Hepatitis

Hepatitis has a broad spectrum of presentations that range from a complete lack of symptoms to severe liver failure. The acute form of hepatitis, generally caused by viral infection, is characterized by constitutional symptoms that are typically self-limiting. Acute hepatitis Acute viral hepatitis follows three distinct phases: • The initial prodromal phase (preceding symptoms) involves non-specific and flu-like symptoms common to many acute viral infections. These include fatigue, nausea, vomiting, poor appetite, joint pain, and headaches. Both drug-induced hepatitis and autoimmune hepatitis can present very similarly to acute viral hepatitis, with slight variations in symptoms depending on the cause. Cases of drug-induced hepatitis can manifest with systemic signs of an allergic reaction including rash, fever, serositis (inflammation of membranes lining certain organs), elevated eosinophils (a type of white blood cell), and suppression of bone marrow activity. Chronic hepatitis is often asymptomatic early in its course and is detected only by liver laboratory studies for screening purposes or to evaluate non-specific symptoms. As the inflammation progresses, patients can develop constitutional symptoms similar to acute hepatitis, including fatigue, nausea, vomiting, poor appetite, and joint pain. Jaundice can occur as well, but much later in the disease process and is typically a sign of advanced disease. Chronic hepatitis interferes with hormonal functions of the liver which can result in acne, hirsutism (abnormal hair growth), and amenorrhea (lack of a menstrual period) in women. Extensive damage and scarring of the liver over time defines cirrhosis, a condition in which the liver's ability to function is permanently impeded. This results in jaundice, weight loss, coagulopathy, ascites (abdominal fluid collection), and peripheral edema (leg swelling). Cirrhosis can lead to other life-threatening complications such as hepatic encephalopathy, esophageal varices, hepatorenal syndrome, and liver cancer. == Causes ==

Causes of hepatitis can be divided into the following major categories: infectious, metabolic, ischemic, autoimmune, genetic, and other. Infectious agents include viruses, bacteria, and parasites. Metabolic causes include prescription medications, toxins (most notably alcohol), and non-alcoholic fatty liver disease. Autoimmune and genetic causes of hepatitis involve genetic predispositions and tend to affect characteristic populations. Infectious Viral hepatitis Viral hepatitis is the most common type of hepatitis worldwide, especially in Asia and Africa. Viral hepatitis is caused by five different viruses (hepatitis A, B, C, D, and E). Hepatitis B, hepatitis C, and hepatitis D are transmitted when blood or mucous membranes are exposed to infected blood and body fluids, such as semen and vaginal secretions. Many families who do not have safe drinking water or live in unhygienic homes have contracted hepatitis because saliva and blood droplets are often carried through the water and blood-borne illnesses spread quickly in unsanitary settings. Hepatitis B and C can present either acutely or chronically. Hepatitis C is the second most common cause of cirrhosis in the US (second to alcoholic hepatitis). In the 1970s and 1980s, blood transfusions were a major factor in spreading hepatitis C virus. Of the protozoans, Trypanosoma cruzi, Leishmania species, and the malaria-causing Plasmodium species all can cause liver inflammation. Pyogenic abscesses commonly involve enteric bacteria such as Escherichia coli and Klebsiella pneumoniae and are composed of multiple bacteria up to 50% of the time. The most important risk factors for the development of alcoholic hepatitis are quantity and duration of alcohol intake. Some drugs such as paracetamol exhibit predictable dose-dependent liver damage while others such as isoniazid cause idiosyncratic and unpredictable reactions that vary by person. The United States–based Drug Induced Liver Injury Network linked more than 16% of cases of hepatotoxicity to herbal and dietary supplements. In the United States, herbal and dietary supplements – unlike pharmaceutical drugs – are unregulated by the Food and Drug Administration. Exposure to other hepatotoxins can occur accidentally or intentionally through ingestion, inhalation, and skin absorption. The industrial toxin carbon tetrachloride and the wild mushroom Amanita phalloides are other known hepatotoxins. Non-alcoholic fatty liver disease Non-alcoholic hepatitis is within the spectrum of non-alcoholic liver disease (NALD), which ranges in severity and reversibility from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) to cirrhosis to liver cancer, similar to the spectrum of alcoholic liver disease. Non-alcoholic liver disease occurs in people with little or no history of alcohol use, and is instead strongly associated with metabolic syndrome, obesity, insulin resistance and diabetes, and hypertriglyceridemia. While imaging can show fatty liver, only liver biopsy can demonstrate inflammation and fibrosis characteristic of NASH. 9 to 25% of patients with NASH develop cirrhosis. The disease is thought to have a genetic predisposition as it is associated with certain human leukocyte antigens involved in the immune response. As in other autoimmune diseases, circulating auto-antibodies may be present and are helpful in diagnosis. Auto-antibodies found in patients with autoimmune hepatitis include the sensitive but less specific anti-nuclear antibody (ANA), smooth muscle antibody (SMA), and atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA). As with other autoimmune diseases, autoimmune hepatitis usually affects young females (though it can affect patients of either sex of any age), and patients can exhibit classic signs and symptoms of autoimmunity such as fatigue, anemia, anorexia, amenorrhea, acne, arthritis, pleurisy, thyroiditis, ulcerative colitis, nephritis, and maculopapular rash. Autoimmune hepatitis is distinct from the other autoimmune diseases of the liver, primary biliary cirrhosis and primary sclerosing cholangitis, both of which can also lead to scarring, fibrosis, and cirrhosis of the liver. Hemochromatosis and Wilson's disease are both autosomal recessive diseases involving abnormal storage of minerals. 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. Other Hepatitis can also occur in neonates and is attributable to a variety of causes, some of which are not typically seen in adults. Congenital or perinatal infection with the hepatitis viruses, toxoplasma, rubella, cytomegalovirus, and syphilis can cause neonatal hepatitis. This disease is termed giant cell hepatitis and may be associated with viral infection, autoimmune disorders, and drug toxicity. == Mechanism ==

