice.
Jaundice is often seen in liver disease such as hepatitis or liver cancer.
It may also indicate leptospirosis or obstruction of the biliary tract, for example by gallstones or pancreatic cancer, or less commonly be congenital in origin.
Yellow discoloration of the skin, especially on the palms and the soles, but not of the sclera and mucous membranes (i.e. oral cavity) is due to carotenemia—a harmless condition important to differentiate from jaundice.
Jaundice can also be caused by other diseases, like malaria, hepatitis, or gallstones.
Jaundice is the most common of all liver problems.
The bile, made by the liver, is a vital digestive fluid needed for proper nutrition. It also stops decaying changes in food.
If the bile is stopped from entering the intestines there is an increase in gases and other products.
Types of Jaundice
There are three types of jaundice:
• Haemolytic jaundice {Pre-hepatic} - caused by destruction of red blood cells. This causes increased bilirubin formation and anaemia
• Obstructive jaundice{Post-hepatic} - caused by a blockage in the pathway where bilirubin is made in the liver cells and where bile goes into the duodenum
• Hepatocellular jaundice{Hepatic} - caused by damage to liver cells. The damage could be from a viral infection or toxic drugs.
Pathology of the different types of jaundice
When a pathological process interferes with the normal functioning of the metabolism and excretion of bilirubin just described, jaundice may be the result.
Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects.
The three categories are:
|Category |Definition |
|Pre-hepatic/ hemolytic |The pathology is occurring prior to the liver. |
|Hepatic/ hepatocellular |The pathology is located within the liver. |
|Post-Hepatic/ cholestatic |The pathology is located after the conjugation of bilirubin in the liver. |
Pre-hepatic
Pre-hepatic jaundice is caused by anything which causes an increased rate of hemolysis (breakdown of red blood cells).
In tropical countries, malaria can cause jaundice in this manner.
Certain genetic diseases, such as sickle cell anemia, spherocytosis, thalassemia and glucose 6-phosphate dehydrogenase deficiency can lead to increased red cell lysis and therefore hemolytic jaundice.
Commonly, diseases of the kidney, such as hemolytic uremic syndrome, can also lead to coloration.
Defects in bilirubin metabolism also present as jaundice, as in Gilbert's syndrome (a genetic disorder of bilirubin metabolism which can result in mild jaundice, which is found in about 5% of the population) and Crigler-Najjar syndrome.
In jaundice secondary to hemolysis, the increased production of bilirubin, leads to the increased production of urine-urobilinogen.
Bilirubin is not usually found in the urine because unconjugated bilirubin is not water-soluble, so, the combination of increased urine-urobilinogen with no bilirubin (since, unconjugated) in urine is suggestive of hemolytic jaundice.
Laboratory findings include:
• Urine: no bilirubin present, urobilinogen > 2 units (i.e., hemolytic anemia causes increased heme metabolism; exception: infants where gut flora has not developed).
• Serum: increased unconjugated bilirubin.
• Kernicterus is associated with increased unconjugated bilirubin, neonates are especially vulnerable to this.
Hepatocellular
Hepatocellular (hepatic) jaundice can be caused by acute or chronic hepatitis, hepatotoxicity, cirrhosis, drug induced hepatitis and alcoholic liver disease.
Cell necrosis reduces the liver's ability to metabolize and excrete bilirubin leading to a buildup of unconjugated bilirubin in the blood.
Other causes include primary biliary cirrhosis leading to an increase in plasma conjugated bilirubin because there is impairment of excretion of conjugated bilirubin into the bile.
The blood contains abnormally raised amount of conjugated bilirubin and bile salts which are excreted in the urine.
Jaundice seen in the newborn, known as neonatal jaundice, is common in newborns as hepatic machinery for the conjugation and excretion of bilirubin does not fully mature until approximately two weeks of age.
Rat fever (leptospirosis) can also cause hepatic jaundice.
In hepatic jaundice, there is invariably cholestasis.
Laboratory findings depend on the cause of jaundice.
• Urine: Conjugated bilirubin present, urobilirubin > 2 units but variable (except in children). Kernicterus is a condition not associated with increased conjugated bilirubin.
• Plasma protein show characteristic changes.
• Plasma albumin level is low but plasma globulins are raised due to an increased formation of antibodies.
Bilirubin transport across the hepatocyte may be impaired at any point between the uptake of unconjugated bilirubin into the cell and transport of conjugated bilirubin into biliary canaliculi.
In addition, swelling of cells and oedema due to inflammation cause mechanical obstruction of intrahepatic biliary tree.
Hence in hepatocellular jaundice, concentration of both unconjugated and conjugated bilirubin rises in the blood.
In hepatocellular disease, there is usually interference in all major steps of bilirubin metabolism—uptake, conjugation and excretion.
However, excretion is the rate-limiting step, and usually impaired to the greatest extent.
As a result, conjugated hyperbilirubinaemia predominates.
The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way.
This conjugated bilirubin is then returned to the blood, probably by rupture of the congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver.
Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type.
Post-hepatic
Post-hepatic jaundice, also called obstructive jaundice, is caused by an interruption to the drainage of bile in the biliary system.
The most common causes are gallstones in the common bile duct, and pancreatic cancer in the head of the pancreas.
Also, a group of parasites known as "liver flukes" can live in the common bile duct, causing obstructive jaundice. Other causes include strictures of the common bile duct, biliary atresia, cholangiocarcinoma, pancreatitis and pancreatic pseudocysts.
A rare cause of obstructive jaundice is Mirizzi's syndrome.
In complete obstruction of the bile duct, no urobilinogen is found in the urine, since bilirubin has no access to the intestine and it is in the intestine that bilirubin gets converted to urobilinogen to be later released into the general circulation.
In this case, presence of bilirubin (conjugated) in the urine without urine-urobilinogen suggests obstructive jaundice, either intra-hepatic or post-hepatic.
The presence of pale stools and dark urine suggests an obstructive or post-hepatic cause as normal feces get their color from bile pigments.
However, although pale stools and dark urine are a feature of biliary obstruction, they can occur in many intra-hepatic illnesses and are therefore not a reliable clinical feature to distinguish obstruction from hepatic causes of jaundice.
Patients also can present with elevated serum cholesterol, and often complain of severe itching or "pruritus" because of the deposition of bile salts.
No single test can differentiate between various classifications of jaundice.
A combination of liver function tests is essential to arrive at a diagnosis.
| Table of diagnostic tests |
|Function test |Pre-hepatic Jaundice |Hepatic Jaundice |Post-hepatic Jaundice |
|Total bilirubin |Normal / Increased |Increased |
|Conjugated bilirubin |Normal |Increased |Increased |
|Unconjugated bilirubin |Normal / Increased |Increased |Normal |
|Urobilinogen |Normal / Increased |Increased |Decreased / Negative |
|Urine Color |Normal |Dark (urobilinogen + conjugated |Dark (conjugated bilirubin) |
| | |bilirubin) | |
|Stool Color |Normal |Normal/Pale |Pale |
|Alkaline phosphatase levels |Normal |Increased |
|Alanine transferase and Aspartate transferase | |Increased |
|levels | | |
|Conjugated Bilirubin in Urine |Not Present |Present |
Neonatal jaundice
Neonatal jaundice is usually harmless: this condition is often seen in infants around the second day after birth, lasting until day 8 in normal births, or to around day 14 in premature births.
Causes of neonatal jaundice
Typical causes for neonatal jaundice include
• normal physiologic jaundice,
• jaundice due to breast feeding, and
• hemolytic disorders that include hereditary spherocytosis,
• glucose-6-phosphate dehydrogenase deficiency,
• pyruvate kinase deficiency,
• ABO/Rh blood type autoantibodies, or infantile pyknocytosis.
Pathology of neonatal jaundice
Serum bilirubin normally drops to a low level without any intervention required: the jaundice is presumably a consequence of metabolic and physiological adjustments after birth.
Complications
In cases where bilirubin rises higher, a brain-damaging condition known as kernicterus can occur, leading to significant lifelong disability; there are concerns that this condition has been rising in recent years due to inadequate detection and treatment of neonatal hyperbilirubinemia.
Treatment of neonatal jaundice
A Bili light is often the tool used for early treatment, which often consists of exposing the baby to intensive phototherapy.
However, in third world countries where procuring such treatment is prohibitably expensive, parents often subject their children to regular daily treatments of baking in the sunlight and sunbathing.
Bilirubin count is lowered through bowel movements and urination so regular and proper feedings are especially important.
Pathophysiology of Common Hepatitis
In order to understand how jaundice results, the pathological processes that cause jaundice to take their effect must be understood.
Jaundice itself is not a disease, but rather a sign of one of many possible underlying pathological processes that occur at some point along the normal physiological pathway of the metabolism of bilirubin.
When red blood cells have completed their life span of approximately 120 days, or when they are damaged, their membranes become fragile and prone to rupture.
As each red blood cell traverses through the reticuloendothelial system, its cell membrane ruptures when its membrane is fragile enough to allow this.
Cellular contents, including hemoglobin, are subsequently released into the blood.
The hemoglobin is phagocytosed by macrophages, and split into its heme and globin portions.
The globin portion, a protein, is degraded into amino acids and plays no role in jaundice.
Two reactions then take place with the heme molecule.
The first oxidation reaction is catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color pigment), iron and carbon monoxide.
The next step is the reduction of biliverdin to a yellow color tetrapyrol pigment called bilirubin by cytosolic enzyme biliverdin reductase.
This bilirubin is "unconjugated," "free" or "indirect" bilirubin.
Approximately 4 mg of bilirubin per kg of blood is produced each day.
The majority of this bilirubin comes from the breakdown of heme from expired red blood cells in the process just described.
However approximately 20 percent comes from other heme sources, including ineffective erythropoiesis, and the breakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes.
Hepatic events
The unconjugated bilirubin then travels to the liver through the bloodstream.
Because this bilirubin is not soluble, however, it is transported through the blood bound to serum albumin.
Once it arrives at the liver, it is conjugated with glucuronic acid (to form bilirubin diglucuronide, or just "conjugated bilirubin") to become more water soluble.
The reaction is catalyzed by the enzyme UDP-glucuronyl transferase.
This conjugated bilirubin is excreted from the liver into the biliary and cystic ducts as part of bile.
Intestinal bacteria convert the bilirubin into urobilinogen.
From here the urobilinogen can take two pathways.
It can either be further converted into stercobilinogen, which is then oxidized to stercobilin and passed out in the feces, or it can be reabsorbed by the intestinal cells, transported in the blood to the kidneys, and passed out in the urine as the oxidised product urobilin.
Stercobilin and urobilin are the products responsible for the coloration of feces and urine, respectively.
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Causes
Jaundice is basically a summer disease which is caused due to high concentration of Bilirubin.
Bilirubin is yellow substance which is found in bile and helps liver break down the worn out red blood cells, which ideally should be transformed into waste and new red blood cells should be formed.
Jaundice is a sign that the liver is not working.
It may be caused by a blockage of the bile ducts which release bile salts and pigment into the intestines.
The bile then gets mixed with blood and this gives a yellow colour to the skin.
Jaundice is caused when the number of damaged red blood cells multiply, the amount of bilirubin in the blood increases fast.
The causes of jaundice are:
1. Enlarged Liver:
Inflammation (swelling or enlargement) of the liver, called hepatitis.
One of the basic causes of jaundice is liver enlargement, which happens due to liver infections.
This is caused by a virus.
The virus can spread and may lead to epidemics caused by:
o overcrowding
o dirty surroundings
o insanitary conditions
o contamination of food and water.
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Liver cirrhosis
Hepatitis E - these are all caused by those viruses
When the liver is enlarged, it finds it difficult to convert bilirubin into waste and thus, it results in mixing of bilirubin with blood.
This is when the skin and urine get the dark yellow colour.
2. Bile Disorder
The blockage of the bile ducts could be caused by Gallstones.
Bile is a substance which substance which promotes the digestive process and produces by the liver.
If this bile shrinks due to stone, tumour or birth defect, then it gets released in the blood.
The skin and urine becomes yellow but the stool is white or brown in colour.
The patient is unable to digest fat and may also suffer blood clotting.
3. Loss Of Blood
The decreased number of red blood cells is the next cause.This condition is called as Pernicious anaemia.
Due to certain illness like malaria, typhoid etc, the production of the red blood cells may fall or cells may even damage.
This lack of red blood cells and the problem of the liver to process bilirubin leads to this disease.
4. Other causes of jaundice are
• Pancreatic cancer
• Alcoholic liver disease
• Diseases affecting the liver such as:
i. typhoid,
ii. malaria,
iii. yellow fever and
iv. tuberculosis.
v. Certain medication
vi. Pregnancy
vii. liver cancer
Symptoms
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Yellow eyes caused by jaundice from hepatitis
The conjunctiva of the eye are one of the first tissues to change color as bilirubin levels rise in jaundice. This is sometimes referred to as scleral icterus.
However, the sclera themselves are not "icteric" (stained with bile pigment) but rather the conjunctival membranes that overlie them.
The yellowing of the "white of the eye" is thus more properly termed conjunctival icterus.
The term "icterus" itself is sometimes incorrectly used to refer to jaundice that is noted in the sclera of the eyes, however its more common and more correct meaning is entirely synonymous with jaundice.
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The symptoms of jaundice are:
• Extreme weakness
• Headache
• Fever
• Loss of appetite
• Tiredness
• Severe constipation
• Nausea
• Yellow coloration of the eyes, tongue, skin and urine.
• Dull pain in the liver region.
• Obstructive jaundice may also cause intense itching.
Jaundice in case of pregnancy leads to is vaginal bleeding, frequent fainting and feeling of thrist.
Diagnosis
[pic]Biliary tract dilation due to obstruction as seen on CAT scan
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Biliary tract dilation due to obstruction
Most patients presenting with jaundice will have various predictable patterns of liver panel abnormalities, though significant variation does exist.
The typical liver panel will include :
Blood levels of enzymes found primarily from the liver, such as
• the aminotransferases (ALT, AST),
• alkaline phosphatase (ALP);
• bilirubin (which causes the jaundice); and
• protein levels, specifically, total protein and albumin.
Other primary lab tests for liver function include GGT and prothrombin time (PT).
