Hepatitis

Hepatitis (plural hepatitides) implies injury to liver characterised by presence of inflammatory cells in the liver tissue. Etymologically from ancient Greek hepar (ηπαρ) or hepato- (ηπατο-) meaning 'liver' and suffix -itis denoting 'inflammation' (c.1727^[1]). The condition can be self limiting, healing on its own or can progress to scarring of the liver. Acute hepatitis is when it lasts less than 6 months and chronic hepatitis is when it persists longer. A group of viruses known as the hepatitis viruses cause most cases of liver damage worldwide. Hepatitis can also be due to toxins (notably alcohol), other infections or from autoimmune process. It may run a subclinical course when the affected person may not feel ill. The patient becomes unwell and symptomatic when the disease impairs liver functions that include, among other things, screening of harmful substances, regulation of blood composition, and production of bile to help digestion.

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Causes

Acute hepatitis

• Viral Hepatitis: Hepatitis A to E (more than 95% of viral cause), Herpes simplex, Cytomegalovirus, Epstein-Barr, yellow fever virus, adenoviruses.
• Non viral infection: toxoplasma, Leptospira, Q fever,^[2] rocky mountain spotted fever^[3]
• Alcohol
• Toxins: Amanita toxin in mushrooms, Carbon tetrachloride, asafetida
• Drugs: Paracetamol, amoxycillin, anti tuberculosis medicines, minocycline and many others (see longer list below).
• Ischemic hepatitis (circulatory insufficiency)
• Pregnancy
• Auto immune conditions e.g. Systemic Lupus Erythematosus (SLE)
• Metabolic diseases e.g. Wilson's disease

Chronic hepatitis

• Viral Hepatitis: Hepatitis B with or without hepatitis D, Hepatitis C (Hepatitis A and E do not lead to chronic disease)
• Autoimmune: Autoimmune hepatitis
• Alcohol
• Drugs: methyl-dopa, nitrofurantoin, isoniazide, ketoconazole
• Non-alcoholic steatohepatitis
• Heredity: Wilson's disease, alpha 1-antitrypsin deficiency
• Primary biliary cirrhosis and primary sclerosing cholangitis occasionally mimic chronic hepatitis^[4]

Signs and symptoms

Acute Hepatitis

Clinically, the course of acute hepatitis varies widely from mild symptoms requiring no treatment to fulminant hepatic failure needing liver transplantation. Acute viral hepatitis are 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.^[4]

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 (33%) and tender hepatomegaly (10%). There can be occasional lymphadenopathy (5%) or splenomegaly (5%).^[5]

Chronic Hepatitis

Majority of patients will remain asymptomatic or mildly symptomatic, abnormal blood tests being the only manifestation. Features may be related to extent of liver damage or the cause of hepatitis. Many experience return of symptoms related to acute hepatitis. Jaundice can be a late feature and may indicate extensive damage. Other features include abdominal fullness from enlarged liver or spleen, low grade fever and fluid retention (ascites). Extensive damage and scarring of liver i.e. cirrhosis leads to weight loss, easy bruising and bleeding tendencies. Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis.^[6]

Findings on clinical examination are usually those of cirrhosis or are related to aetiology.

Types of hepatitis

Please see the respective articles for more detailed information.

See also: Infectious canine hepatitis

Viral

Most cases of acute hepatitis are due to viral infections:

• Hepatitis A
• Hepatitis B
• Hepatitis C
• Hepatitis B with D
• Hepatitis E
• Hepatitis F (existence unknown)
• Hepatitis G
• In addition to the hepatitis viruses (please note that the hepatitis viruses are not all related). Other viruses can also cause hepatitis, including cytomegalovirus, Epstein-Barr virus, yellow fever, etc.