The specific mechanism varies and depends on the underlying cause of the hepatitis. Generally, there is an initial insult that causes liver injury and activation of an inflammatory response, which can become chronic, leading to progressive fibrosis and cirrhosis. Rather, infection of liver cells activates the innate and adaptive arms of the immune system leading to an inflammatory response which causes cellular damage and death, including viral-induced apoptosis via the induction of the death receptor-mediated signaling pathway. Depending on the strength of the immune response, the types of immune cells involved and the ability of the virus to evade the body's defense, infection can either lead to clearance (acute disease) or persistence (chronic disease) of the virus. People with impaired immune response are at greater risk of developing chronic infection. Type I interferons are the cytokines that drive the antiviral response. In alcoholic hepatitis, chronic excess alcohol use is the culprit. == Diagnosis ==

Diagnosis of hepatitis is made on the basis of some or all of the following: a person's signs and symptoms, medical history including sexual and substance use history, blood tests, imaging, and liver biopsy. Blood testing includes liver enzymes, serology (i.e. for autoantibodies), nucleic acid testing (i.e. for hepatitis virus DNA/RNA), blood chemistry, and complete blood count. Generally, AST and ALT are elevated in most cases of hepatitis regardless of whether the person shows any symptoms. CT and especially MRI are able to provide a higher level of detail, allowing visualization and characterize such structures as vessels and tumors within the liver. Unlike steatosis and cirrhosis, no imaging test is able to detect liver inflammation (i.e. hepatitis) or fibrosis. The combination of antigen and antibody positivity can provide information about the stage of infection (acute or chronic), the degree of viral replication, and the infectivity of the virus. Thus, in patients who have no or negligible alcohol use, the diagnosis is unlikely to be alcoholic hepatitis. In those who drink alcohol, the diagnosis may just as likely be alcoholic or nonalcoholic hepatitis especially if there is concurrent obesity, diabetes, and metabolic syndrome. In this case, alcoholic and nonalcoholic hepatitis can be distinguished by the pattern of liver enzyme abnormalities; specifically, in alcoholic steatohepatitis AST>ALT with ratio of AST:ALT>2:1 while in nonalcoholic steatohepatitis ALT>AST with ratio of ALT:AST>1.5:1. Liver biopsies show identical findings in patients with ASH and NASH, specifically, the presence of polymorphonuclear infiltration, hepatocyte necrosis and apoptosis in the form of ballooning degeneration, Mallory bodies, and fibrosis around veins and sinuses. == Virus screening ==