Some bone and heart disorders can lead to an increase in ALP and the aminotransferases, so the first step in differentiating these from liver problems is to compare the levels of GGT, which will only be elevated in liver-specific conditions.
The second step is distinguishing from biliary (cholestatic) or liver (hepatic) causes of jaundice and altered lab results.
The former typically indicates a surgical response, while the latter typically leans toward a medical response.
ALP and GGT levels will typically rise with one pattern while AST and ALT rise in a separate pattern.
If the ALP (10–45 IU/L) and GGT (18–85) levels rise proportionately about as high as the AST (12–38 IU/L) and ALT (10–45 IU/L) levels, this indicates a cholestatic problem.
On the other hand, if the AST and ALT rise is significantly higher than the ALP and GGT rise, this indicates an hepatic problem.
Finally, distinguishing between hepatic causes of jaundice, comparing levels of AST and ALT can prove useful.
AST levels will typically be higher than ALT.
This remains the case in most hepatic disorders except for hepatitis (viral or hepatotoxic).
Alcoholic liver damage may see fairly normal ALT levels, with AST 10x higher than ALT.
On the other hand, if ALT is higher than AST, this is indicative of hepatitis. Levels of ALT and AST are not well correlated to the extent of liver damage, although rapid drops in these levels from very high levels can indicate severe necrosis.
Low levels of albumin tend to indicate a chronic condition, while it is normal in hepatitis and cholestasis.
Lab results for liver panels are frequently compared by the magnitude of their differences, not the pure number, as well as by their ratios.
The AST:ALT ratio can be a good indicator of whether the disorder is alcoholic liver damage (10), some other form of liver damage (above 1), or hepatitis (less than 1).
Bilirubin levels greater than 10x normal could indicate neoplastic or intrahepatic cholestasis.
Levels lower than this tend to indicate hepatocellular causes.
AST levels greater than 15x tends to indicate acute hepatocellular damage.
Less than this tend to indicate obstructive causes.
ALP levels greater than 5x normal tend to indicate obstruction, while levels greater than 10x normal can indicate drug (toxic) induced cholestatic hepatitis or Cytomegalovirus.
Both of these conditions can also have ALT and AST greater than 20× normal. GGT levels greater than 10x normal typically indicate cholestasis.
Levels 5–10× tend to indicate viral hepatitis.
Levels less than 5× normal tend to indicate drug toxicity.
Acute hepatitis will typically have ALT and AST levels rising 20–30× normal (above 1000), and may remain significantly elevated for several weeks.
Acetaminophen toxicity can result in ALT and AST levels greater than 50x normal.
Complications
Complications of jaundice include :-
• sepsis
• cholangitis,
• biliary cirrhosis,
• pancreatitis,
• coagulopathy,
• renal and
• liver failure.
Other complications are related to the underlying disease and the procedures employed in the diagnosis and management of individual diseases.
Cholangitis especially the suppurative type (Charcot’s triad or Raynaud’s pentad) is usually secondary to choledocholithiasis.
It may also complicate procedures like ERCP.
Management
Treatment should include correction of coagulopathy, fluid/electrolyte anomaly, antibiotics and biliary drainage with ERCP where available or trans-hepatic drainage or surgery.
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Other Varities Of Hepatitis
Hepatitis A
Definition and Explanation
Hepatitis A (formerly known as infectious hepatitis and epidemical virus) is an acute infectious disease of the liver caused by the hepatitis A virus (Hep A), an RNA virus, usually spread by the fecal-oral route; transmitted person-to-person by ingestion of contaminated food or water or through direct contact with an infectious person.
Tens of millions of individuals worldwide are estimated to become infected with Hep A each year.
Incubation period
The time between infection and the appearance of the symptoms (the incubation period) is between two and six weeks and the average incubation period is 28 days.
About Hepatitis A
In developing countries, and in regions with poor hygiene standards, the incidence of infection with this virus is high and the illness is usually contracted in early childhood.
As incomes rise and access to clean water increases, the incidence of HAV decreases.
Hepatitis A infection causes no clinical signs and symptoms in over 90% of infected children and since the infection confers lifelong immunity, the disease is of no special significance to those infected early in life.
In Europe, the United States and other industrialized countries, on the other hand, the infection is contracted primarily by susceptible young adults, most of whom are infected with the virus during trips to countries with a high incidence of the disease or through contact with infectious persons.
HAV infection produces a self-limited disease that does not result in chronic infection or chronic liver disease.
However, 10–15% of patients might experience a relapse of symptoms during the 6 months after acute illness.
Acute liver failure from Hepatitis A is rare (overall case-fatality rate: 0.5%).
The risk for symptomatic infection is directly related to age, with >80% of adults having symptoms compatible with acute viral hepatitis and the majority of children having either asymptomatic or unrecognized infection.
Antibody produced in response to HAV infection persists for life and confers protection against reinfection.
The disease can be prevented by vaccination, and hepatitis A vaccine has been proven effective in controlling outbreaks worldwide.
Signs and symptoms
Early symptoms of hepatitis A infection can be mistaken for influenza, but some sufferers, especially children, exhibit no symptoms at all. Symptoms typically appear 2 to 6 weeks, (the incubation period), after the initial infection.
Symptoms usually last less than 2 months, although some people can be ill for as long as 6 months.
• Fatigue
• Fever
• Abdominal pain
• Nausea
• Appetite loss
• Jaundice, a yellowing of the skin or whites of the eyes
• Bile is removed from blood stream and excreted in urine, giving it a dark amber colour
• Clay-coloured feces
Virology
|Hepatitis A |
|[pic] |
|Electron micrograph of hepatitis A virions. |
|Virus classification |
|Group: |Group IV ((+)ssRNA) |
|Family: |Picornaviridae |
|Genus: |Hepatovirus |
|Species: |Hepatitis A virus |
Pathology of Hepatitis A
Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine.
The blood carries the virus to its target, the liver, where it multiplies within hepatocytes and Kupffer cells (liver macrophages).
Virions are secreted into the bile and released in stool.
HAV is excreted in large quantities approximately
11 days prior to appearance of symptoms or anti-HAV IgM antibodies in the blood.
The incubation period is 15–50 days and mortality is less than 0.5%.
Within the liver hepatocytes the RNA genome is released from the protein coat and is translated by the cell's own ribosomes.
Unlike other members of the Picornaviruses this virus requires an intact eukaryote initiating factor 4G (eIF4G) for the initiation of translation.
The requirement for this factor results in an inability to shut down host protein synthesis unlike other picornaviruses.
The virus must then inefficiently compete for the cellular translational machinery which may explain its poor growth in cell culture.
Presumably for this reason the virus has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host.
Precisely how this strategy works is not quite clear yet.
There is no apparent virus-mediated cytotoxicity presumably because of the virus' own requirement for an intact eIF4G and liver pathology is likely immune-mediated.
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Structure of HAV
The Hepatitis virus (HAV) is a Picornavirus; it is non-enveloped and contains a single-stranded RNA packaged in a protein shell.
There is only one serotype of the virus, but multiple genotypes exist.
Codon use within the genome is biased and unusually distinct from its host.
It also has a poor internal ribosome entry site
In the region that codes for the HAV capsid there are highly conserved clusters of rare codons that restrict antigenic variability.
Genotypes
Only one serotype and seven different genetic groups (four humans and three simian) have been described.
The human genotypes are numbered I-III. Six subtypes have been described (IA, IB, IIA, IIB, IIIA, IIIB).
The simian genotypes have been numbered IV-VI. A single isolate of genotype VII isolated from a human has also been described.
Genotype III has been isolated from both humans and owl monkeys.
Most human isolates are of genotype I. Of the type I isolates subtype IA accounts for the majority.
The mutation rate in the genome has been estimated to be 1.73 - 9.76 x 10−4 nucleotide substitution per site per year.
The human strains appear to have diverged from the simian ~3600 years ago.]
The mean age of genotypes III and IIIA strains has been estimated to be 592 and 202 years respectively.
Transmission
The virus spreads by the fecal-oral route and infections often occur in conditions of poor sanitation and overcrowding.
Hepatitis A can be transmitted by the parenteral route but very rarely by blood and blood products.
Food-borne outbreaks are not uncommon, and ingestion of shellfish cultivated in polluted water is associated with a high risk of infection.
Approximately 40% of all acute viral hepatitis is caused by HAV. Infected individuals are infectious prior to onset of symptoms, roughly 10 days following infection.
The virus is resistant to detergent, acid (pH 1), solvents (e.g., ether, chloroform), drying, and temperatures up to 60 °C.
It can survive for months in fresh and salt water.
Common-source (e.g., water, restaurant) outbreaks are typical.
Infection is common in children in developing countries, reaching 100% incidence, but following infection there is lifelong immunity.
HAV can be inactivated by:
• chlorine treatment (drinking water),
• formalin (0.35%, 37 °C, 72 hours),
• peracetic acid (2%, 4 hours),
• beta-propiolactone (0.25%, 1 hour), and
• UV radiation (2 μW/cm2/min).
Diagnosis
[pic]
Serum IgG, IgM and ALT following Hepatitis A virus infection
Although HAV is excreted in the feces towards the end of the incubation period, specific diagnosis is made by the detection of HAV-specific IgM antibodies in the blood.
IgM antibody is only present in the blood following an acute hepatitis A infection.
It is detectable from one to two weeks after the initial infection and persists for up to 14 weeks.
The presence of IgG antibody in the blood means that the acute stage of the illness is past and the person is immune to further infection.
IgG antibody to HAV is also found in the blood following vaccination and tests for immunity to the virus are based on the detection of this antibody.
During the acute stage of the infection, the liver enzyme alanine transferase (ALT) is present in the blood at levels much higher than is normal.
The enzyme comes from the liver cells that have been damaged by the virus.
Hepatitis A virus is present in the blood, (viremia), and feces of infected people up to two weeks before clinical illness develops.
Prevention
Hepatitis A can be prevented by vaccination, good hygiene and sanitation.[1][19]
The vaccine protects against HAV in more than 95% of cases for longer than 20 years.
It contains inactivated hepatitis A virus providing active immunity against a future infection.
In the USA the vaccine was first phased in 1996 for children in high-risk areas, and in 1999 it was spread to areas with elevating levels of infection.
The vaccine is given by injection.
An initial dose provides protection starting two to four weeks after vaccination; the second booster dose, given six to twelve months later, provides protection for over twenty years.
Treatment in allopathy
There is no specific treatment for hepatitis A.
Sufferers are advised to rest, avoid fatty foods and alcohol (these may be poorly tolerated for some additional months during the recovery phase and cause minor relapses), eat a well-balanced diet, and stay hydrated.
Prognosis
The United States Centers for Disease Control and Prevention (CDC) in 1991 reported a low mortality rate for hepatitis A of 4 deaths per 1000 cases for the general population but a higher rate of 17.5 per 1000 in those aged 50 and over.
The risk of death from acute liver failure following HAV infection increases with age and when the person has underlying chronic liver disease.
Young children who are infected with hepatitis A typically have a milder form of the disease, usually lasting from 1–3 weeks, whereas adults tend to experience a much more severe form of the disease.
Epidemiology
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Hepatitis A Distribution 2005
Antibodies to HAV (anti-HAV) in the blood are a marker of past or current infection.
High-income regions (Western Europe, Australia, New Zealand, Canada, the United States, Japan, the Republic of Korea, and Singapore) have very low HAV endemicity levels .
A high proportion of susceptible adults, low-income regions (sub-Saharan Africa and parts of South Asia) have high endemicity levels and almost no susceptible adolescents and adults.
Most middle-income regions have a mix of intermediate and low endemicity levels.
Anti-HAV prevalence suggest that middle-income regions in Asia, Latin America, Eastern Europe, and the Middle East currently have an intermediate or low level of endemicity.
The countries in these regions may have an increasing burden of disease from hepatitis A.
There were 30,000 cases of Hepatitis A reported to the CDC in the U.S. in 1997. The agency estimates that there were as many as 270,000 cases each year from 1980 through 2000.
Hepatitis B
Definition
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.
About HBV
Hepatitis B virus is an 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.
History
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.[91]
The earliest record of an epidemic caused by hepatitis B virus was made by Lurman in 1885.
An outbreak of smallpox occurred in Bremen in 1883 and 1,289 shipyard employees were vaccinated with lymph from other people.
After several weeks, and up to eight months later, 191 of the vaccinated workers became ill with jaundice and were diagnosed as suffering from serum hepatitis.
Other employees who had been inoculated with different batches of lymph remained healthy.
Lurman's paper, now regarded as a classical example of an epidemiological study, proved that contaminated lymph was the source of the outbreak.
Later, numerous similar outbreaks were reported following the introduction, in 1909, of hypodermic needles that were used, and, more importantly, reused, for administering Salvarsan for the treatment of syphilis.
The virus was not discovered until 1965 when Baruch Blumberg, then working at the National Institutes of Health (NIH), discovered the Australia antigen (later known to be hepatitis B surface antigen, or HBsAg) in the blood of Australian aboriginal people.
Although a virus had been suspected since the research published by MacCallum in 1947, D.S. Dane and others discovered the virus particle in 1970 by electron microscopy.
By the early 1980s the genome of the virus had been sequenced, and the first vaccines were being tested.
Causes, incidence, and risk factors
Hepatitis B infection can be spread through having contact with the
➢ blood,
➢ semen,
➢ vaginal fluids, and
➢ other body fluids of someone who already has a hepatitis B infection.
Infection can be spread through:
• Blood transfusions (not common in the United States)
• Direct contact with blood in health care settings
• Sexual contact with an infected person
• Tattoo or acupuncture with unclean needles or instruments
• Shared needles during drug use
• Shared personal items (such as toothbrushes, razors, and nail clippers) with an infected person
The hepatitis B virus can be passed to an infant during childbirth if the mother is infected.
However, Hepatitis B viruses cannot be spread by holding hands, sharing eating utensils or drinking glasses, kissing, hugging, coughing, sneezing, or breastfeeding.
Risk factors for hepatitis B infection include:
• Being born, or having parents who were born in regions with high infection rates (including Asia, Africa, and the Caribbean)
• Being infected with HIV
• Being on hemodialysis
• Having multiple sex partners
• Men having sex with men
How does hepatitis B virus cause liver injury?
