Hepatitis
Classification and external resources
Alcoholic hepatitis evident by fatty change, cell necrosis, Mallory bodies
ICD-10	K75.9
ICD-9	573.3
DiseasesDB	20061
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. The name is from the Greek hepar (ἧπαρ), the root being hepat- (ἡπατ-), meaning liver, and suffix -itis, meaning "inflammation" (c. 1727).^[1] The condition can be self-limiting (healing on its own) or can progress to fibrosis (scarring) and cirrhosis.

Hepatitis may occur with limited or no symptoms, but often leads to jaundice, anorexia (poor appetite) and malaise. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. A group of viruses known as the hepatitis viruses cause most cases of hepatitis worldwide, but it can also be due to toxins (notably alcohol, certain medications, some industrial organic solvents and plants), other infections and autoimmune diseases.

Signs and symptoms[link]

Acute[link]

Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice in a third and tender hepatomegaly (swelling of the liver) in about 10%. Some exhibit lymphadenopathy (enlarged lymph nodes, in 5%) or splenomegaly (enlargement of the spleen, in 5%).^[2]

Acute viral hepatitis is more likely to be asymptomatic in younger people. Symptomatic individuals may present after convalescent stage of 7 to 10 days, with the total illness lasting 2 to 6 weeks.^[3]

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

Chronic[link]

Chronic hepatitis often leads to 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 occurrence of jaundice indicates advanced liver damage. On physical examination there may be enlargement of the liver.^[4]

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

Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis.^[4]

Pathology[link]

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[link]

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

In submassive necrosis – a rare presentation of acute hepatitis – there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease.^[5][6] Two distinct patterns of necrosis have been recognised: (1) zonal coagulative necrosis or (2) panlobular (nonzonal) necrosis.^[7] Numerous macrophages and lymphocytes are present. Necrosis and inflammation of the biliary tree occurs.^[8] 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).^[9]

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

Chronic[link]

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

Chronic active hepatitis was the term used to described cases of hepatitis 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 with piecemeal (periportal) necrosis (or interface hepatitis) with or without fibrosis.'^[10]

Chronic persistent hepatitis was the term used to describe chronic hepatitis with no significant periportal necrosis or regeneration with a fairly dense mononuclear portal infiltrate. Councilman bodies are frequently seen within the lobule. This condition is now referred to as 'chronic hepatitis without piecemeal necrosis (or interface hepatitis).'^[10]

Chronic lobular hepatitis was the term used to describe chronic hepatitis with persistent parenchymal focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal infiltrates. This is now referred to as 'chronic hepatitis without piecemeal necrosis (or interface hepatitis).'^[10]

These terms have since been deprecated.^[10] This was done because it was realised that these conditions could alter over time and what might have been regarded as a relatively benign lesion could still progress to cirrhosis. The simpler term 'chronic hepatitis' is now preferred in association with the causative agent (when known) and a grade based on the degree of inflammation, piecemeal or bridging necrosis (interface hepatitis) and the stage of fibrosis. Several grading systems have been proposed but none have been adopted universally.

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

Specific cases[link]

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.^[11] Perivenular, pericellular fibrosis (known as 'chicken wire fibrosis' because of its appearance on trichrome or van Gieson stains) with partial or complete obliteration of the central vein is also very suggestive of alcohol abuse.

Cardiac, ischemic and venous outflow obstruction all cause similar patterns.^[12] The sinusoids are often dilated and filled with erythrocytes. The liver cell plates may be compressed. Coagulative necrosis of the hepatocytes can occur around the central vein. Hemosiderin and lipochrome laden macrophages and inflammatory cells may be found. At the edge of the fibrotic zone cholestasis may be present. The portal tracts are rarely significantly involved until late in the course.

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

Hepatitis E causes different histological patterns that depend on the host's background.^[13] 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 peacemeal necrosis and fibrosis.

Causes[link]

Acute[link]

• Viral hepatitis (15 families)
  • Adenoviridae: Adenoviruses
  • Arenaviruses: Guanarito virus,^[14] Junín virus,^[14] Lassa fever virus,^[14] Lujo virus,^[15] Machupo virus^[14] and Sabiá virus^[14]
  • Bunyaviruses: Crimean-Congo hemorrhagic fever virus,^[16] Dobrava virus,^[17] Hantaan virus,^[18] Puumala virus,^[19] Rift Valley fever virus,^[20] Seoul virus^[21] and SFTS virus^[22]
  • Coronaviridae: Severe acute respiratory syndrome virus^[23]
  • Erythrovirus: Parvovirus B19^[24]
  • Flaviviruses: Akhurma virus,^[25] Dengue,^[26] Hepatitis C, Kyasanur Forest disease virus,^[27] Omsk hemorrhagic fever virus,^[27] Yellow fever
  • Filoviruses: Ebola virus and Marburg virus^[28]
  • Hepadnaviridae: Hepatitis B
  • Hepeviridae: Hepatitis E
  • Herpesviruses: Cytomegalovirus,^[29] Epstein Barr virus,^[30] Varicella zoster virus, Human herpesvirus 6, Human herpesvirus 7 and Human herpesvirus 8^[31]
  • Orthomyxoviruses: Influenza^[32]
  • Parvoviridae: Parvovirus B19^[24]
  • Picornaviruses: Echovirus,^[33] Hepatitis A
  • Reovirus: Colorado tick fever virus,^[34] Reovirus 3^[35]
  • Unassigned family: Hepatitis D