The purpose of screening for viral hepatitis is to identify people infected with the disease as early as possible, even before symptoms and transaminase elevations may be present. This allows for early treatment, which can both prevent disease progression and decrease the likelihood of transmission to others. Hepatitis A Hepatitis A causes an acute illness that does not progress to chronic liver disease. Therefore, the role of screening is to assess immune status in people who are at high risk of contracting the virus, as well as in people with known liver disease for whom hepatitis A infection could lead to liver failure. People in these groups who are not already immune can receive the hepatitis A vaccine. Those at high risk and in need of screening include: • People in close contact (either living with or having sexual contact) with someone who has hepatitis A • People traveling to an area with endemic hepatitis A • People who do not have access to clean water • People who use illicit drugs • People with liver disease • People with poor sanitary habits such as not washing hands after using the restroom or changing diapers The presence of anti-hepatitis A IgG in the blood indicates past infection with the virus or prior vaccination. Hepatitis B The CDC, WHO, USPSTF, and ACOG recommend routine hepatitis B screening for certain high-risk populations. Specifically, these populations include people who are: • Beginning immunosuppressive or cytotoxic therapy People who are high-risk whose blood tests negative for HBsAg can receive the hepatitis B vaccine to prevent future infection. Screening consists of a blood test that detects the anti-hepatitis D virus antibody. If the anti-hepatitis D virus antibody is present, a confirmatory test to detect HDV RNA DNA indicates chronic disease. == Prevention ==

Vaccines Hepatitis A The CDC recommends the hepatitis A vaccine for all children beginning at age one, as well as for those who have not been previously immunized and are at high risk for contracting the disease. For children 12 months of age or older, the vaccination is given as a shot into the muscle in two doses 6–18 months apart and should be started before the age 24 months. The dosing is slightly different for adults depending on the type of the vaccine. If the vaccine is for hepatitis A only, two doses are given 6–18 months apart depending on the manufacturer. They also recommend it for those who desire it or are at high risk. Other There are currently no vaccines available in the United States for hepatitis C or E. As of March 2016, the United States government was in the process of recruiting participants for the phase IV trial of the hepatitis E vaccine. Behavioral changes Hepatitis A Because hepatitis A is transmitted primarily through the oral-fecal route, the mainstay of prevention aside from vaccination is good hygiene, access to clean water and proper handling of sewage. The hepatitis D virus requires that a person first be infected with hepatitis B virus, so prevention efforts should focus on limiting the spread of hepatitis B. In people who have chronic hepatitis B infection and are at risk for superinfection with the hepatitis D virus, the preventive strategies are the same as for hepatitis B. Hepatitis E Hepatitis E is spread primarily through the oral-fecal route but may also be spread by blood and from mother to fetus. The mainstay of hepatitis E prevention is similar to that for hepatitis A (namely, good hygiene and clean water practices). Alcoholic and metabolic hepatitis As excessive alcohol consumption can lead to hepatitis and cirrhosis, the following are maximal recommendations for alcohol consumption: • Men – ≤ 4 drinks on any given day and ≤ 14 drinks per week • Women – ≤ 3 drinks on any given day and ≤ 7 drinks per week To prevent MAFLD it is recommended to maintain a normal weight, eat a healthy diet, avoid added sugar, and exercise regularly. Successes Hepatitis A In the United States, universal immunization has led to a two-thirds decrease in hospital admissions and medical expenses due to hepatitis A. Hepatitis B In the United States new cases of hepatitis B decreased 75% from 1990 to 2004. The group that saw the greatest decrease was children and adolescents, likely reflecting the implementation of the 1999 guidelines. The data are unclear as to whether the decline can be attributed to needle exchange programmes. Alcoholic hepatitis Because people with alcoholic hepatitis may have no symptoms, it can be difficult to diagnose and the number of people with the disease is probably higher than many estimates. Programs such as Alcoholics Anonymous have been successful in decreasing death due to cirrhosis, but it is difficult to evaluate their success in decreasing the incidence of alcoholic hepatitis. == Treatment ==