Most of the damage from the hepatitis B virus occurs because of the way the body responds to the infection.
The hepatitis B virus reproduces in liver cells, but the virus itself is not the direct cause of damage to the liver.
Rather, the presence of the virus triggers an immune response from the body as the body tries to eliminate the virus and recover from the infection.
When the body's immune system detects the infection, it sends out special cells to fight it off.
However, these disease-fighting cells can lead to liver inflammation.
Therefore, there is a balance between the protective and destructive effects of the immune response to the hepatitis B virus.
This infection has two possible phases;
1) Acute and
2) Chronic.
1. Acute hepatitis B refers to newly acquired infections. Affected individuals notice symptoms approximately 1 to 4 months after exposure to the virus. In most people with acute hepatitis, symptoms resolve over weeks to months and they are cured of the infection. However, a small number of people develop a very severe, life-threatening form of acute hepatitis called fulminant hepatitis.
2. Chronic hepatitis B is an infection with HBV that lasts longer than 6 months. Once the infection becomes chronic, it may never go away completely.
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).
➢ 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
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Structure
[pic]
The genome organisation of HBV. The genes overlap.
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 42 nM in diameter and are sometimes referred to as "Dane particles".
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, but pleomorphic forms exist, including filamentous and spherical bodies lacking a core.
These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus.
[pic]
Hepatitis B virus replication.
The life cycle of hepatitis B virus is complex.
Hepatitis B is one of a few known pararetroviruses: non-retroviruses that still do use reverse transcription in their replication process.
The virus gains entry into the cell by binding to an unknown receptor on the surface and being endocytosed in.
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 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.
Genotype A is most commonly found in the Americas, Africa, India and Western Europe. 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 adrq.
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 than 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.
Pathogenesis
Hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells, known as hepatocytes.
The receptor is not yet known, though there is evidence that the receptor in the closely related duck hepatitis B virus is carboxypeptidase D.
The virions bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis.
PreS and IgA receptors are accused of this interaction.
HBV-preS-specific receptors are 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
➢ 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
Signs and tests
The following tests are done to identify and monitor liver damage from hepatitis B:
• Albumin level
• Liver function tests
• Prothrombin time
The following tests are done to help diagnose and monitor people with hepatitis B:
• Antibody to HBsAg (Anti-HBs) -- a positive result means you have either had hepatitis B in the past, or have received a hepatitis B vaccine
• Antibody to hepatitis B core antigen (Anti-HBc) -- a positive result means you had a recent infection or an infection in the past
• Hepatitis B surface antigen (HBsAg) -- a positive result means you have an active infection
• Hepatitis E surface antigen (HBeAg) -- a positive result means you have a hepatitis B infection and are more likely to spread the infection to others through sexual contact or sharing needles
Patients with chronic hepatitis will need ongoing blood tests to monitor their status.
[pic]
Hepatitis B viral antigens and antibodies detectable in the blood following acute infection.
[pic]
Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person.
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.
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.
[pic]Ground glass hepatocytes as seen in a chronic hepatitis B. Liverbiopsy. H&E stain.
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
Several vaccines have been developed for the prevention of hepatitis B virus infection.
These rely on the use of one of the viral envelope proteins (hepatitis B surface antigen or HBsAg).
The vaccine was originally prepared from plasma obtained from people who had long-standing hepatitis B virus infection.
However, it is made using a synthetic recombinant DNA technology that does not contain blood products.
One cannot be infected with hepatitis B from this vaccine.
The risk of transmission from mother to newborn can be reduced from 20–90% to 5–10% by administering to the newborn hepatitis B vaccine (HBV 1) and hepatitis B immune globulin (HBIG) within 12 hours of birth, followed by a second dose of hepatitis B vaccine (HBV 2) at 1–2 months and a third dose at and no earlier than 6 months (24 weeks).
Since 2% of infants vaccinated will not develop immunity after the first three dose series, infants born to hepatitis B-positive mothers are tested at 9 months for hepatitis B surface antigen (HBsAg) and the antibody to the hepatitis B surface antigen (anti-HBs).
If post-vaccination test results indicate that the child is still susceptible, a second three dose series at (0, 1 and 6 months) is administered.
If the child is still susceptible after the second series, a third series is not recommended.
Following vaccination, hepatitis B surface antigen may be detected in serum for several days; this is known as vaccine antigenaemia.
The vaccine is administered in either two-, three-, or four-dose schedules into infants and adults, which provides protection for 85–90% of individuals.
Protection has been observed to last 12 years in individuals who show adequate initial response to the primary course of vaccinations, and that immunity is predicted to last at least 25 years.
Unlike hepatitis A, hepatitis B does not generally spread through water and food.
Instead, it is transmitted through body fluids; thus, prevention is the avoidance of such transmission: unprotected sexual contact, blood transfusions, re-use of contaminated needles and syringes, and vertical transmission during child birth.
Infants may be vaccinated at birth.
Lifestyle measures for preventing transmission of hepatitis B:
• Avoid sexual contact with a person who has acute or chronic hepatitis B.
• Use a condom and practice safe sex.
• Avoid sharing personal items, such as razors or toothbrushes.
• Do not share drug needles or other drug equipment (such as straws for snorting drugs).
• Clean blood spills with a solution containing 1 part household bleach to 10 parts water.
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
[pic]
Estimate of disability-adjusted life year for hepatitis B per 100,000 inhabitants as of 2004.
| no data | 100-125 |
| 500 |
| 80-100 | |
[pic]
Prevalence of hepatitis B virus as of 2005.
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%. 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.
Complications
There is a much higher rate of hepatocellular carcinoma in people who have chronic hepatitis B than in the general population.
Other complications may include:
• Chronic persistent hepatitis
• Cirrhosis
• Fulminant hepatitis, which can lead to liver failure and possibly death
What is the scope of the problem?
Hepatitis B is estimated that 350 million individuals worldwide are infected with the virus, which causes 620,000 deaths worldwide each year.
According to the Centers for Disease Control (CDC), approximately 46,000 new cases of hepatitis B occurred in the United States in 2006.
In the United States, rates of new infection were highest among people aged 25 to 44 years (3.1 cases per 100,000 population) and lowest among those younger than 15 years of age (0.02 per 100,000).
This reflects the major modes of transmission of hepatitis B (sexual transmission, illicit drug use, exposure to infected blood) and the effect of universal vaccination of infants.
In the United States, there has been a 75% decrease in newly diagnosed cases of hepatitis B during the past decade.
This decrease is attributed to increased vaccination and to heightened public awareness of HIV/AIDS and the resulting safer sexual practices.
When a person first gets hepatitis B, they are said to have an 'acute' infection.
Most people are able to eliminate the virus and are cured of the infection.
Some are not able to clear the virus and have 'chronic' infection with hepatitis B that is usually life-long .
In the United States an estimated 800,000 to 1.4 million people are chronically infected with hepatitis B and the disease causes about 3000 deaths each year.
Hepatitis B is found throughout the world. Some countries have much higher rates of infection than the United States; for example, in Southeast Asia and Sub-Saharan Africa, as many as 15% to 20% of adults are chronically infected with hepatitis B.
The good news is that infection with HBV is usually preventable because there is an effective vaccine. Use of the vaccine has resulted in an 82% decrease in the number of new infections reported in the United States each year.
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Hepatitis C
Definition
Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV).
Explanation
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 130–170 million people worldwide are infected with hepatitis C.
The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proven in 1989.
Hepatitis C only infects 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 cause of liver transplantation, though the virus usually recurs after transplantation.
No vaccine against hepatitis C is available.
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.
Pathophysiology
The cause of hepatitis C, HCV, is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family and Flavivirus genus.
The natural targets of HCV are hepatocytes and, possibly, B lymphocytes.
Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells.
In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis.
Findings from studies suggest at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C.
RNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies.
These represent minor molecular variations with only 1-2% nucleotide heterogeneity.
HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development
Signs and symptoms
About 75% of people have no symptoms when they first acquire hepatitis C viral infection.
The remaining 25% may complain of fatigue, loss of appetite, muscle aches or fever.
Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection.
Over time, the liver in people with chronic infection may begin to experience the effects of the persistent inflammation caused by the immune reaction to the virus.
Blood tests may show elevated levels of liver enzymes, a sign of liver damage, which is often the first suggestion that the infection may be present.
Patients may become easily fatigued or complain of nonspecific symptoms.
As cirrhosis develops, symptoms increase and may include :
• weakness,
• loss of appetite,
• weight loss,
• breast enlargement in men,
• a rash on the palms,
• difficulty with the clotting of blood, and
• spider-like blood vessels on the skin.
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.
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.
Most experience minimal or no symptoms during the initial few decades of the infection, although chronic hepatitis C can be associated with fatigue.
Hepatitis C after many years becomes the primary cause of cirrhosis and liver cancer.
About 10–30% of people develop cirrhosis over 30 years.
Cirrhosis is more common in those co-infected with hepatitis B or HIV, alcoholics, and those of male gender.
Those who develop cirrhosis have a 20-fold greater risk of hepatocellular carcinoma, a rate of 1–3% per year, and if this is complicated by excess alcohol the risk becomes 100 fold greater.
Hepatitis C is the cause of 27% of cirrhosis cases and 25% of hepatocellular carcinoma worldwide.
Liver cirrhosis may lead to portal hypertension, ascites (accumulation of fluid in the abdomen), easy bruising or bleeding, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy.
It is a common cause for requiring a liver transplant.
Extrahepatic
Hepatitis C is also rarely associated with Sjögren's syndrome (an autoimmune disorder), thrombocytopenia, lichen planus, diabetes mellitus, and B-cell lymphoproliferative disorders.
Thrombocytopenia is estimated to occur in 0.16% to 45.4% of people with chronic hepatitis C.
Putative associations with Hyde's prurigo nodularis and membranoproliferative glomerulonephritis have been reported.
Hepatitis C infection is also associated with a condition called mixed cryoglobulinemia, which is inflammation of small and medium sized blood vessels (or vasculitis) caused by deposition of immune complexes involving cryoglobulins.
Virology
.
[pic]
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 indicated numerically from one to seven.
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 HCV genome consists of a single, open reading frame and 2 untranslated, highly conserved regions, 5'-UTR and 3'-UTR, at both ends of the genome.
The genome has approximately 9500 base pairs and encodes a single polyprotein of 3011 amino acids that are processed into 10 structural and regulatory proteins (see the image below).
[pic]Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.
Structural components include the core and 2 envelope proteins, E1 and E2.
Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, thought to result from selective pressure by virus-specific antibodies.
The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV.
The nonstructural components include NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7, whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown.
One region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity–determining region.
These enzymes are critical in viral replication and are attractive targets for future antiviral therapy.
HCV genomic analysis by means of arduous gene sequencing of many viruses has led to the division of HCV into 6 genotypes based on homology.
Numerous subtypes have also been identified.
Arabic numerals denote the genotype, and lower-case letters denote the subtypes for lesser homology within each genotype.
Genotypes
Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level.
The major HCV genotype worldwide is genotype 1, which accounts for 40-80% of all isolates.
Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC.
Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent.
HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype details are as follows:
• Genotype 1a occurs in 50-60% of patients in the United States; this type is difficult to eradicate using current medications
• Genotype 1b occurs in 15-20% of patients in the United States; subtype 1b is also difficult to eradicate using current medications; this type is most prevalent in Europe, Turkey, and Japan
• Genotype 1c occurs in less than 1% of patients in the United States
• Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication
• Genotypes 3a and 3b occur in 4-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland
• Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa
• Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa
• Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao
Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among persons in Scotland who abuse intravenous drugs.
Transmission
[pic]
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%.
While twelve countries had rates greater than 80%. Occurrence of hepatitis C among prison inmates in the United States are ten 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 transplantation 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 of blood to 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 acquiring hepatitis C and their blood testing positive depending on the method.
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 a risk factor.
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 only recommends condom use to prevent hepatitis C transmission in those with multiple partners.
Body piercings
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.
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
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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.
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 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.
Liver enzymes are variable during the initial part of the infection and on average begin to rise at seven weeks after infection.
Liver enzymes are poorly related with 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 only 5–50% of those infected in the United States and Canada become aware of their status.
Testing is recommended in those at high risk, which includes 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.
However, in 2012, the U.S. Centers for Disease Control and Prevention (CDC) recommended a single screening test for those born between 1945 and 1965.
Prevention
As of 2011, no vaccine protects against contracting hepatitis C.
However, a number are 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.
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.
Prognosis
Responses to treatment vary by genotype. Sustained response is about 40-50% in people with HCV genotype 1 given 48 weeks of treatment.
Sustained response is seen in 70-80% of people with HCV genotypes 2 and 3 with 24 weeks of treatment.
Sustained response is about 65% in those with genotype 4 given 48 weeks of treatment.
The evidence for treatment in genotype 6 disease is sparse, and the evidence that exists is for 48 weeks of treatment at the same doses as are used for genotype 1 disease.
Epidemiology
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Prevalence of hepatitis C worldwide in 1999
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Disability-adjusted life year for hepatitis C in 2004 per 100,000 inhabitants
| no data | 35-40 |
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It is estimated that 130–170 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.
Rates have increased substantially in the 20th century due to a combination of IDU and intravenous medication or poorly sterilized medical equipment.
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.
Prevalence 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.
[pic]Hepatitis C. Causes of chronic liver disease
Hepatitis D
Definition
Hepatitis D, also referred to as hepatitis D virus (HDV) and classified as Hepatitis delta virus, is a disease caused by a small circular enveloped RNA virus.
Explanation
It is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a subviral satellite because it can propagate only in the presence of the hepatitis B virus (HBV).
Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).
Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone.
These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased chance of developing liver cancer in chronic infections.
In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.
History
Hepatitis D virus was first reported in the mid-1977, by an Italian researcher, Mario Rizzetto, as a nuclear antigen in patients infected with HBV who had severe liver disease .
This nuclear antigen was then thought to be a hepatitis B antigen and was called the delta antigen.
Subsequent experiments in chimpanzees showed that the hepatitis delta antigen (HDAg) was a structural part of a pathogen that required HBV infection to replicate.
