Hepatitis

Alcoholic hepatitis evident by fatty change, cell

necrosis, Mallory bodies
Classification and external resources
Specialty
Infectious disease, gastroenterology
ICD-10
K75.9
ICD-9-CM 573.3
DiseasesDB 20061
MedlinePlus 001154
MeSH
D006505
Hepatitis (plural: hepatitides) is a medical condition defined by the inflammation of the
liver and characterized by the presence of inflammatory cells in the tissue of the organ.
Hepatitis may occur with limited or no symptoms, but often leads to jaundice (a yellow
discoloration of the skin, mucous membrane, and conjunctiva), poor appetite, and malaise.
Hepatitis is acute when it lasts less than six months and chronic when it persists longer.
Acute hepatitis can be self-limiting (healing on its own), can progress to chronic hepatitis, or,
rarely, can cause acute liver failure.[1] Chronic hepatitis may have no symptoms, or may
progress over time to fibrosis (scarring of the liver) and cirrhosis (chronic liver failure).[2]
Cirrhosis of the liver increases the risk of developing hepatocellular carcinoma (a form of
liver cancer).[3]
Worldwide, viral hepatitis is the most common cause of liver inflammation.[4] Other causes
include autoimmune diseases and ingestion of toxic substances (notably alcohol), certain
medications (such as paracetamol), some industrial organic solvents, and plants.
The term is derived from the Greek hpar (), meaning "liver", and the suffix -itis (-),
meaning "inflammation" (c. 1727).[5]

Contents

1 Signs and symptoms

o 1.1 Acute
o

1.2 Chronic

2 Causes
o

2.1 Viral hepatitis

2.2 Alcoholic hepatitis

2.3 Toxic and drug-induced hepatitis

2.4 Autoimmune

2.5 Non-alcoholic fatty liver disease

2.6 Ischemic hepatitis

2.7 Giant cell hepatitis

3 Mechanism

4 Diagnosis
o

4.1 Viral hepatitis

4.2 Differential diagnosis

4.3 Pathology

5 Prognosis

6 Prevention
o

6.1 Vaccines

7 See also

8 References

9 External links

Signs and symptoms

A person with jaundice

Acute

Initial symptoms are non-specific and flu-like, common to almost all acute viral infections,
and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and
headache. More specific symptoms, which can be present in acute hepatitis from any cause,
are profound loss of appetite, aversion to smoking among smokers, choluria (dark urine),
jaundice (yellowing of the eyes and skin), and abdominal discomfort. Before patients develop
jaundice, physical findings are uncommon. However, 5-10% of people with hepatitis develop
tender enlargement of the liver, enlarged lymph nodes, and enlargement of the spleen.[6]
Acute viral hepatitis is more likely to be asymptomatic in children. General symptoms may
last for 12 weeks before jaundice develops, with the total illness lasting weeks.[7]
A small proportion of people with acute hepatitis progress to acute liver failure, in which the
liver is unable to remove harmful substances from the blood (leading to confusion and coma
due to hepatic encephalopathy) and produce blood proteins (leading to peripheral edema and
bleeding).[6]

Chronic
Chronic hepatitis may cause nonspecific symptoms such as malaise, tiredness, and weakness,
and often leads to no symptoms at all. It is commonly identified on blood tests performed
either for screening or to evaluate nonspecific symptoms. The presence of jaundice indicates
advanced liver damage. On physical examination there may be enlargement of the liver.[8]
Extensive damage to and scarring of liver (i.e., cirrhosis) leads to weight loss, easy bruising
and bleeding, peripheral edema (swelling of the legs), and accumulation of ascites (fluid in
the abdomen). Eventually, cirrhosis may lead to various complications: esophageal varices
(enlarged veins in the wall of the esophagus that can cause life-threatening bleeding), hepatic
encephalopathy (confusion and coma), and hepatorenal syndrome (kidney dysfunction).
Acne, abnormal menstruation, lung scarring, and inflammation of the thyroid gland and
kidneys may be present in women with autoimmune hepatitis.[8] Hepatitis associated aplastic
anemia may occur 2-3 months after an acute attack of hepatitis.[9][10]