• Bacterial
  • Anaplasma^[36]
  • Babesia^[37]
  • Bartonella^[38]
  • Chlamydia trachomatis^[39]
  • Coxiella burnetii^[40]
  • Ehrlichia^[41]
  • Leptospira
  • Listeria^[42]
  • Mycobacterium tuberculosis^[43]
  • Nocardia^[44]
  • Novosphingobium aromaticivorans^{[45][46][47][48]}
  • Orientia tsutsugamushi^[49][50][51]
  • Rickettsia^[51]
  • Rhodococcus^[52]
  • Salmonella^[53]
  • Streptococcus pyogenes^[54]
  • Treponema pallidum^[55]
  • Yersinia^[56]

• Protozoal
  • Entamoeba histolytica^[57]
  • Cryptosporidium^[58]
  • Isospora^[59][60]
  • Leishmania^[57]
  • Plasmodium^[61]
  • Toxoplasma

• Parasitic
  • Ascaris lumbricoides^[57]
  • Ancylostoma^[62]
  • Baylisascaris^[63]
  • Capillaria hepatica^[64]
  • Clonorchis sinensis^[57]
  • Dicrocoelium dendriticum^[65]
  • Echinococcus^[57]
  • Fasciola hepatica^[57]
  • Fasciolopsis buski^[66]
  • Metorchis^[67]
  • Necator^[62]
  • Opisthorchis^[57]
  • Paragonimus^[68]
  • Strongyloides stercoralis^[69]
  • Schistosoma^[70]
  • Toxocara^[71]

• Fungal
  • Aspergillus^[72]
  • Candida^[73]
  • Cryptococcus^[64]
  • Histoplasma^[74]
  • Microsporidium^[75][76][77]
• Algal
  • Prototheca^[78][79]

This unreferenced section requires citations to ensure verifiability.

• Non infectious
  • Alcohol
  • Auto immune conditions: systemic lupus erythematosus
  • Drugs: Paracetamol, amoxycillin, antituberculosis medicines, minocycline and many others (see longer list below).
  • Ischemic hepatitis (circulatory insufficiency)
  • Metabolic diseases: Wilson's disease
  • Pregnancy
  • Toxins: Amanita toxin in mushrooms, carbon tetrachloride, asafetida

Chronic[link]

• Alcohol
• Autoimmune
  • Autoimmune hepatitis
• Drugs
  • Isoniazid
  • Ketoconazole
  • Methyldopa
  • Nitrofurantoin
• Inherited
  • Wilson's disease
  • Alpha 1-antitrypsin deficiency
• Non-alcoholic steatohepatitis
• Primary biliary cirrhosis and primary sclerosing cholangitis occasionally mimic chronic hepatitis^[3]
• Viral hepatitis: Hepatitis B with or without hepatitis D, hepatitis C (neither hepatitis A nor hepatitis E causes chronic hepatitis)

Discussion[link]

Alcoholic hepatitis[link]

Ethanol, mostly in alcoholic beverages, is a significant cause of hepatitis. Usually alcoholic hepatitis comes after a period of increased alcohol consumption. Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen ascites, and modest elevation of liver blood tests. Alcoholic hepatitis can vary from mild with only liver test elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and liver failure. Severe cases are characterized by either obtundation (dulled consciousness) or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both categories is 50% within 30 days of onset.

Alcoholic hepatitis is distinct from cirrhosis caused by long term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Patients who drink alcohol to excess are also more often than others found to have hepatitis C.^{[citation needed]} The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis.

Drug-induced[link]

A large number of drugs can cause hepatitis:^[80]

• Agomelatine (antidepressant)
• Allopurinol
• Amitriptyline (antidepressant)
• Amiodarone (antiarrhythmic)
• Atomoxetine ^[81]
• Azathioprine^[82]
• Halothane (a specific type of anesthetic gas)
• Hormonal contraceptives
• Ibuprofen and indomethacin (NSAIDs)
• Isoniazid (INH), rifampicin, and pyrazinamide (tuberculosis-specific antibiotics)
• Ketoconazole (antifungal)
• Loratadine (antihistamine)
• Methotrexate (immune suppressant)
• Methyldopa (antihypertensive)
• Minocycline (tetracycline antibiotic)
• Nifedipine (antihypertensive)
• Nitrofurantoin (antibiotic)
• Paracetamol (acetaminophen in the United States) can cause hepatitis when taken in an overdose. The severity of liver damage may be limited by prompt administration of acetylcysteine.
• Phenytoin and valproic acid (antiepileptics)
• Troglitazone (antidiabetic, withdrawn in 2000 for causing hepatitis)
• Zidovudine (antiretroviral i.e., against HIV)
• Some herbs and nutritional supplements^[83]

The clinical course of drug-induced hepatitis is quite variable, depending on the drug and the patient's tendency to react to the drug. For example, halothane hepatitis can range from mild to fatal as can INH-induced hepatitis. Hormonal contraception can cause structural changes in the liver. Amiodarone hepatitis can be untreatable since the long half life of the drug (up to 60 days) means that there is no effective way to stop exposure to the drug. Statins can cause elevations of liver function blood tests normally without indicating an underlying hepatitis. Lastly, human variability is such that any drug can be a cause of hepatitis.