The entire virus was cloned and sequenced in 1986, and obtained its own genus deltavirus
Virology
Structure and Genome
|Hepatitis delta virus delta antigen |
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The HDV is a small, spherical virus with a 36 nm diameter.
It has an outer coat containing three HBV envelope proteins (called large, medium, and small hepatitis B surface antigens, and host lipids surrounding an inner nucleocapsid.
The nucleocapsid contains single-stranded, circular RNA of 1679 nucleotides and about 200 molecules of hepatitis D antigen (HDAg) for each genome.
The central region of HDAg has been shown to bind RNA.
Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg.
The hepatitis D circular genome is unique to animal viruses because of its high GC nucleotide content.
The HDV genome exists as an enveloped negative sense, single-stranded, closed circular RNA nucleotide sequence is 70% self-complementary, allowing the genome to form a partially double stranded RNA structure that is described as rod-like.
With a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals.
It has been proposed that HDV may have originated from a class of plant viruses called viroids.
Life Cycle
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The receptor that HDV recognizes on human hepatocytes has not been identified; however it is thought to be the same as the HBV receptor because both viruses have the same outer coat.
HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg.
Mapping by mutagenesis of this domain has shown that aminoacid residues 9-15 make up the receptor binding site.
After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg Since the nucleocapsid does not contain an RNA polymerase to replicate the virus’ genome, the virus makes use of the cellular RNA polymerases
Initially just RNA pol II, now RNA polymerases I and III have also been shown to be involved in HDV replication.
Normally RNA polymerase II utilizes DNA as a template and produces mRNA.
Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.
The RNA polymerases treat the RNA genome as double stranded DNA due to the folded rod-like structure it is in.
Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg.
Synthesis of antigenomic RNA occurs in the nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II.
HDV RNA is synthesized first as linear RNA that contains many copies of the genome.
The genomic and antigenomic RNA contain a sequence of 85 nucleotides that acts as a ribozyme, which self-cleaves the linear RNA into monomers.
This monomers are then ligated to form circular RNA.
There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity.
Delta antigens
A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV is known to produce one protein, namely HDAg.
It comes in two forms; a 27kDa large-HDAg, and a small-HDAg of 24kDa.
The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg.
Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg.
However, editing by cellular enzyme adenosine deaminase-1 changes the stop codon to UCG, allowing the large-HDAg to be produced .
Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection.
HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication.
HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles.
Thus RNA editing by the cellular enzymes is critical to the virus’ life cycle because it regulates the balance between viral replication and virion assembly.
Evolution
Three genotypes (I-III) were originally described.
Genotype I has been isolated in Europe, North America, Africa and some Asia.
Genotype II has been found in Japan, Taiwan, and Yakutia (Russia).
Genotype III has been found exclusively in South America (Peru, Colombia, and Venezuela).
Some genomes from Taiwan and the Okinawa islands have been difficult to type but have been placed in genotype 2.
However it is not known that there are at least 8 genotypes of this virus (HDV-1 to HDV-8).
Phylogenetic studies suggest an African origin for this pathogen.
Hepatitis D Symptoms
When a person becomes infected with the hepatitis D virus (HDV), the virus begins to multiply within the liver.
Fourteen days to 180 days later, a person may develop hepatitis D symptoms.
However, not everyone infected with the hepatitis D virus will actually have symptoms.
Also, some of the people who do develop symptoms will have only very mild symptoms.
You can look and feel perfectly healthy, yet still be infected with the disease and infect others.
Specific Hepatitis D Symptoms
For a person with hepatitis D, symptoms (especially early symptoms) may include one or several of the following:
• Fatigue
• Excessive tiredness
• Not feeling very hungry
• Nausea or vomiting
• Diarrhea
• A low-grade fever
• Muscle pain
• Joint pain
• Sore throat
• Mild abdominal pain (or stomach pain)
• Dark urine
• Light-colored stool.
Oftentimes, these early symptoms may be confused with those commonly seen with the stomach flu .
Jaundice (yellowing of the skin or the whites of the eyes) usually occurs several days after early symptoms of hepatitis D first appear.
However, it may occur up to two weeks after symptoms begin.
At this point, early symptoms tend to improve; but other new symptoms, such as abdominal pain (or stomach pain) on the right side, may appear.
Clinical features
An HDV infection absolutely requires an associated HBV infection.
The outcome of disease largely depends on whether the two viruses infect simultaneously (coinfection), or whether the newly HDV-infected person is a chronically infected HBV carrier (superinfection).
Coinfection of HBV and HDV (simultaneous infection with the two viruses) results in both acute type B and acute type D hepatitis.
The incubation period depends on the HBV titre of the infecting inoculum.
Depending on the relative titres of HBV and HDV, a single bout or two bouts of hepatitis may be seen.
Coinfections of HBV and HDV are usually acute, self-limited infections.
The chronic form of hepatitis D is seen in less than 5% of HBV - HDV coinfected patient.
Acute hepatitis D occurs after an incubation period of 3 - 7 weeks, and a preicteric phase begins with symptoms of
• fatigue,
• lethargy,
• anorexia and
• nausea, lasting usually 3 to 7 days.
During this phase, ALT and AST activities become abnormal.
The appearance of jaundice is typical at the onset of the icteric phase.
Fatigue and nausea persist, clay-colored stools and dark urine appear, and serum bilirubin levels become abnormal.
In patients with acute, self-limiting infection, convalescence begins with the disappearance of clinical symptoms.
Fatigue may persist for longer periods of time.
Superinfection of HBV and HDV (HDV infection of a chronically infected HBV carrier) causes a generally severe acute hepatitis with short incubation time that leads to chronic type D hepatitis in up to 80% of cases.
Superinfection is associated with fulminant acute hepatitis and severe chronic active hepatitis, often progressive to cirrhosis.
During the acute phase of HDV infection, synthesis of both HBsAg and HBV DNA are inhibited until the HDV infection is cleared.
Chronic viral hepatitis D is usually initiated by a clinically apparent acute infection.
Symptoms are less severe than in acute hepatitis, and while serum ALT and AST levels are elevated, bilirubin and albumin levels and prothrombin time may be normal.
In chronic hepatitis D, the HBV markers are usually suppressed.
Progression to cirrhosis usually takes 5 - 10 yrs, but it can appear 2 years after onset of infection.
About 60 to 70% of patients with chronic hepatitis D develop cirrhosis. A high proportion of these patients die of hepatic failure.
Hepatocellular carcinoma (HCC) occurs in chronically infected HDV patients with advanced liver disease with the same frequency as in patients with ordinary hepatitis B.
HCC may actually be more a secondary effect of the associated cirrhosis than a direct carcinogenic effect of the virus.
Taken together, three phases of chronic hepatitis D have been proposed:
a) an early active phase with active HDV replication and suppression of HBV,
b) a second moderately active one with decreasing HDV and reactivating HBV,
c) a third late one with development of cirrhosis and hepatocellular carcinoma caused by replication of either virus or with remission resulting from marked reduction of both viruses.
Complications
One serious complication that can occur during this acute hepatitis D infection is fulminant hepatitis -- a serious condition that results in liver failure.
Up to 5 percent of people who get infected with the hepatitis B virus at the same time as the hepatitis D virus will develop fulminant hepatitis.
Up to 20 percent of people with chronic hepatitis B will develop fulminant hepatitis with an acute hepatitis D infection.
Fulminant viral hepatitis is rare, but still about 10 times more common in hepatitis D than in other types of viral hepatitis.
It is characterized by hepatic encephalopathy showing changes in
• personality,
• disturbances in sleep,
• confusion
• difficulty concentrating,
• abnormal behavior,
• somnolence and
• coma.
The mortality rate of fulminant hepatitis D reaches 80%.
Liver transplantation is indicated.
Some factors that can increase the risk of developing fulminant hepatitis include:
• Being older
• Having severe liver disease (cirrhosis)
• Having had a liver transplant.
Transmission
The routes of transmission of hepatitis D are similar to those for hepatitis B.
Infection is largely restricted to persons at high risk of hepatitis B infection, particularly injecting drug users and persons receiving clotting factor concentrates.
Worldwide more than 15 million people are co-infected.
HDV is rare in most developed countries, and is mostly associated with intravenous drug use.
However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America.
In all, about 20 million people may be infected with HDV.
Treatment and Prevention
There is no vaccine for Hepatitis D virus, but there is a vaccine for Hepatitis B.
Hepatitis D needs the presence of the Hepatitus B virus in order become infectous.
Hepatitis E
Definition
Hepatitis E is a viral hepatitis (liver inflammation) caused by infection with a virus called hepatitis E virus (HEV).
HEV is a positive-sense single-stranded RNA icosahedral virus with a 7.5 kilobase genome.
HEV has a fecal-oral transmission route.
It is one of five known hepatitis viruses: A, B, C, D, and E.
Infection with this virus was first documented in 1955 during an outbreak in New Delhi, India.
Explanation
Every year there are 20 million hepatitis E infections, over three million acute cases of hepatitis E, and 70 000 hepatitis E-related deaths.
Hepatitis E is usually self-limiting but may develop into fulminant hepatitis (acute liver failure).
The hepatitis E virus is transmitted via the faecal-oral route, principally via contaminated water.
Hepatitis E is found worldwide, but the prevalence is highest in East and South Asia.
China has produced and licensed the first vaccine to prevent hepatitis E virus infection, although it is not yet available globally.
Globally, there are approximately 20 million incident hepatitis E infections every year.
Virology
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Although it was originally classified in the Caliciviridae family, the virus has since been classified into the genus Hepevirus, but was not assigned to a viral family.
The virus itself is a small non-enveloped particle.
The genome is approximately 7200 bases in length, is a polyadenylated single-strand RNA molecule that contains three discontinuous and partially overlapping open reading frames (ORFs) along with 5' and 3' cis-acting elements, which have important roles in HEV replication and transcription.
ORF1 encode a methyltransferase, protease, helicase and replicase; ORF2 encode the capsid protein and ORF3 encodes a protein of undefined function.
A three-dimensional, atomic-resolution structure of the capsid protein in the context of a virus-like particle has been described.
An in vitro culture system is not yet available.
As of 2009 there are approximately 1,600 sequences of both human and animal isolates of HEV available in open-access sequence databases.
Species of this genus infect humans, pigs, boars, deer, rats, rabbits and birds.
Epidemology
There is only one serotype of the virus and classification is based on the nucleotide sequences of the genome.
Genotype 1 has been classified into five subtypes.
The number of genotype 2 can be classified into two subtypes.
Genotypes 3 and 4 have been into ten and seven subtypes respectively.
Hepatitis E is found worldwide and different genotypes of the hepatitis E virus determine differences in epidemiology.
For example, genotype 1 is usually seen in developing countries and causes community level outbreaks while genotype 3 is usually seen in the developed countries and does not cause outbreaks.
Globally, 70 000 deaths and 3.4 million cases of acute hepatitis E are attributable to infection with hepatitis E virus genotypes 1 and 2.
The highest seroprevalence rates (number of persons in a population who test positive for the disease) are observed in regions where low standards of sanitation increase the risk for transmission of the virus.
Over 60% of all hepatitis E infections and 65% of all hepatitis E deaths occur in East and South Asia, where seroprevalence rates of 25% are common in some age groups.
In Egypt, half the population aged above five years is serologically positive for the hepatitis E virus.
Recent outbreaks
In 2004, there were two major outbreaks, both of them in sub-Saharan Africa.
There was an outbreak in Chad in which, as of September 27, there were 1,442 reported cases and 46 deaths.
The second was in Sudan with, as of September 28, 6,861 cases and 87 deaths.
Increasingly, hepatitis E is being seen in developed nations, with reports of cases in the UK, US and Japan.
The disease is thought to be a zoonosis in that animals are thought to be the source. Both deer and swine have been implicated.
In 2011, a minor outbreak was reported in Tangail, a neighborhood of Dhaka, Bangladesh.
In June 2012, an outbreak was reported in city of Ichalkaranji, Maharashtra, India.
As of June 14, 2012, 3232 cases were reported and 18 died. and 3 died in Shirol taluka of Kolhapur Maharashtra ,India in june 2012
In July 2012, an outbreak was reported in South Sudanese refugee camps in Maban County near the Sudan border.
South Sudan's Ministry of Health reported over 400 cases and 16 fatalities.
Animals as a reservoir
Domestic animals have been reported as a reservoir for the hepatitis E virus, with some surveys showing infection rates exceeding 95% among domestic pigs.
Transmission after consumption of wild boar meat and uncooked deer meat has been reported as well.
The rate of transmission to humans by this route and the public health importance of this are, however, still unclear.
A number of other small mammals have been identified as potential reservoirs:
• the lesser bandicoot rat (Bandicota bengalensis),
• the black rat (Rattus rattus brunneusculus) and
• the Asian house shrew (Suncus murinus).
A new virus designated rat hepatitis E virus has been isolated.
An avian virus has been described that is associated with hepatitis-splenomegaly syndrome in chickens.
This virus is genetically and antigenically related to mammalian HEV, and probably represents a new genus in the family.
Replicative virus has been found in the small intestine, lymph nodes, colon and liver of experimentally infected pigs.
Transmission
The hepatitis E virus is transmitted mainly through the faecal-oral route due to faecal contamination of drinking water. Other transmission routes have been identified, which include:
• foodborne transmission from ingestion of products derived from infected animals;
• zoonotic transmission from animals to humans;
• transfusion of infected blood products;
• vertical transmission from a pregnant woman to her fetus.
Although humans are considered the natural host for the hepatitis E virus, antibodies to the hepatitis E virus or closely related viruses have been detected in primates and several other animal species.
Hepatitis E is a waterborne disease, and contaminated water or food supplies have been implicated in major outbreaks.
The ingestion of raw or uncooked shellfish has also been identified as the source of sporadic cases in endemic areas.
The risk factors for hepatitis E are related to poor sanitation in large areas of the world and shedding of the hepatitis E virus in faeces.
Symptoms
The incubation period following exposure to the hepatitis E virus ranges from three to eight weeks, with a mean of 40 days.
The period of communicability is unknown.
The hepatitis E virus causes acute sporadic and epidemic viral hepatitis.
Symptomatic infection is most common in young adults aged 15–40 years.
Although infection is frequent in children, the disease is mostly asymptomatic or causes a very mild illness without jaundice (anicteric) that goes undiagnosed.