Causes
Viral hepatitis is the most common cause of hepatitis worldwide.[11] Other common causes of
non-viral hepatitis include toxic and drug-induced, alcoholic, autoimmune, fatty liver, and
metabolic disorders.[12] Less commonly some bacterial, parasitic, fungal, mycobacterial and
protozoal infections can cause hepatitis.[13][14] Additionally, certain complications of
pregnancy and decreased blood flow to the liver can induce hepatitis.[13][15] Cholestasis
(obstruction of bile flow) due to hepatocellular dysfunction, biliary tract obstruction, or
biliary atresia can result in liver damage and hepatitis.[16][17]

Viral hepatitis
The most common causes of viral hepatitis are the five unrelated hepatotropic viruses
hepatitis A, hepatitis B, hepatitis C, hepatitis D (which requires hepatitis B to cause disease),
and hepatitis E.

Hepatitis B is the most common viral hepatitis worldwide, affecting as much as 10% of the
adult population in endemic areas[18] and causing approximately 780,000 deaths per year
worldwide. It is most often transmitted vertically in areas of high incidence (perinatally) from
mother to baby during birth) or horizontally by being exposed to infected blood or blood
products. While less common, Hepatitis B can also be spread through exposure to mucous
membranes. A vaccine is routinely given in the developed world.[19]
In the United States, Hepatitis C has become the most common viral hepatitis since
widespread vaccination of Hepatitis B in the mid-1980's. It affects an estimated 3.2 million
adults living in the United States. Roughly 60-70% of HCV-infected adults living in the
United States are unaware of their infection. Even following decades without symptoms,
HCV-infected persons remain a source of transmission to others and they are also at elevated
risk for developing chronic liver disease and/or other chronic HCV-related diseases.[20]

Alcoholic hepatitis
Main article: Alcoholic hepatitis
Excessive alcohol consumption is a significant cause of hepatitis and liver damage
(cirrhosis). Alcoholic hepatitis usually develops over years-long exposure to alcohol. Alcohol
intake in excess of 80 grams of alcohol a day in men and 40 grams a day in women is
associated with development of alcoholic hepatitis. Alcoholic hepatitis can vary from mild
asymptomatic disease to severe liver inflammation and liver failure. Symptoms and physical
exam findings are similar to other causes of hepatitis. Laboratory findings are significant for
elevated transaminases, usually with elevation of aspartate transaminase (AST) in a 2:1 ratio
to alanine transaminase (ALT).[21][22]
Alcoholic hepatitis may lead to cirrhosis and is more common in patients with long-term
alcohol consumption and those infected with hepatitis C.[23] Patients who drink alcohol to
excess are also more often than others found to have hepatitis C.[24] The combination of
hepatitis C and alcohol consumption accelerates the development of cirrhosis.[25]

Toxic and drug-induced hepatitis

Main article: Hepatotoxicity
A large number of medications and other chemical agents can cause hepatitis. In the United
States acetaminophen, antibiotics, and central nervous system medications are among the
most common causes of drug-induced hepatitis. Acetaminophen, also known as paracetamol,
is the leading cause of acute liver failure in the United States.[26] Herbal remedies and dietary
supplements may also cause hepatitis; these are the most common causes of drug-induced
hepatitis in Korea.[27] Risk factors for drug-induced hepatitis include increasing age, female
sex, and previous drug-induced hepatitis. Genetic variability is increasingly understood as a
key predisposing risk factor to drug-induced hepatitis.[28][29]
Toxins and medications can cause liver injury through a variety of mechanisms, including
direct cell damage, disrupting cell metabolism, and inducing structural changes.[30] Some
medications, like acetaminophen, cause predictable dose-related liver damage, whereas others
cause idiosyncratic reactions that vary among individuals.[29]

Exposure to other hepatotoxins can occur accidentally or intentionally through ingestion,

inhalation, and skin absorption. Occupational exposure may occur in many work fields and
can present acutely or insidiously.[31] Mushroom poisoning is a common toxic exposure that
may result in hepatitis.[32]

Autoimmune
Main article: Autoimmune hepatitis
Autoimmune hepatitis is a chronic disease caused by an abnormal immune response against
liver cells.[33] The disease is thought to have a genetic predisposition as it is associated with
certain human leukocyte antigens.[34] The symptoms of autoimmune hepatitis are similar to
other hepatitides and may have a fluctuating course from mild to very severe. Women with
the disease may have abnormal menstruation or become amenorrheic. The disease occurs in
people of all ages but most commonly in young women. Many people with autoimmune
hepatitis have other autoimmune diseases.[35]