Hepatitis A

Hepatitis A or infectious jaundice is caused by a picornavirus. It is transmitted by the orofecal route, transmitted to humans through methods such as contaminated food. It causes an acute form of hepatitis and does not have a chronic stage. The patient's immune system makes antibodies against hepatitis A that confer immunity against future infection. People with hepatitis A are advised to rest, stay hydrated and avoid alcohol. A vaccine is available that will prevent infection from hepatitis A for life. Hepatitis A can be spread through personal contact, consumption of raw sea food or drinking contaminated water. This occurs primarily in third world countries. Strict personal hygiene and the avoidance of raw and unpeeled foods can help prevent an infection. Infected people excrete the hepatitis A virus with their faeces two weeks before and one week after the appearance of jaundice. The time between the infection and the start of the illness can run from 15 to 45 days, and approximately 15% of sufferers may experience relapsing symptoms from six months to a year following initial diagnosis.

Hepatitis B

Hepatitis B is caused by a hepadnavirus, which can cause both acute and chronic hepatitis. Chronic hepatitis develops in the 15% of patients who are unable to eliminate the virus after an initial infection. Identified methods of transmission include blood (blood transfusion, now rare), tattoos (both amateur and professionally done), sexually (through sexual intercourse or through contact with blood or bodily fluids), or via mother to child by breast feeding (minimal evidence of transplacental crossing). However, in about half of cases the source of infection cannot be determined. Blood contact can occur by sharing syringes in intravenous drug use, shaving accessories such as razor blades, or touching wounds on infected persons. Needle-exchange programmes have been created in many countries as a form of prevention. Patients with chronic hepatitis B have antibodies against hepatitis B, but these antibodies are not enough to clear the infection that establishes itself in the DNA of the affected liver cells. The continued production of virus combined with antibodies is a likely cause of immune complex disease seen in these patients. A vaccine is available that will prevent infection from hepatitis B for life. Hepatitis B infections result in 500,000 to 1,200,000 deaths per year worldwide due to the complications of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatitis B is endemic in a number of (mainly South-East Asian) countries, making cirrhosis and hepatocellular carcinoma big killers. There are six FDA-approved treatment options available for persons with a chronic hepatitis B infection: alpha-interferon, pegylated interferon adefovir, entecavir, telbivudine and lamivudine. About 45% of persons on treatment achieve a sustained response.

Hepatitis C

Hepatitis C (originally "non-A non-B hepatitis") is caused by a flavivirus. It can be transmitted through contact with blood (including through sexual contact where the two parties' blood is mixed) and can also cross the placenta. Hepatitis C may lead to a chronic form of hepatitis, culminating in cirrhosis. It can remain asymptomatic for 10-20 years. Patients with hepatitis C are susceptible to severe hepatitis if they contract either hepatitis A or B, so all hepatitis C patients should be immunized against hepatitis A and hepatitis B if they are not already immune. The virus can cause cirrhosis of the liver. HCV viral levels can be reduced to undetectable levels by a combination of interferon and the antiviral drug ribavirin. The genotype of the virus determines the rate of response to this treatment regimen. Genotype 1 is more resistant to interferon therapy than other HCV genotypes.

Hepatitis D

Hepatitis D is considered a subviral satellite, as it can only propagate in the presence of the Hepatitis B virus.

Hepatitis E

Hepatitis E produces symptoms similar to hepatitis A, although it can take a fulminant course in some patients, particularly pregnant women; it is more prevalent in the Indian subcontinent.

Hepatitis F

Hepatitis F is a hypothetical virus linked to hepatitis. Several hepatitis F candidates emerged in the 1990s; none of these reports have been substantiated.

Hepatitis G

Another type of hepatitis, hepatitis G, has been identified,^[7] and is probably spread by blood and sexual contact.^[8] There is, however, doubt about whether it causes hepatitis, or is just associated with hepatitis, as it does not appear to be primarily replicated in the liver.^[9]

Other viral infections can cause hepatitis (inflammation of the liver):

• Mumps virus
• Rubella virus
• Cytomegalovirus
• Epstein-Barr virus
• Other herpes viruses

Alcoholic hepatitis

Main article: Alcoholic hepatitis

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. The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis in Western countries.