Typical signs and symptoms of hepatitis include:
• jaundice (yellow discoloration of the skin and sclera of the eyes, dark urine and pale stools);
• anorexia (loss of appetite);
• an enlarged, tender liver (hepatomegaly);
• abdominal pain and tenderness;
• nausea and vomiting;
• fever.
These symptoms are largely indistinguishable from those experienced during any acute phase of hepatic illness and typically last for one to two weeks.
In rare cases, acute hepatitis E can result in fulminant hepatitis (acute liver failure) and death.
Overall population mortality rates from hepatitis E range from 0.5% to 4.0%.
Fulminant hepatitis occurs more frequently during pregnancy.
Pregnant women are at greater risk of obstetrical complications and mortality from hepatitis E, which can induce a mortality rate of 20% among pregnant women in their third trimester.
Cases of chronic hepatitis E infection have been reported in immunosuppressed people.
Reactivation of hepatitis E infection has also been reported in immunocompromised people.
Diagnosis
Cases of hepatitis E are not clinically distinguishable from other types of acute viral hepatitis.
Diagnosis of hepatitis E infection is therefore usually based on the detection of specific antibodies to the virus in the blood.
Two additional diagnostic tests require specialized laboratory facilities and are used only in research studies.
These are:
• reverse transcriptase polymerase chain reaction (RT-PCR) to detect the hepatitis E virus RNA;
• immune electron microscopy to detect the hepatitis E virus.
Hepatitis E should be suspected in outbreaks of waterborne hepatitis occurring in developing countries, especially if the disease is more severe in pregnant women, or if hepatitis A has been excluded.
Treatment
There is no available treatment capable of altering the course of acute hepatitis.
Prevention is the most effective approach against the disease.
As hepatitis E is usually self-limiting, hospitalization is generally not required.
However, hospitalization is required for people with fulminant hepatitis and should also be considered for infected pregnant women.
Prevention
The risk of infection and transmission can be reduced by:
• maintaining quality standards for public water supplies ;
• establishing proper disposal systems to eliminate sanitary waste.
On an individual level, infection risk can be reduced by:
• maintaining hygienic practices such as hand washing with safe water, particularly before handling food;
• avoiding drinking water and/or ice of unknown purity;
• avoiding eating uncooked shellfish, and uncooked fruits or vegetables that are not peeled or that are prepared by people living in or travelling in highly endemic countries.
• A vaccine based on recombinant viral proteins has been developed and recently tested in a high-risk population (military personnel of a developing country).
• The vaccine appeared to be effective and safe, but further studies are needed to assess the long-term protection and the cost-effectiveness of hepatitis E vaccination.
• In 2011, the first vaccine to prevent hepatitis E infection was registered in China.
• A different vaccine (HEV 239, sold as Hecolin by its developer Xiamen Innovax Biotech) was approved for the disease in 2012 by the Chinese Ministry of Science and Technology, following a phase 3 trial on two groups of 50,000 people each from Jiangsu Province where none of the vaccinated became infected during a 12 month period, compared to 15 in the group given placebo treatment.
Although it is not available globally, it could potentially become available in a number of other countries.
Guidelines for epidemic measures
In epidemics, WHO recommends:
• determining the mode of transmission;
• identifying the population specifically exposed to increased risk of infection;
• eliminating a common source of infection;
• improving sanitary and hygienic practices to eliminate faecal contamination of food and water.
WHO response
WHO is working in the following areas to prevent and control viral hepatitis:
• raising awareness, promoting partnerships and mobilizing resources;
• evidence-based policy and data for action;
• prevention of transmission; and
• screening, care and treatment.
WHO also organizes World Hepatitis Day on 28 July every year to increase awareness and understanding of viral hepatitis
Hepatitis F
Definition
Hepatitis F is a hypothetical virus linked to hepatitis.
Several hepatitis F candidates emerged in the 1990s; none of these reports have been substantiated.
Virology
Hepatitis F is a new virus in the Hepatitis family, that is affecting may people worldwide.
A disease that became more evident in the 1990s, this virus has often been referred to as the ‘non-existent virus’ or even a ‘hypothetical virus’.
The virus is also called as VLP or Virus like Particles because of their small size.
Soon, the virus affects the liver like all other cases of Hepatitis and around 20% of cases result in fatality.
In 1994, Deka et al. reported that novel viral particles had been discovered in the stool of post-transfusion, non-hepatitis A, non-hepatitis B, non-hepatitis C, non-hepatitis E patients.
Injection of these particles into the bloodstream of Indian rhesus monkeys caused hepatitis, and the virus was named hepatitis F or Toga virus.
Further investigations failed to confirm the existence of the virus, and it was delisted as a cause for infectious hepatitis.
A subsequently-discovered virus thought to cause hepatitis was named Hepatitis G virus, though its role in hepatitis has not been confirmed and it is now considered synonymous with GB virus C and is an "orphan virus" with no causal links to any human disease.
Hepatitis F’s discovery
After scientists discovered Hepatitis A, B, C, D and E, they noticed another strand of Hepatitis virus that couldn’t exactly be classified within the reaches of these 5 types.
Sometimes between 1991 and 1992, Japanese doctors noticed that this was a completely new class of virus and named it Hepatitis F.
It was in 1993 that Hepatitis F was termed as a mutant virus from HBV in Japan and this was verified by the help of a PCR study.
Further studies were done until 1994, when this virus was understood better by means of experimentations and lab examinations and doctors were better able to understand the symptoms of Hepatitis F and its treatment.
symptoms
Like other forms of Hepatitis, Hepatitis F also has symptoms that include:
• Abdominal pain
• Vomiting
• Fatigue and fever
• Appetite loss
• Jaundice or dark yellow urine
• Nausea & Diarrhea
• Anorexia
It is also accompanied by joint pain and a rash, though this symptom is seen only at the last stages of the disease.
Diagnosis
To diagnose Hepatitis F is very important in order for the patient to get the right medical treatment.
Since the disease can be fatal, timely treatment is based on accurate diagnostics.
The doctor will study a variety of things
• Patient’s medical history
• Sexual activity
• Surgeries done in the past
Based on these, the doctor will recommend a liver panel test along with blood tests to diagnose the disease.
Some doctors will also suggest a RIBA II and ELISA II tests.
In certain cases, diagnosis becomes very difficult which will create the need for a liver biopsy.
Since the right treatment is very important, the patient will need to undergo a small treatment where a small tissue sample of the liver will be studied under the microscope to give more accurate results.
Fact is; since the Hepatitis F virus is a fairly new virus, the tests and diagnostics to accurately pin point the disease is not yet very advanced.
Treatment
Currently, there is no cure for Hepatitis F. since the virus is fairly new and a mutant of the HBV virus, many scientists and doctors around the globe are working round the clock to come up with a cure.
Until medicines and vaccination for curing Hepatitis F are discovered, the doctor can do nothing more than trying to treat the immediate symptoms of the disease to bring comfort to the patient.
This is why diagnosing Hepatitis F timely is so important.
If the doctors can detect the Hepatitis F virus early on, the case for survival improves in patients.
Hepatitis G
Definition
Hepatitis G is a liver disease or rather inflammation of liver that is caused by the hepatitis G virus or the HGV.
Virology
The HGV is the newly discovered far off relative of the hepatitis C virus.
The other term for HGV is GB.
The virus is benign is nature.
It was mentioned for the first time in the early 1996.
Not much is known about the nature of sickness HGV causes or the infection frequency or the prevention procedure and so on.
Transmission
Reports reveal that most cases of hepatitis were due to transfusion of blood containing the HGV virus.
Thus patients with conditions like hemophilia or any other condition that demands the supply of blood were highly susceptible to getting hepatitis G.
Also
• health care workers,
• hemodialysis patients,
• injected drug users,
• acupuncturists,
• those who use tattoos or
• other body piercing arts etc
can contact hepatitis G infection.
Furthermore infected mothers can transfer the virus to her newborn.
So can the virus be sexually transmitted as well.
Causes & Symptoms
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Whether hepatitis G actually makes one sick is not very clear.
Some believe it does whereas some believe it does not.
Some researchers hold the opinion that the sickness is mild whereas others think it is chronic enough to lead to a liver failure even.
Some researchers believe that a single HGV acts on the liver whereas others believe that the virus acts in a group to produce a cumulative result.
In some cases Hepatitis G co-exists with HIV or Hepatitis C virus and often go undiagnosed since it shows up no symptom and remains in latent form for as long as nine years at a stretch.
Diagnosis & treatment
Diagnosis plays a key role in the treatment of any disease.
It is in fact the first step towards treatment.
Without proper diagnosis you cannot at all treat a disease.
The means of detecting or diagnosing hepatitis G is the DNA test.
It is the only diagnosis means and quite an expensive one.
The DNA diagnosis procedure is a complicated procedure and is not very much available.
Efforts are being made however to generate an assay for the HGV antibody which develops as a result of the virus invasion
Hepatitis G: Do’s & Don’ts
A patient with Hepatitis G has to observe the following ‘do’s’ and ‘don’ts’:
• He should not consume fatty or spice-rich food and also should limit the intake of protein.
• He should get adequate rest and sleep.
• He should stay away from alcohol.
• He should not smoke.
• He should dink at least 8-10 glasses of water per day to flush out the toxins.
• He should curb the intake of caffeinated beverages.
• He should live a stress-free life. He should practice yoga and meditation to get rid of his stress
• He should practice light free-hand exercises
• He should use contraceptive measures while indulging in sexual activities
• He should take his medicines timely and go for timely check-ups
Autoimmune Hepatitis
Definition
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver.
Anomalous presentation of human leukocyte antigen (HLA) class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis.
This abnormal immune response results in inflammation of the liver, which can lead to further complications, including cirrhosis.
Immune serum markers frequently are present, autoantibodies against liver-specific and non–liver-specific antigens and increased immunoglobulin G (IgG) levels.
The disease often is associated with other autoimmune diseases.
Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.
Explanation
Autoimmune hepatitis has an incidence of 1-2 per 100,000 per year, and a prevalence of 10-20/100,000.
As with most other autoimmune diseases, it affects women much more often than men (70%).
Liver enzymes are elevated, as may be bilirubin.
Historical background
In 1950, Waldenstrom first described a form of chronic hepatitis in young women.
This condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked hypergammaglobulinemia.
Kunkel, in 1950, and Bearn, in 1956, described other features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea.
In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis.
This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956.
Researchers currently know that no direct link exists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis; thus, lupoid hepatitis is not associated with SLE.
The development of viral serologic tests represented another important step forward.
These permitted hepatologists to differentiate chronic viral hepatitis from other types of chronic liver disease, including autoimmune hepatitis.
Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and females of all ages.
This condition can coexist with other liver diseases (eg, chronic viral hepatitis) and also may be triggered by certain viral infections (eg, hepatitis A) and chemicals (eg, minocycline).
The histopathologic description of autoimmune hepatitis has undergone several revisions over the years.
In 1992, an international panel codified the diagnostic criteria.
The term autoimmune hepatitis was selected to replace terms such as autoimmune liver disease and autoimmune chronic active hepatitis.
The panel waived the requirement of 6 months of disease activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and reaffirmed the nonviral nature of the disease.
The panel also designated incompatible histologic features, such as cholestatic histology, the presence of bile duct injury, and ductopenia.
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Etiology
The etiology of autoimmune hepatitis is unknown.
Several factors (eg, viral infection, drugs, environmental agents) may trigger an autoimmune response and autoimmune disease.
In a few patients with autoimmune hepatitis, illness onset follows acute hepatitis A, hepatitis B, or Epstein-Barr virus infections.
Autoantibodies are common in patients with chronic hepatitis C virus (HCV) infection.
Some patients with chronic HCV infection exhibit liver-kidney microsomal type 1 (LKM-1) antibody.
Some cases of drug-induced liver disease have an immune-mediated basis.
A number of drugs (eg, methyldopa, nitrofurantoin, minocycline, adalimumab, infliximab,) can produce an illness with the clinical features of autoimmune hepatitis.
Although most cases improve when the drug is stopped, chronic cases of autoimmune hepatitis may be seen, even after drug withdrawal.
Casswall et al found Helicobacter species DNA in 50% of liver biopsies from patients with autoimmune hepatitis and ulcerative colitis.
Classification
Four subtypes are recognised, but the clinical utility of distinguishing subtypes is limited.
1. positive ANA and SMA, elevated immunoglobulin G (classic form, responds well to low dose steroids);
2. positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3;
3. positive antibodies against soluble liver antigen (this group behaves like group 1) (anti-SLA, anti-LP)
4. no autoantibodies detected (~20%)
Clinical features
Clinical features of autoimmune hepatitis widely vary.
Most cases have an insidious onset.
Patients may be asymptomatic or have nonspecific symptoms (eg, fatigue, anorexia, weight loss, behavioral changes, amenorrhea).
Systemic or cutaneous abnormalities occur in 25% of patients.
Epistaxis, bleeding gums, and bruises with minimal trauma are frequent complaints.
Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established cirrhosis.
Autoimmune hepatitis rarely presents as fulminant hepatic failure.
Approximately one third of patients present with symptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice.
In some patients, the acute illness may appear to resolve spontaneously; however, patients invariably develop signs and symptoms of chronic liver disease.
Other patients experience rapid progression of the disease to acute liver failure, as marked by coagulopathy and jaundice.
Ascites and hepatic encephalopathy also may ensue.
The chronic hepatitis associated with autoimmune hepatitis may range in severity from a subclinical illness without symptoms and with abnormal results on liver chemistries to a disabling chronic liver disease.
Symptoms and physical examination findings may stem from the various extrahepatic diseases associated with autoimmune hepatitis.
Common symptoms include the following:
• Fatigue
• Upper abdominal discomfort
• Mild pruritus
• Anorexia
• Myalgia
• Diarrhea
• Cushingoid features
• Arthralgias
• Skin rashes (including acne)
• Edema
• Hirsutism
• Amenorrhea
• Chest pain from pleuritis
• Weight loss and intense pruritus (unusual)
Many patients have histologic evidence of cirrhosis at the onset of symptoms.
This is true both for patients with an initial presentation of acute hepatitis and for patients with chronic hepatitis.