Non-alcoholic fatty liver disease

Main article: Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is the occurrence of fatty liver in people who have
little or no history of alcohol use. In the early stage there are usually no symptoms, as the
disease progresses symptoms typical of chronic hepatitis may develop.[36] NAFLD is
associated with metabolic syndrome, obesity, diabetes, and hyperlipidemia.[37] Severe
NAFLD leads to inflammation, fibrosis, and cirrhosis, a state referred to as non-alcoholic
steatohepatitis (NASH). Diagnosis requires excluding other causes of hepatitis, including
excessive alcohol intake.[38] While imaging can show fatty liver, only liver biopsy can
demonstrate inflammation and fibrosis characteristic of NASH.[39] NASH is recognized as the
third most common cause of liver disease in the United States.[36]

Ischemic hepatitis
Main article: Ischemic hepatitis
Injury to liver cells due to insufficient blood or oxygen results in ischemic hepatitis (or shock
liver).[40] The condition is most often associated with heart failure but can also be caused by
shock or sepsis. Blood testing of a person with ischemic hepatitis will show very high levels
of transaminase enzymes (AST and ALT). The condition usually resolves if the underlying
cause is treated successfully. Ischemic hepatitis rarely causes permanent liver damage.[41]

Giant cell hepatitis

Giant cell hepatitis is a rare form of hepatitis that predominantly occurs in newborns and
children. Diagnosis is made on the basis of the presence of multinucleated hepatocyte giant
cells on liver biopsy.[42] The cause of giant cell hepatitis is unknown but the condition is
associated with viral infection, autoimmune disorders, and drug toxicity.[43][44]

Mechanism

The specific mechanism varies and depends on the underlying cause for the condition. In
viral hepatitis, the presence of the virus in the liver cells causes the immune system to attack
the liver, resulting in inflammation and impaired function.[45] In autoimmune hepatitis, the
immune system attacks the liver due to the autoimmune disease.[46] In some hepatitis, often
including hepatitis caused by alcoholism, fat deposits accumulate in the liver, resulting in
fatty liver disease, also called steatohepatitis.[47]

Diagnosis
Diagnosis is made by assessing an individual's symptoms, physical exam, and medical
history, in conjunction with blood tests, liver biopsy, and imaging. Blood testing includes
blood chemistry, liver enzymes, serology and nucleic acid testing. Abnormalities in blood
chemistry and enzyme results may be indicative of certain causes or stages of hepatitis.[48][49]
Imaging can identify steatosis of the liver but liver biopsy is required to demonstrate fibrosis
and cirrhosis.[39] A biopsy is unnecessary if the clinical, laboratory, and radiologic data
suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and
cirrhosis itself predisposes for complications caused by liver biopsy.[50]
Liver chemistry test
Alanine transaminase (ALT)
Aspartate transaminase (AST)
Bilirubin
Alkaline phosphatase
Prothrombin time
Albumin (ALB)
Gamma-glutamyl transpeptidase (GGT)
Bile acids
Lactate dehydrogenase

Clinical implication of abnormality

Hepatocellular damage
Hepatocellular damage
Cholestasis
Cholestasis
Impaired synthetic function
Impaired synthetic function
Cholestasis
Cholestasis
Hepatocellular damage

Viral hepatitis
Main article: viral hepatitis
Viral hepatitis is mostly diagnosed through clinical laboratory testing. Some of these tests
react with the virus or parts of the virus, such as the Hepatitis B surface antigen test or
nucleic acid tests.[51][52] Many of the tests are serological tests that react to the antibodies
formed by the immune system. For some major causes of viral hepatitis, such as Hepatitis B,
there are multiple serological tests used that provide additional information for diagnosis.[53]

Differential diagnosis
Several diseases can present with signs, symptoms, and/or liver function test abnormalities
similar to hepatitis. In severe cases of alpha 1-antitrypsin deficiency (A1AD), excess protein
in liver cells causes inflammation and cirrhosis.[54] Some metabolic disorders cause damage to
the liver through a variety of mechanisms. In hemochromatosis and Wilson's disease toxic
accumulation of dietary minerals results in inflammation and cirrhosis.[55]