Other toxins[link]

Other Toxins can cause hepatitis:

• Amatoxin-containing mushrooms, including the Death Cap (Amanita phalloides), the Destroying Angel (Amanita ocreata), and some species of Galerina. A portion of a single mushroom can be enough to be lethal (10 mg or less of α-amanitin).
• White phosphorus, an industrial toxin and war chemical.
• All chlorinated hydrocarbons (i.e. Carbon tetrachloride, chloroform, and trichloroethylene) can cause steatohepatitis (hepatitis with fatty liver).
• Cylindrospermopsin, a toxin from the cyanobacterium Cylindrospermopsis raciborskii and other cyanobacteria.

Metabolic disorders[link]

Some metabolic disorders cause different forms of hepatitis. Hemochromatosis (due to iron accumulation) and Wilson's disease (copper accumulation) can cause liver inflammation and necrosis.

Non-alcoholic steatohepatitis (NASH) is effectively a consequence of metabolic syndrome.

Obstructive[link]

"Obstructive jaundice" is the term used to describe jaundice due to obstruction of the bile duct (by gallstones or external obstruction by cancer). If longstanding, it leads to destruction and inflammation of liver tissue.

Autoimmune[link]

Anomalous presentation of human leukocyte antigen (HLA) class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection; causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis.

Alpha 1-antitrypsin deficiency[link]

In severe cases of alpha 1-antitrypsin deficiency (A1AD), the accumulated protein in the endoplasmic reticulum causes liver cell damage and inflammation.

Non-alcoholic fatty liver disease[link]

Non-alcoholic fatty liver disease (NAFLD) is the occurrence of fatty liver in people who have no history of alcohol use. It is most commonly associated with obesity (80% of all obese people have fatty liver). It is more common in women. Severe NAFLD leads to inflammation, a state referred to as non-alcoholic steatohepatitis (NASH), which on biopsy of the liver resembles alcoholic hepatitis (with fat droplets and inflammatory cells, but usually no Mallory bodies).

The diagnosis depends on medical history, physical exam, blood tests, radiological imaging and sometimes a liver biopsy. The initial evaluation to identify the presence of fatty infiltration of the liver is medical imaging, including such ultrasound, computed tomography (CT), or magnetic resonance (MRI). However, imaging cannot readily identify inflammation in the liver. Therefore, the differentiation between steatosis and NASH often requires a liver biopsy. It can also be difficult to distinguish NASH from alcoholic hepatitis when the patient has a history of alcohol consumption. Sometimes in such cases a trial of abstinence from alcohol along with follow-up blood tests and a repeated liver biopsy are required.

NASH is becoming recognized as the most important cause of liver disease second only to hepatitis C in numbers of patients going on to cirrhosis.^{[citation needed]}

Ischemic hepatitis[link]

Ischemic hepatitis is caused by decreased circulation to the liver cells. Usually this is due to decreased blood pressure (or shock), leading to the equivalent term "shock liver". Patients with ischemic hepatitis are usually very ill due to the underlying cause of shock. Rarely, ischemic hepatitis can be caused by local problems with the blood vessels that supply oxygen to the liver (such as thrombosis, or clotting of the hepatic artery^{[disambiguation needed ]} which partially supplies blood to liver cells). Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT), which may exceed 1000 U/L. The elevation in these blood tests is usually transient (lasting 7 to 10 days). It is rare that liver function will be affected by ischemic hepatitis.

Giant cell hepatitis[link]

Giant cell hepatitis is a rare form of hepatitis (~100 cases reported) that predominantly occurs in children. Diagnosis is made on the basis of the presence of hepatocellular multinucleate giant cells.^[7][84][85] Cases presenting in adults are rare and tend to be rapidly progressive.^{[86][87][88][89][90]} The cause is currently unknown but an infectious cause is suspected.^[91][92] The condition tends to improve with the use of ribivirin suggesting a viral origin.^[93][94] Hepatitis E,^[95] hepatitis C,^[96] paramyxovirus,^{[97][98][99][100]} papillomavirus^[101][102] and Human herpes virus 6^[103][104] have been suggested as causes. A similar condition has been reported in cats but it is not known if there is any connection between these conditions.^[105]

See also[link]

• World Hepatitis Day
• Hepatocellular carcinoma

References[link]

External links[link]

• WHO fact sheet of hepatitis
• Viral Hepatitis at the Centers for Disease Control