Thus, subclinical disease often precedes the onset of symptoms.
As many as 20% of patients present initially with signs of decompensated cirrhosis.
In other patients, chronic hepatitis progresses to cirrhosis after years of unsuccessful immunosuppressant therapy marked by multiple disease relapses.
This is said to occur in 20-40% of patients.
Patients with cirrhosis may experience classic symptoms of portal hypertension, namely variceal bleeding, ascites, and hepatic encephalopathy.
Patients with complications of cirrhosis should be referred for consideration of liver transplantation.
Associated disease
Autoimmune hepatitis, especially type 2, is associated with a wide variety of other disorders.
Involvement of other systems may present at disease onset or may develop during the course of active liver disease.
Most of these conditions are immunologic in origin.
Patients may present with manifestations of the following hematologic disorders:
• Hypersplenism
• Autoimmune hemolytic anemia
• Coombs-positive hemolytic anemia
• Pernicious anemia
• Idiopathic thrombocytopenic purpura
• Eosinophilia
Gastrointestinal disease associated with autoimmune hepatitis includes inflammatory bowel disease, which is seen in 6% of cases.
The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt performance of cholangiography to exclude primary sclerosing cholangitis (PSC).
A study of 140 pediatric patients with autoimmune hepatitis, autoimmune cholangitis, and overlap syndrome identified 23 patients with celiac disease.
Associated endocrinologic conditions include Graves disease (6%) and autoimmune thyroiditis (12%).
Associated rheumatologic complications include the following:
• Rheumatoid arthritis and Felty syndrome
• Sjögren syndrome
• Systemic sclerosis
• Mixed connective-tissue disease
• Erythema nodosum
• Leukocytoclastic vasculitis (patients may present with leg ulcers)
Other associated conditions are as follows:
• Proliferative glomerulonephritis
• Fibrosing alveolitis
• Pericarditis and myocarditis
• Febrile panniculitis
• Lichen planus
• Uveitis
Pediatric presentation
In 1997, Gregorio et al published a series of 52 cases of autoimmune hepatitis in children (32 children with autoimmune hepatitis type 1 [AIH-1] and 20 children with autoimmune hepatitis type 2 [AIH-2]).
The following summary of clinical features of AIH was based on 20 years of treating these children at King's College Hospital.
Median patient ages were 10 years for AIH-1 and 7.4 years for AIH-2.
Other autoimmune disorders occurred in 20% of patients and 40% of their relatives; these included autoimmune thyroiditis, celiac disease, inflammatory bowel disease, diabetes mellitus, and other disorders.
AIH-2 can be part of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an autosomal recessive genetic disorder in which liver disease is reportedly present in about 20% of cases.
In 50% of the children, acute presentation mimicked acute viral hepatitis (ie, abdominal discomfort, vomiting, nausea, jaundice).
Fulminant hepatic failure occurred in 11% of the children and was more common in patients with AIH-2.
Insidious presentation was characterized by intermittent jaundice or nonspecific symptoms.
Routine blood analysis revealed incidental findings of abnormal liver enzymes.
Patients with autoimmune hepatitis developed cirrhosis and portal hypertension.
In 2005, Oettinger et al published a series of 142 children with autoimmune hepatitis.
Clinical findings included the following:
• Jaundice (58%)
• Nonspecific weakness (57%)
• Anorexia (47%)
• Abdominal pain (38%)
• Paleness (26%)
AIH-1 was found in 73% of the children, AIH-2 was found in 25% of the children, and 4 children could not be classified.
Liver biopsy showed active hepatitis (52%), cirrhosis (38%), and mild inflammatory activity (10%).
Additional autoimmune disorders often occur in children with autoimmune hepatitis.
In children with AIH-1, associated autoimmune disorders include the following:
• Ulcerative colitis
• Sclerosing cholangitis
• Arthritis
• Vasculitis
• Glomerulonephritis
• Diabetes mellitus
In children with AIH-2, associated autoimmune disorders include the following:
• Polyendocrinopathy
• Alopecia areata
• Diabetes mellitus
• Thyroiditis
Acute liver failure occurs primarily between the ages of 13 months and 4 years in children with AIH-2. It typically occurs after puberty in patients with AIH-1.
Symptoms in females
If the patient is classically a young female ,they may present with signs of chronic liver disease (cirrhosis, low albumin, spider nivae etc) or acute hepatitis (25% present with fever, jaundice, painful hepatomegaly etc).
Commonly, the patient will have amenorrhoea - this may be the presenting complaint.
The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers.
The genetic predisposition may relate to several defects in immunologic control of autoreactivity.
An environmental agent triggers the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated.
Genetic predisposition
Genetic susceptibility to developing autoimmune hepatitis has been associated with the HLA haplotypes B8, B14, DR3, DR4, and Dw3.
C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.
HLA-DR3–positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy and more often results in liver transplantation; in addition, these patients are younger than other patients at the time of their initial presentation.
HLA-DR4–positive patients are more likely to develop extrahepatic manifestations of their disease.
Patients with autoimmune hepatitis have low levels of T lymphocytes that express the CD8 marker and a specific defect in a subpopulation of T cells that controls the immune response to specific liver cell membrane antigens.
Autoimmune hepatitis has also been associated with the complement allele C4AQO, resulting in a partial deficiency of complement component C4.
C4 has a well-known role in virus neutralization; failure to eliminate viruses may lead to immune reaction against antigen on infected cells.
Environmental triggers
Among the several viruses implicated as triggering agents are rubella, Epstein-Barr, and hepatitis A, B, and C.
Some authors have shown a high amino acid sequence homology between hepatitis C virus (HCV) polyprotein and CYP2D6, the molecular target of liver-kidney microsomal type 1 (LKM-1) antibody, which suggests that molecular mimicry may trigger production of LKM-1 antibody in HCV infection.
Drugs may also trigger autoimmune hepatitis; however, no specific drug has been identified as an etiologic agent for autoimmune hepatitis.
Drug-metabolizing enzymes of phase 1 and phase 2 (ie, cytochrome P-450, uridine diphosphate glucuronosyltransferase proteins) are targets of virus-induced and drug-induced autoimmunity, as well as autoimmune hepatitis.
Pathogenesis
Current evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cell-mediated immunologic attack.
Aberrant display of human leukocyte antigen (HLA) class II on the surface of hepatocytes facilitates the exposure of normal liver cell membrane constituents to antigen-presenting cells (APCs).
APCs present hepatic antigens to uncommitted helper T lymphocytes (TH 0). APCs and helper T lymphocytes interact at the ligand-ligand level, which, in turn, activates TH 0.
This activation is followed by functional differentiation into helper T cell 1 (TH 1) or helper T cell 2 (TH 2), according to the cytokines prevailing in the tissue and the nature of the antigen.
TH 1 primarily secretes interleukin 2 (IL-2) and interferon gamma, which activate macrophages and enhance expression of HLA classes I and II, thus perpetuating the immune recognition cycle.
TH 2 cells primarily produce interleukins 4, 5, and 10, which stimulate autoantibody production by B lymphocytes.
The reasons for the aberrant HLA display are unclear.
It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection), and chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid).
The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens.
Physiologically, TH 1 and TH 2 cells antagonize each other.
Regulatory mechanisms strictly control the autoantigen recognition process; their failure perpetuates an autoimmune attack.
Liver cell injury can be caused by the action of cytotoxic lymphocytes that are stimulated by IL-2, complement activation, engagement of natural killer lymphocytes by the autoantibody bound to the hepatocyte surface, or reaction of autoantibodies with liver-specific antigens expressed on hepatocyte surfaces.
Autoantibody-coated hepatocytes from patients with autoimmune hepatitis are killed when incubated with autologous allogenic lymphocytes.
The effector cell was shown to be an Fc receptor-positive mononuclear cell.
Wen and others have shown that T-cell clones from liver biopsy specimens in children with autoimmune hepatitis who express the γ/δ T-cell receptor are preferentially cytotoxic to liver-derived cells.
Evidence for an autoimmune pathogenesis includes the following:
• Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells
• Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen, hepatic lectin)
• Association with hypergammaglobulinemia and the presence of a rheumatoid factor
• Association with other autoimmune diseases
• Response to steroid and/or immunosuppressive therapy
The autoantibodies described in these patients include the following:
• Antinuclear antibody (ANA), primarily in a homogeneous pattern
• Anti–smooth muscle antibody (ASMA) directed at actin
• Anti–liver-kidney microsomal antibody (anti–LKM-1)
• Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18
• Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin
• Antimitochondrial antibody (AMA) - AMA is the sine qua non of primary biliary cirrhosis (PBC) but may be observed in the so-called overlap syndrome with autoimmune hepatitis.
• Antiphospholipid antibodies.
Epidemiology
International statistics
The prevalence of autoimmune hepatitis is estimated to be 0.1-1.2 cases per 100,000 individuals in Western Europe.
The reported prevalence of autoimmune hepatitis in Europe ranges from 11.6-16.9 cases per 100,000 persons.
The reported prevelance is higher than the estimated prevalance.
This is approximately the same prevalence as primary biliary cirrhosis and twice as high as the prevalence of primary sclerosing cholangitis.
Autoimmune hepatitis accounts for about 3% of liver transplantations in Europe.
The reported prevalence in Japan is only 0.08-0.015 cases per 100,000 persons in Japan.
The ratio of incidence of AIH-1 to AIH-2 is
• 1.5-2:1 in Europe and Canada and
• 6-7:1 in North America, South America, and Japan.
AIH-2 is more commonly described in southern Europe than in northern Europe, the United States, or Japan.
In an analysis of data from 33,379 patients with liver cirrhosis, Michitaka et al concluded that autoimmune hepatitis is the etiologic agent in 1.9% of such cases in Japan.
Racial, sexual, and age-related differences in incidence
The disease is most common in whites of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers.
The Japanese population has a low frequency of HLA-DR3 markers. In Japan, autoimmune hepatitis is associated with HLA-DR4.
Women are affected more often than men (70-80% of patients are women).
Autoimmune hepatitis has a bimodal age distribution, with a first peak of incidence at age 10-20 years and a second at age 45-70 years.
Approximately one half of affected individuals are younger than 20 years; incidence peaks in premenstrual girls.
Patients with AIH-2 tend to be younger; 80% of patients with AIH-2 are children.
However, autoimmune hepatitis may occur in people of any age, including infants and older adults.
The diagnosis should not be overlooked in individuals older than 70 years.
Men may be affected more commonly than women in older age groups.
Physical Examination
Common findings on physical examination are as follows:
• Hepatomegaly (83%)
• Jaundice (69%)
• Splenomegaly (32%)
• Spider angiomata (58%)
• Ascites (20%)
• Encephalopathy (14%)
All of these findings may be observed in patients with disease that has progressed to the point of cirrhosis with ensuing portal hypertension.
However, hepatomegaly, jaundice, splenomegaly, and spider angiomata also may be observed in patients who do not have cirrhosis.
Complications
Complications may include the following:
• Cirrhosis and complications of cirrhosis (eg, ascites, coagulopathy, hepatic coma)
• Portal hypertension
• Esophageal varices
• Malnutrition (with poor growth in children)
GI tract bleeding as a complication of portal hypertension is usually rare.
Diagnosis
The diagnosis of autoimmune hepatitis is best achieved with a combination of clinical, laboratory and histological findings.
Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who has acute hepatitis or acute liver failure (defined by the new onset of coagulopathy).
The workup of such patients should include testing for :
• serum autoantibodies,
• serum protein electrophoresis, and
• quantitative immunoglobulins.
Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of acute autoimmune hepatitis.
A number of specific antibodies found in the blood
• antinuclear antibody (ANA),
• anti-Smooth Muscle Antibody (SMA),
• liver/kidney microsomal antibody (LKM-1, LKM-2, LKM-3)
• anti soluble liver antigen (SLA/LP) and
• anti-mitochondrial antibody (AMA)) are of use, as is finding an increased Immunoglobulin G level.
However, the diagnosis of autoimmune hepatitis always requires a liver biopsy.
Expert oppinion has been summarized by the International Autoimmune Hepatitis Group, which has published criteria which utilize clinical and laboratory data that can be used to help determine if a patient has autoimmune hepatitis.
Overlapping presentation with primary biliary cirrhosis and primary sclerosing cholangitis has been observed.
Laboratory findings in autoimmune hepatitis include the following:
• Elevated serum aminotransferase levels (1.5-50 times reference values)
• Elevated serum immunoglobulin levels, primarily immunoglobulin G (IgG)
• Seropositive results for ANAs, SMAs, or LKM-1 or anti–liver cytosol 1 (anti-LC1) antibodies
In 50% of patients, abnormal results on liver function tests include decreased albumin levels and prolonged prothrombin time.
Alcoholic hepatitis
Definition
Alcoholic hepatitis is hepatitis (inflammation of the liver) due to excessive intake of alcohol.
Explanation
It is usually found in association with hepatosteatosis, an early stage of alcoholic liver disease, and may contribute to the progression of fibrosis, leading to cirrhosis
Symptoms are jaundice, ascites (fluid accumulation in the abdominal cavity), fatigue and hepatic encephalopathy (brain dysfunction due to liver failure).
Mild cases are self-limiting, but severe cases have a high risk of death.
Symptoms and signs
Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen (ascites), and modest elevation of liver enzyme levels (as determined by liver function tests).
Alcoholic hepatitis can vary from mild with only liver enzyme elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and even liver failure.
Severe cases are characterized by either obtundation (dulled consciousness) or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both severe categories is 50% within 30 days of onset.
Alcoholic hepatitis is distinct from cirrhosis caused by long-term alcohol consumption.
Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis.
Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption.
Some alcoholics develop acute hepatitis as an inflammatory reaction to the cells affected by fatty change.
This is not directly related to the dose of alcohol.
Some people seem more prone to this reaction than others.
This is called alcoholic steatonecrosis and the inflammation probably predisposes to liver fibrosis.
Etiology and Pathophysiology
Some signs and pathological changes in liver histology include:
• Mallory's hyaline - a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.
• Ballooning degeneration - hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary ducts, leading to diffuse cholestasis.