Pathology

The liver, like all organs, responds to injury in a limited number of ways and a number of
patterns have been identified. Liver biopsies are rarely performed for acute hepatitis and
because of this the histology of chronic hepatitis is better known than that of acute hepatitis.
Acute
In acute hepatitis the lesions (areas of abnormal tissue) predominantly contain diffuse
sinusoidal and portal mononuclear infiltrates (lymphocytes, plasma cells, Kupffer cells) and
swollen hepatocytes. Eosinophilic cells (Councilman bodies) are common. Hepatocyte
regeneration and cholestasis (canalicular bile plugs) typically are present. Bridging hepatic
necrosis (areas of necrosis connecting two or more portal tracts) may also occur. There may
be some lobular disarray. Although aggregates of lymphocytes in portal zones may occur
these are usually neither common nor prominent. The normal architecture is preserved. There
is no evidence of fibrosis or cirrhosis (fibrosis plus regenerative nodules). In severe cases
prominent hepatocellular necrosis around the central vein (zone 3) may be seen.
In submassive necrosis a rare presentation of acute hepatitis there is widespread
hepatocellular necrosis beginning in the centrizonal distribution and progressing towards
portal tracts. The degree of parenchymal inflammation is variable and is proportional to
duration of disease.[56][57] Two distinct patterns of necrosis have been recognised: (1) zonal
coagulative necrosis or (2) panlobular (nonzonal) necrosis.[58] Numerous macrophages and
lymphocytes are present. Necrosis and inflammation of the biliary tree occurs.[59] Hyperplasia
of the surviving biliary tract cells may be present. Stromal haemorrhage is common.
The histology may show some correlation with the cause:

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

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

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

Where patients have recovered from this condition, biopsies commonly show multiacinar
regenerative nodules (previously known as adenomatous hyperplasia).[60]
Massive hepatic necrosis is also known and is usually rapidly fatal. The pathology resembles
that of submassive necrosis but is more marked in both degree and extent.
Chronic
Chronic hepatitis has been better studied and several conditions have been described.
Chronic hepatitis with piecemeal (periportal) necrosis (or interface hepatitis) with or without
fibrosis[61] (formerly chronic active hepatitis) is any case of hepatitis occurring for more than
6 months with portal based inflammation, fibrosis, disruption of the terminal plate, and
piecemeal necrosis. This term has now been replaced by the diagnosis of 'chronic hepatitis'.
Chronic hepatitis without piecemeal necrosis (formerly called chronic persistent hepatitis) has
no significant periportal necrosis or regeneration with a fairly dense mononuclear portal