Drug induced hepatitis

A large number of drugs can cause hepatitis. The anti-diabetic drug troglitazone was withdrawn in 2000 for causing hepatitis. Other drugs associated with hepatitis:^[10]

• Allopurinol
• Amitriptyline (antidepressant)
• Amiodarone (antiarrhythmic)
• Azathioprine^[11][12]
• Halothane (a specific type of anesthetic gas)
• Hormonal contraceptives
• Ibuprofen and indomethacin (NSAIDs)
• Isoniazid (INH), rifampicin, and pyrazinamide (tuberculosis-specific antibiotics)
• Ketoconazole (antifungal)
• Methyldopa (antihypertensive)
• Minocycline (tetracycline antibiotic)
• Nifedipine (antihypertensive)
• Nitrofurantoin (antibiotic)
• Phenytoin and valproic acid (antiepileptics)
• Zidovudine (antiretroviral i.e. against HIV)
• Some herbs and nutritional supplements

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 that cause hepatitis

Toxins and drugs 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.
• Paracetamol (acetaminophen in the United States) can cause hepatitis when taken in an overdose. The severity of liver damage can be limited by prompt administration of acetylcysteine.
• Carbon tetrachloride ("tetra", a dry cleaning agent), chloroform, and trichloroethylene, all chlorinated hydrocarbons, cause steatohepatitis (hepatitis with fatty liver).
• Cylindrospermopsin, a toxin from the cyanobacterium Cylindrospermopsis raciborskii and other cyanobacteria.

Metabolic disorders

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.

See below for non-alcoholic steatohepatitis (NASH), effectively a consequence of metabolic syndrome.

Obstructive

"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

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.

Autoimmune hepatitis has an incidence of 1-2 per 100,000 per year, and a prevalence of 15-20/100,000. As with most other autoimmune diseases, it affects women much more often than men (8:1). Liver enzymes are elevated, as is bilirubin. Autoimmune hepatitis can progress to cirrhosis. Treatment is with steroids and disease-modifying antirheumatic drugs (DMARDs).

The diagnosis of autoimmune hepatitis is best achieved with a combination of clinical and laboratory findings. A number of specific antibodies found in the blood (antinuclear antibody (ANA), smooth muscle antibody (SMA), Liver/kidney microsomal antibody (LKM-1) 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. In complex cases a scoring system can be used to help determine if a patient has autoimmune hepatitis, which combines clinical and laboratory features of a given case.

Four subtypes are recognised, but the clinical utility of distinguishing subtypes is limited.

1. Positive ANA and SMA, raised immunoglobulin G (classic form, responds well to low dose steroids)
2. Positive LKM-1 (typically female children and teenagers; disease can be severe)
3. All antibodies negative, positive antibodies against soluble liver antigen (SLA)(now designated SLP/LP). This group behaves like group 1.
4. No autoantibodies detected (~13%)

Alpha 1-antitrypsin deficiency

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

Nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a type of hepatitis which resembles alcoholic hepatitis on liver biopsy (fat droplets, inflammatory cells, but usually no Mallory's hyaline) but occurs in patients who have no known history of alcohol abuse. NASH is more common in women and the most common cause is obesity or the metabolic syndrome. A related but less serious condition is called "fatty liver" (steatosis hepatis), which occurs in up to 80% of all clinically obese people. A liver biopsy for fatty liver shows fat droplets throughout the liver, but no signs of inflammation or Mallory's hyalin.

The diagnosis depends on 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 radiologic imaging including ultrasound, computed tomographic imaging, or magnetic resonance imaging. However, radiologic 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 repeat 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.

Ischemic hepatitis

See also: Ischemic hepatitis

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 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.

Hepatitis awareness

World Hepatitis Awareness Day is an annual event organised by several worldwide hepatitis advocacy groups to raise awareness of infectious hepatitis and demand action to curb the spread of the disease and treat people who are infected.

References