• Inflammation - neutrophilic invasion is triggered by the necrotic changes and presence of cellular debris within the lobules. Ordinarily the amount of debris is removed by Kupffer cells, although in the setting of inflammation they become overloaded, allowing other white cells to spill into the parenchyma. These cells to hepatocytes with Mallory bodies.
If chronic liver disease is also present:
• Fibrosis
• Cirrhosis - a progressive and permanent type of fibrotic degeneration of liver tissue.
Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute.
Genetic, environmental, nutritional, metabolic, and immunologic factors, as well as cytokines and viral disease have been invoked.
Ethanol metabolism
Most tissues of the body, including the skeletal muscles, contain the necessary enzymes for the oxidative or nonoxidative metabolism of ethanol.
However, the major site of ethanol metabolism is the liver.
Within the liver, 3 enzyme systems—
• the cytosolic alcohol dehydrogenase (ADH) system,
• microsomal ethanol-oxidizing system (MEOS), and
• peroxisomal catalase system—can oxidize ethanol.
Cytosolic ADH uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent.
ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3 separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms may account for significant differences in ethanol elimination rates.
The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen.
The central enzyme of MEOS is cytochrome P-450 2E1 (CYP2E1).
This enzyme, in addition to catalyzing ethanol oxidation, is also responsible for the biotransformation of other drugs, such as acetaminophen, haloalkanes, and nitrosamines.
Ethanol upregulates CYP2E1, and the proportion of alcohol metabolized via this pathway increases with the severity and duration of alcohol use.
Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.
The product of all 3 reactions is acetaldehyde, which is then further metabolized to acetate by acetaldehyde dehydrogenase (ALDH).
Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.
Genetic factors
Although the evidence to prove a genetic predilection to alcoholism is adequate, the role of genetic factors in determining susceptibility to alcoholic liver injury is much less clear.
Most people who are alcoholics do not develop severe or progressive liver injury.
Attempts to link persons who are susceptible with specific human leukocyte antigen (HLA) groups have yielded inconsistent results, as have studies of genetic polymorphisms of collagen, ADH, ALDH, and CYP2E1.
Similar conclusions were reached in a meta-analysis of 50 studies pertaining to the association of alcoholic liver disease and genetic polymorphism.
Nonetheless, the fact remains that only a small fraction of even heavy alcoholics develop severe liver disease (ie, cirrhosis).
Thus, future case-control studies investigating the genetic basis of alcohol-induced liver disease are urgently needed.
The genetic factor that most clearly affects susceptibility is sex.
For a given level of ethanol intake, women are more susceptible than men to developing alcoholic liver disease
Malnutrition
Most patients with alcoholic hepatitis exhibit evidence of protein-energy malnutrition (PEM).
In the past, nutritional deficiencies were assumed to play a major role in the development of liver injury.
This assumption was supported by several animal models in which susceptibility to alcohol-induced cirrhosis could be produced by diets deficient in choline and methionine.
This view changed in the early 1970s after key studies by Lieber and DeCarli performed in baboons demonstrated that alcohol ingestion could lead to steatohepatitis and cirrhosis in the presence of a nutritionally complete diet. However, subsequent studies have suggested that enteral or parenteral nutritional supplementation in patients with alcoholic hepatitis may improve survival.
Toxic effects on cell membranes
Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell membranes.
Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins.
Ethanol damage to mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis.
Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.
Hypermetabolic state of the hepatocyte
Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of the hepatic lobule.
This zone is known to be sensitive to hypoxic damage.
Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism via MEOS does not result in energy capture via formation of ATP.
Rather, this pathway leads to loss of energy in the form of heat.
In some studies, antithyroid drugs, such as propylthiouracil (PTU), that reduce the basal metabolic rate of the liver have shown to be beneficial in the treatment of alcoholic hepatitis.
Generation of free radicals and oxidative injury
Free radicals, superoxides and hydroperoxides, are generated as byproducts of ethanol metabolism via the microsomal and peroxisomal pathways.
In addition, acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic defense against free radicals.
Other antioxidant defenses, including selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism.
Peroxidation of membrane lipids accompanies alcoholic liver injury and may be involved in cell death and inflammation.
Steatosis
Oxidation of ethanol requires conversion of NAD to the reduced form NADH.
Because NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, thus causing accumulation of fat within the hepatocytes (steatosis).
Some of the excess NADH may be reoxidized in the conversion of pyruvate to lactate.
Accumulation of fat in hepatocytes may occur within days of alcohol ingestion; with abstinence from alcohol, the normal redox state is restored, the lipid is mobilized, and steatosis resolves.
Although steatosis has generally been considered a benign and reversible condition, rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma formation, and fibrosis, and it may contribute to progressive liver injury.
Nonoxidative metabolism of ethanol may lead to the formation of fatty acid ethyl esters, which may also be implicated in the pathogenesis of alcohol-induced liver damage.
Formation of acetaldehyde adducts
Acetaldehyde may be the principal mediator of alcoholic liver injury.
The deleterious effects of acetaldehyde include impairment of the mitochondrial beta-oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione.
In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts.
This binding may trigger an immune response through formation of neoantigens, impair function of intracellular transport through precipitation of intermediate filaments and other cytoskeletal elements, and stimulate hepatic stellate cells to produce collagen.
Levels of acetaldehyde in the liver represent a balance between its rate of formation (determined by the alcohol load and activities of the 3 alcohol-dehydrogenating enzymes) and its rate of degradation by ALDH.
ALDH is downregulated by long-term ethanol abuse, with resultant acetaldehyde accumulation.
Role of the immune system
Active alcoholic hepatitis often persists for months after cessation of drinking.
In fact, its severity may worsen during the first few weeks of abstinence.
This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury.
Levels of serum immunoglobulins, especially the immunoglobulin A (IgA) class, are increased in persons with alcoholic hepatitis.
Antibodies directed against acetaldehyde-modified cytoskeletal proteins can be demonstrated in some individuals.
Autoantibodies, including antinuclear and anti–single-stranded or anti–double-stranded DNA antibodies, have also been detected in some patients with alcoholic liver disease.
B and T lymphocytes are noted in the portal and periportal areas, and natural killer lymphocytes are noted around hyalin-containing hepatocytes.
Patients have decreased peripheral lymphocyte counts with an associated increase in the ratio of helper cells to suppressor cells, signifying that lymphocytes are involved in a cell-mediated inflammatory process.
Lymphocyte activation upon exposure to liver extracts has been demonstrated in patients with alcoholic hepatitis.
Immunosuppressive therapy with glucocorticoids appears to improve survival and accelerate recovery in patients with severe alcoholic hepatitis.
Cytokines
Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells.
Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)–1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis.
Inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis, as shown in the images below.
[pic]Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-κB = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis factor. [pic]Mechanisms of cytokine injury. IL = interleukin ; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.
Role of concomitant viral disease
Alcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses.
Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion.
Possible mechanisms include the impairment of immune-mediated viral killing or enhanced virus gene expression due to the interaction of alcohol and hepatitis C virus.
Acetaminophen-alcohol interactions
Long-term alcohol abuse has been established as potentiating acetaminophen toxicity via induction of CYP2E1 and depletion of glutathione.
Alcoholic patients may develop severe, even fatal, toxic liver injury after ingestion of standard therapeutic doses of acetaminophen.
Diagnosis
The diagnosis is made in a patient with history of significant alcohol intake who develops worsening liver function tests, including elevated bilirubin and aminotransferases.
The ratio of aspartate aminotransferase to alanine aminotransferase is usually 2 or more.In most cases, the liver enzymes do not exceed 500.
The changes on liver biopsy are important in confirming a clinical diagnosis.
Physical examination
Patients with alcoholic hepatitis are commonly febrile with tachycardia. Mild tachypnea with primary respiratory alkalosis may be observed.
The liver is usually enlarged, often with mild hepatic tenderness.
Hepatomegaly results from both steatosis and swelling of injured hepatocytes.
Manifestations of hepatic failure or portal hypertension may include :
• scleral icterus with darkening of the urine,
• splenomegaly,
• asterixis (a flapping tremor characteristic of metabolic encephalopathies),
• peripheral edema, and
• bulging flanks with shifting abdominal dullness (indicating the presence of ascites).
• Spider angiomata,
• proximal muscle wasting,
• altered hair distribution, and
• gynecomastia may be observed, although these findings most commonly reflect coexistent cirrhosis.
Epidemiology
Alcohol abuse is the most common cause of serious liver disease in Western societies.
In the United States alone, alcoholic liver disease affects more than 2 million people (ie, approximately 1% of the population).
The true prevalence of alcoholic hepatitis, especially of its milder forms, is unknown, because patients may be asymptomatic and never seek medical attention.
Globally, the prevalence of alcoholic hepatitis appears to differ widely among different countries.
In the Western hemisphere, when liver biopsies were performed in people who drank moderate to heavy amounts of alcohol and were asymptomatic, the prevalence of alcoholic hepatitis was found to be approximately 25-30%.
Racial and age differences in incidence
Although no genetic predilection is noted for any particular race, alcoholism and alcoholic liver disease are more common in minority groups, particularly among Native Americans.
Likewise, since the 1960s, death rates of alcoholic hepatitis and cirrhosis have consistently been far greater for the nonwhite population than the white population.
The nonwhite male rate of alcoholic hepatitis is 1.7 times the white male rate, 1.9 times the nonwhite female rate, and almost 4 times the white female rate.
Alcoholic hepatitis can develop at any age.
However, its prevalence parallels the prevalence of ethanol abuse in the population, with a peak incidence in individuals aged 20-60 years.
Sexual differences in incidence
Women are more susceptible than men to the adverse effects of alcohol.
Women develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol abuse than men, and alcoholic hepatitis progresses more rapidly in women than in men.
The estimated minimum daily ethanol intake required for the development of cirrhosis is 40 g for men and 20 g for women older than 15-20 years.
Furthermore, for patients who continue to drink after a diagnosis of alcoholic liver disease, the 5-year survival rate is approximately 30% for women compared with 70% for men.
To date, no single factor can account for this increased female susceptibility to alcoholic liver damage.
Lower gastric mucosal alcohol dehydrogenase (ADH) content in women has been suggested to possibly lead to less first-pass clearance of alcohol in the stomach.
A higher prevalence of autoantibodies has been found in the sera of alcoholic females compared with alcoholic males, but their clinical significance is questionable.
Perhaps hormonal influences on the metabolism of alcohol or the higher prevalence of immunologic abnormalities is responsible for the differences described in the prevalence of alcoholic liver damage between men and women.
Prognosis
The long-term prognosis of individuals with alcoholic hepatitis depends heavily on whether patients have established cirrhosis and whether they continue to drink.
With abstinence, patients with this disease exhibit progressive improvement in liver function over months to years, and histologic features of active alcoholic hepatitis resolve.
If alcohol abuse continues, alcoholic hepatitis invariably persists and progresses to cirrhosis over months to years.
Mild alcoholic hepatitis is a benign disorder with negligible short-term mortality.
However, when alcoholic hepatitis is of sufficient severity to cause hepatic encephalopathy, jaundice, or coagulopathy, mortality can be substantial.
The overall 30-day mortality rate in patients hospitalized with alcoholic hepatitis is approximately 15%; however, in patients with severe liver disease, the rate approaches or exceeds 50%.
In those lacking encephalopathy, jaundice, or coagulopathy, the 30-day mortality rate is less than 5%.
Overall, the 1-year mortality rate after hospitalization for alcoholic hepatitis is approximately 40%.
In one study, the overall mortality among patients with severe alcoholic hepatitis was 66%. Age, white blood cell (WBC) count, prothrombin time (PT), and female sex were all independent risk factors for the dismal outcome.
Jaundice In Siddha(Manjal kamalai)
According to siddhars jaundice is named as “ Manjal Kamalai” or “Manjal Noi”.
Iyal :-
Yellowish colouration of urine,eyes,tongue,body as a whole is defined as kamalai.
Kamalai means “Kamam + Illai”,it means “not interested in any thing or action” .
It is also named as pithu noi means “pithu in the body travels against the normal physiological route and get mixed with the blood and shows it externally by changing the normal body’s colour in to the colour of pitham that is yellow in colour.
It is also named as “Manjal Noi” because the body changes in to yellow colour during the disease period.
Noi varum valli:-
• Taking food which induces the rise of pitham and kabam.
• Taking excess food than the need which causes indigestion,this condition along with the increased pithakabam destroys the work of all vayues and seneer(blood) there by attacks the valapateeral (Liver) and causes its thapitham(inflammation),makes the bile to mix with blood and this blood flow in to muscles,skin,nailbeds,tongue,uvula and stay there and causes this disease.
• Another reason is when there occurs rain during the peak of summer there occurs increase of kapam in the prevalence of increased pitha kutram and causes kamalai .
Signs and symptoms :-
• Hand,face,palm,eyes,body becomes white.
• Geneeral body tiredness.
• Shivering of body.
• Frequent breathlessness.
• Constipation.
• Excessive sleep.
• Heaviness of head.
• Yellowishness of body.
• General anasarca.
• Dumpness of ear.
• Hyper salivation.
• Nausea.
• Bitterness of tongue.
• Dyspepsia.
• Indigestion.
• Dryness of skin.
• Shrinking of skin like toads skin.
• Yellowishness of urine.
These are the signs and symptoms of manjal kamalai as per yukimuni’s thought.
Types of kamalai:-
There are 13 types of kamalai according to yuki muni.
They are:-
• Udhu kamalai
• Varal kamalai
• Vatha kamalai
• Pitha kamalai
• Kaba kamalai
• Vathakaba kamalai
• Pithakaba kamalai
• Mukutra kamalai
• Perum kamalai
• Alagu kamalai
• Senkamala kamalai
• Kumba kamalai
• Kunma kamalai
Types that can be treated and cured are:-
• Pitha kamalai
• Perumkamalai
• Kaba kamalai
• Udhu kamalai
• Varal kamalai
• Vathakaba kamalai
• Pithakaba kamalai.
Types which cannot be easily treated and cured are:-
• Kumba kamalai
• Kunma kamalai
• Mukkutra kamalai
• Vatha kamalai
• Senkamala kamalai
• Alagu kamalai
Mukutra verupadu:- Due to excessive intake of food which increases Pitha kutram and also due to sleeplessness,roaming excessively in sun the pitha kutram increases than it’s normal level,at this time if some extrinsic or intrinsic factors induces the increase of kaba kutram it joins pitham and destroys the work of paravukal(viyanan) and blood and causes the diseases kamalai. Then other vayues function also gets affected.