infiltrate. Councilman bodies are frequently seen within the lobule. Instead it includes
persistent parenchymal focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal
infiltrates.
The older terms have been deprecated because the conditions are now understood as being
able to alter over time so that what might have been regarded as a relatively benign lesion
could still progress to cirrhosis. The simpler term chronic hepatitis is now preferred in
association with the causative agent (when known) and a grade based on the degree of
inflammation, piecemeal or bridging necrosis (interface hepatitis) and the stage of fibrosis.
Several grading systems have been proposed but none have been adopted universally.
Cirrhosis is a diffuse process characterized by regenerative nodules that are separated from
one another by bands of fibrosis. It is the end stage for many chronic liver diseases. The
pathophysiological process that results in cirrhosis is as follows: hepatocytes are lost through
a gradual process of hepatocellular injury and inflammation. This injury stimulates a
regenerative response in the remaining hepatocytes. The fibrotic scars limit the extent to
which the normal architecture can be reestablished as the scars isolate groups of hepatocytes.
This results in nodule formation. Angiogenisis (new vessel formation) accompanies scar
production which results in the formation of abnormal channels between the central hepatic
veins and the portal vessels. This in turn causes shunting of blood around the regenerating
parenchyma. Normal vascular structures including the sinusoidal channels may be obliterated
by fibrotic tissue leading to portal hypertension. The overall reduction in hepatocyte mass, in
conjunction with the portal blood shunting, prevents the liver from accomplishing its usual
functions the filtering of blood from the gastrointestinal tract and serum protein production.
These changes give rise to the clinical manifestations of cirrhosis.
Specific causes
Most of the causes of hepatitis cannot be distinguished on the basis of the pathology but some
do have particular features that are suggestive of a particular diagnosis. The presence of
micronodular cirrhosis, Mallory bodies and fatty change within a single biopsy are highly
suggestive of alcoholic injury.[62] Perivenular, pericellular fibrosis (known as 'chicken wire
fibrosis' because of its appearance on trichrome or Van Gieson's stains) with partial or
complete obliteration of the central vein is also very suggestive of alcohol abuse.
Cardiac, ischemic and venous outflow obstruction all cause similar patterns.[63] The sinusoids
are often dilated and filled with erythrocytes. The liver cell plates may be compressed.
Coagulative necrosis of the hepatocytes can occur around the central vein. Hemosiderin and
lipochrome laden macrophages and inflammatory cells may be found. At the edge of the
fibrotic zone cholestasis may be present. The portal tracts are rarely significantly involved
until late in the course.
Biliary tract disease including primary biliary cirrhosis, sclerosing cholangitis, inflammatory
changes associated with idiopathic inflammatory bowel disease and duct obstruction have
similar histology in their early stages. Although these diseases tend to primarily involve the
biliary tract they may also be associated with chronic inflammation within the liver and
difficult to distinguish on histological grounds alone. The fibrotic changes associated with
these diseases principally involve the portal tracts with cholangiole proliferation, portal tract
inflammation with neutrophils surrounding the cholangioles, disruption of the terminal plate
by mononuclear inflammatory cells and occasional hepatocyte necrosis. The central veins are

either not involved in the fibrotic process or become involved only late in the course of the
disease. Consequently the centralportal relationships are minimally distorted. Where
cirrhosis is present it tends to be in the form of a portalportal bridging fibrosis.
Hepatitis E causes different histological patterns that depend on the host's background.[64] In
immunocompetent patients the typical pattern is of severe intralobular necrosis and acute
cholangitis in the portal tract with numerous neutrophils. This normally resolves without
sequelae. Disease is more severe in those with preexisting liver disease such as cirrhosis. In
the immunocompromised patients chronic infection may result with rapid progression to
cirrhosis. The histology is similar to that found in hepatitis C virus with dense lymphocytic
portal infiltrate, constant piecemeal necrosis and fibrosis.

Prognosis
The outcome of hepatitis depends heavily on the disease or condition that is causing the
symptoms. For some causes, such as subclinical Hepatitis A infection, the person may not
experience any symptoms and will recover without any long-term effects. For other causes
hepatitis can result in irreparable damage to the liver and require a liver transplant.[6] A subset
referred to in a 1993 classification as "hyperacute" liver failure can happen in less than a
week.[65]
The liver can regenerate damaged cells.[66] Chronic damage to the liver can result in the
formation of scar tissue called fibrosis and can result in nodules that block the liver from
functioning properly; this condition is called cirrhosis and is not reversible.[67] Cirrhosis may
indicate a liver transplant is necessary. Another complication of chronic hepatitis is liver
cancer, specifically hepatocellular carcinoma.[68]
In March 2015 the World Health Organisation issued its first guidelines for the treatment of
chronic hepatitis B. This condition is affecting some 240 million people worldwide. These
guidelines are for the prevention, care and treatment of persons living with chronic hepatitis
B.[69]

Prevention
Vaccines

Global distribution of hepatitis B

Vaccines are available to prevent hepatitis A and B. Hepatitis A immunity is achieved in 99100% of persons receiving the two-dose inactivated virus vaccine. The hepatitis A vaccine is
not approved for children under one year of age.[70] Vaccines to prevent hepatitis B have been
available since 1986 and have been incorporated into at least 177 national immunization
programs for children. Immunity is achieved in greater than 95% of children and young

adults receiving the three-dose recombinant virus vaccine. Vaccination within 24 hours of
birth can prevent transmission from an infected mother. Adults over 40 years of age have
decreased immune response to the vaccine. The World Health Organization recommends
vaccination of all children, particularly newborns in countries where hepatitis B is common to
prevent transmission from the mother to child.[71]