Nadi nadai:- Pithakabam and Pithavatham are the nadi for kamalai.
Siddha management:-More than half of all liver disease could be prevented if we acted on the knowledge we already have.
Avoiding or limiting the use of alcoholic beverages. Man-made chemicals also pose an extreme threat to the liver
Once cirrhosis has been diagnosed, sodium and fluids should be restricted, and all alcohol consumption must cease.
Antiemetics, diuretics, and supplemental vitamins are prescribed.
Patients should avoid exposure to infections and eat small but frequent meals of nutritious foods.
The liver is the only organ that can generate healthy, new tissue.
It is therefore possible to regenerate a cirrhosis-damaged liver if extraordinary therapies are followed and the underlying cause of the cirrhosis is eliminated.
Herbs in siddhaMedicine for Treating Liver Disease:-
Hepatitis A virus can be taken care of very easily with herbs.
Many of the herbs have shown remarkable results in clinical trials and studies.
Some of these are :-
• Eclipta Alba (Bhringaraj),
• Boerhavia diffusa (Punarnava) , and
• Picrorhiza kurroa (Katuki).
We can supply Concentrated Extracts in Tablet form of all these Herbs
It is recommend that people take these herbs on a prophylactic basis when travelling to parts of the world where hepatitis infection is a risk.
Siddha Treatment for Hepatitis B / Hepatitis C :-
HBV and HCV are more serious infections.
We must be careful how we use herbs for prevention of HBV and HCV.
The herbs mentioned earlier have shown a protective action in HBV, and using them on a regular basis may be a good way to prevent HBV.
Siddha medicines play a significant role in protecting the liver from cirrhosis and from liver cancer.
Animal and clinical studies done with Phyllanthus Amarus, Phyllanthus Niruri, and Eclipta Alba have proven their ability to reverse HBV infections in approximately 60% to 70% of patients.
More significantly, with these herbs we are able to stop the process, which leads to cirrhosis and cancer of the liver.
This means that even if we are not able to make some patients negative for HBV and HCV, we can still protect them from cirrhosis of the liver, in which the liver stops functioning, and liver cancer.
Take very good care of your health. To protect your liver, avoid alcohol and caffeine. Drink green tea, exercise, reduce stress, and use the herbs mentioned above. Give this hard-working and essential part of your body a rest and a tune-up, and you will be rewarded with better health, more energy and higher disease resistance.
Research work on Hepatoprotective Plants -
Andrographis paniculata (kalmegh)
Andrographolide, the active constituent isolated from the plant Andrographis paniculata, showed a significant dose dependent (0.75 - 12 mg/kg p.o. x7) protective activity against paracetamol-induced toxicity on ex vivo preparation of isolated rat hepatocytes.
It significantly increased the percent viability of the hepatocytes as tested by trypan blue exclusion and oxygen uptake tests.
It completely antagonized the toxic effects of paracetamol on certain enzymes (GOT, GPT and alkaline phosphatase) in serum as well as in isolated hepatic cells.
Andrographolide was found to be more potent than silymarin, a standard hepatoprotective agent.
For centuries Andrographis has been an important herb in the Asian healing systems of Ayurveda, Unani and Traditional Chinese Medicine.
Traditionally this herb has been used to potentiate immune system response to inflammation and infections, and as an anti-inflammatory, antipyretic (lowers fevers) and a hepatoprotective (liver protector).
Boerhavia diffusa (Punarnava)
An alcoholic extract of whole plant Boerhavia diffusa given orally exhibited hepatoprotective activity against experimentally induced carbon tetrachloride hepatotoxicity in rats and mice.
The extract also produced an increase in normal bile flow in rats suggesting a strong choleretic activity.
The extract does not show any signs of toxicity up to an oral dose of 2g/kg in mice.
Eclipta alba (Bhringaraj)
The hepatoprotective effect of the ethanol/water (1:1) extract of Eclipta alba was studied at subcellular levels in rats against (CCl4) -induced hepatotoxicity.
The loss of hepatic lysomal acid phosphatase and alkaline phosphatase by (CCl4) was significantly restored by Ea.
The study shows that hepatoprotective activity of Ea is by regulating the levels of hepatic microsomal drug metabolising enzymes.[6]
Swertia Chirata(Chirayata)
Simultaneous treatments with S. Chirata (in different doses, viz, 20, 50, and 100 mg/kg body wt daily) and (CCl4) caused improvement at both biochemical and histopathological parameters compared to that of (CCl4) treatment alone but it was most effective when S. chirata was administered in a moderate dose (50 mg/kg body wt).
Terminalia belerica(Baheda)
Compound I isolated from fraction TB5 of Terminalia belerica and finally identified as 3,4,5-trihydroxy benzoic acid (gallic acid) was evaluated for its hepatoprotective activity against carbon tetrachloride (CCl4) - induced physiological and biochemical alterations in the liver.
Administration of compound I led to significant reversal of majority of the altered parameters.
Our results confirm the presence of hepatoprotective activity in altered parameters.
Our results confirm the presence of hepatoprotective activity in Compound I.
Tinospora cordifolia(Guduchi)
Outstanding results in people suffering from jaundice have been obtained using a herb called Tinospora Cordifolia.
The herb is used in malignant obstructive jaundice: half of the group received conventional treatment - drugs and drainage - the other half were treated with drainage plus T. Cordifolia.
After conclusion of treatment, 50% of the drug-treated group were found to have blood poisoning while none of the herb treated group developed this problem.
After surgery, only 40% of the drug-treated group survived, whereas an amazing 92.4% 0f those treated with the herb lived.
The hepatoprotective effect of T. Cordifolia has been studied in carbon tetrachloride induced liver damage in rats.
While acute damage was enhanced by prior exposure to the drug, it proved effective in the prevention of fibrosis, and in stimulating regeneration of hepatic tissue.
Picrorhiza kuroa (Katuki)
Picrorrhiza Kurroa is one of the herbs they recommend to support the liver not only in everyday situations, but in cases where severe viral infections attack found protection against viral hepatitis, and other studies have demonstrated its helpfulness in protecting against alcohol.
The hepatoprotective activity of picroliv, the irridoid glycoside mixture from Picrorhiza kuroa, was determined in adult male albino rats.
Pretreatment with picroliv prevented the hepatotoxic effects of paracetamol and galactosamine as evidenced by various biochemical and histopathological observations.
Maximum hepatoprotective effect was observed with daily oral doses of 6 and 12 mg/kg for 7 or 8 days.
The antihepatotoxic action of picroliv seems likely due to an alteration in the biotransformation of the toxic substances resulting in decreased formation of reactive metabolites.
Siddha Medicine for Jaundice
The best Siddha medicine for jaundice is Keelanelli herb.
It grows abundantly in almost all areas of Tamil nadu.
In ancient days people are not aware of jaundice vaccine and they know the power of this plant to in jaundice treatment.
Keelanelli medicine is still used in nattu vaitiyam to get fast and complete cure against this disease.
This is the best Siddha medicine for jaundice.
It is used to treat :
• urine problems,
• intestinal problems,
• throat infection,
• stomach infections,
• eye problems,
• heat,
• menstrual problems,
• anemia, and wound healing and not feeling hungry.
It is having tiny leaves with small bud like below the stem area. The whole part of the plant is used to treat jaundice disease.
Aravindh Herbals Treatment
For
Jaundice
Jaundice which is named as kamalai by sidhars is having best known remedy n siddha medicine. One of the best treatment is from aravindh herbal labs formulation “Aeroliv Capsule”
Aeroliv capsule contains the following ingredients:
• Indigofera tinctoria
• Phyllanthus amarus or Phyllanthus niruri
• Andrographis paniculata
• Glycyrrhiza glabra
• Annabedi chendorum
• Mandora chenduram
• Velli parpam
The explanation of the above combination of the drug is explained below with evidences for their action against jaundice.
Indigofera tinctoria
| | |
| |
|[pic] |
|Kingdom: |Plantae |
|Phylum: |Angiosperms |
|Class: |Eudicots |
|Sub class: |Rosids |
|Order: |Fabales |
|Family: |Fabaceae |
|Genus: |Indigofera |
|Species: |tinctoria |
|Binomial name |
|Indigofera tinctoria |
Common vernacular names
English : Indian indigo
Hindi : Nil
Malayalam : Nilamari Amri.
Sanskrit:Neelini
Explanation
Indigofera tinctoria bears the common name True indigo. The plant was one of the original sources of indigo dye.
Today most dye is synthetic, but natural dye from I. tinctoria is still available, marketed as natural coloring.
The plant is also widely grown as a soil-improving groundcover.
Dye is obtained from the processing of the plant's leaves.
They are soaked in water and fermented in order to convert the glycoside indican naturally present in the plant to the blue dye indigotin.
The precipitate from the fermented leaf solution is mixed with a strong base such as lye, pressed into cakes, dried, and powdered.
The powder is then mixed with various other substances to produce different shades of blue and purple.
[pic]
Distribution
It has been naturalized to tropical and temperate Asia, as well as parts of Africa, but its native habitat is unknown since it has been in cultivation worldwide for many centuries.
Morphological Description
True indigo is a densely branching shrub one to two meters high.
It may be an annual, biennial, or perennial, depending on the climate in which it is grown.
It has light green pinnate compound leaves with 6-14 leaflets. Leaves are green with bluish tint.
Pink or violet flowers many, small and nearly sessile in spicate receme inflorescence are seen.
Tender branches are also bluish green colored.
Fruits are cylindric pods, 2-3 cm long, greenish grey when young and dark brown on ripening.
Seeds are 10-15 per pods.
The plant is a legume, so it is rotated into fields to improve the soil in the same way that other legume crops such as alfalfa and beans are.
[pic]
Chemical constitutions
The rotenoids deguelin, dehydrodeguelin, rotenol, rotenone, tephrosin and sumatrol can be found in I. tinctoria.
Whole plant contains flavonoids, apigenin, kaempferol, luteolin and quercetin.
It contains alkaloid indican.
Actions :
• Hepato-protective,
• Anti-periodic,
• Stimulant,
• Antidote,
• Alterative,
• Deobstruent,
• Purgative,
• Antiseptic,
• Astringent dye.
[pic]
Siddha Medicinal Uses :
1. The leaves are dried in shade, powdered and given in dose of 1 to 5 grams for three times a day for any type of toxicity (herbal,metal or poison of any living creature), fever due to derranged vatham, kamalai (jaundice), mantham (indigestion) etc.
2. The root is crushed and prepared into decoction, and given for gunmam (abdominal disorders), vellai(leucorrhoea), all types of toxicities etc.
3. The leaves are crushed, prepared into decoction and given for toxicities,fever,arthritis etc.
4. The leaf juice is given in the dose of 10-20ml along with honey twice daily for jaundice, inflammation of liver etc.
5. For poisonous bites the samoolam or the whole plant is ground and applied as a paste over the bitten area. Also the leaf juice is given internally to the patient.
6. Its Stem chewed to cure cough and decoction of Leaves used to cure chest pains .
7. The twine paste cures dislocation.
8. It is used in asities, snake poison, diseases due to metallic toxemia and in dog bite and extract in rabid dog bite, epilepsy and other nervous disorders.
9. Ointment used in sores, old ulcers and piles.
10. Decoction of leaves used in menorrhagia.
11. Roots used in urinary complaints and hepatitis.
[pic]
Pharmacological studies
Anti hyperglycemic activity
Anti-diabetic and nephroprotective activity of Indigofera tinctoria leaves, using STZinduced diabetic rats as model for clinical type-1and type-2 diabetes is investigated.
At a regular interval of an experimental protocol blood glucose, urinary creatinine, total proteins and organs to body weight ratio were studied.
The histo-pathological study was carried out by STZ-induced diabetic and antidiabetic rat’s pancreas.
Statistical analysis of the results shown that in STZ-induced diabetic rats chloroform and alcohol extracts of I.tinctoria leaves at 40, 80, 160 and 200 mg/kg doses.
Significant effect of alcoholic extract from 4th day to 16th day of the study. I.tinctoria leaves extract improved renal creatinine clearance and reduce
renal total protein loss demonstrating nephro protective properties.
The organ to body weight ratio studies carried out on last day, shown
pancreas and liver specific effects of I.tinctorialeaves.
These results were also supported by histopathological studies. The present study conclude that alcoholic extract of I.tinctoria leaves with long-term treatment may be beneficial in the management of type-1 and type-2 diabetes13.
[pic]
Anti bacterial,Anti oxidant and Cyto toxicity Effect
Antibacterial, anti oxidant and cytotoxic activity of the leaf extract of indigofera tinctoria isdetermined
Antibacterial activity was carried out on in vitro lung cancer cell line. The extract screened for phytochemical analysis was found to contain bioactive compounds like falvonoid, saponins, tannins,steroidal terpens, phenols and anthroquinone were
identified by GC -MS analysis.
The leaf extract I.tinctoria having the ability to inhibit the growth of gram positive bacteria namely Staphylococcus aureus, Bacillus pumilus and Streptococcus
pyrogens and zone of inhibition was observed 16 and 17 mm, respectively but not shown growth of inhibition on gram negative bacteria Escherichia and pseudomonas aeruginosa.
Strong antioxidant activity was observed both qualitatily and quantitatively.
The strong antioxidant was observed at 250ugml-1 with an IC 50 value of 51.66 which is higher than that of standarad ascorbic acid.
The cytotoxic effect of I.tinctoria leaf extract on lung cancer cell line NCI-H69 was studied.
The percentage cell viability of cells was found to decrease at increasing concentration.
GC-MS analysis of the leaf extract shows 6 compounds.
This study suggests that ethanol extract of Indigofera tinctoria have profound antibacterial,antioxidant and cytotoxic effect14.
[pic]
Anti-Inflamatory effect
The anti-inflammatory activity of Ethanolic extract of I.tinctoria leaves is elucidated (500 & 1000mg/kg).
When compare to control as well as positive control Ibuprofen (Standard drug) group values are expressed as mean and SD.
Statistical significance was determinded using the student’s t-test.
Values with p ................
................
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