The treatment of hepatitis varies according to the type, whether it is acute or chronic, and the severity of the disease. • Activity: Many people with hepatitis prefer bed rest, though it is not necessary to avoid all physical activity while recovering. The best way to reduce the long-term risk of HCC is to achieve sustained virological response (SVR). Currently available treatments include indirect and direct acting antiviral drugs. Hepatitis E Similar to hepatitis A, treatment of hepatitis E is supportive and includes rest and ensuring adequate nutrition and hydration. Hospitalization may be required for particularly severe cases or for pregnant women. Patients should also be treated appropriately for related signs and symptoms, such as ascites, hepatic encephalopathy, and infection. Available treatment options include pentoxifylline (PTX), which is a nonspecific TNF inhibitor, corticosteroids, such as prednisone or prednisolone (CS), corticosteroids with N-acetylcysteine (CS with NAC), and corticosteroids with pentoxifylline (CS with PTX).  The modified Maddrey's discriminant function may be used to evaluate the severity and prognosis in alcoholic hepatitis and evaluates the efficacy of using alcoholic hepatitis corticosteroid treatment. Metabolic hepatitis The main treatment of NASH is gradual weight loss and increased physical activity. In the United States, no medications have been approved to treat this disease. Autoimmune hepatitis Autoimmune hepatitis is commonly treated by immunosuppressants such as the corticosteroids prednisone or prednisolone, the active version of prednisolone that does not require liver synthesis, either alone or in combination with azathioprine, and some have suggested the combination therapy is preferred to allow for lower doses of corticosteroids to reduce associated side effects, Treatment of autoimmune hepatitis consists of two phases; an initial and maintenance phase. The initial phase consists of higher doses of corticosteroids which are tapered down over a number of weeks to a lower dose. If used in combination, azathioprine is given during the initial phase as well. Once the initial phase has been completed, a maintenance phase that consists of lower dose corticosteroids, and in combination therapy, azathioprine until liver blood markers are normalized. Treatment results in 66–91% of patients achieving normal liver test values in two years, with the average being 22 months. == Prognosis ==

Acute hepatitis Nearly all patients with hepatitis A infections recover completely without complications if they were healthy prior to the infection. Similarly, acute hepatitis B infections have a favorable course towards complete recovery in 95–99% of patients. Cirrhosis has been reported to develop in 20–50% of patients with chronic hepatitis C. Other rare complications of acute hepatitis include pancreatitis, aplastic anemia, peripheral neuropathy, and myocarditis. Mortality rates in cases of fulminant hepatitis rise over 80%, but those patients that do survive often make a complete recovery. Liver transplantation can be life-saving in patients with fulminant liver failure. Hepatitis D infections can transform benign cases of hepatitis B into severe, progressive hepatitis, a phenomenon known as superinfection. Chronic hepatitis Acute hepatitis B infections become less likely to progress to chronic forms as the age of the patient increases, with rates of progression approaching 90% in vertically transmitted cases of infants compared to 1% risk in young adults. Chronic hepatitis C progresses towards cirrhosis, with estimates of cirrhosis prevalence of 16% at 20 years after infection. While the major causes of mortality in hepatitis C is end stage liver disease, hepatocellular carcinoma is an important additional long term complication and cause of death in chronic hepatitis. Rates of mortality increase with progression of the underlying liver disease. Series of patients with compensated cirrhosis due to HCV have shown 3,5, and 10-year survival rates of 96, 91, and 79% respectively. The 5-year survival rate drops to 50% upon if the cirrhosis becomes decompensated. == Epidemiology ==

Viral hepatitis Hepatitis A Hepatitis A is found throughout the world and manifests as large outbreaks and epidemics associated with fecal contamination of water and food sources. Hepatitis A viral infection is predominant in children ages 5–14 with rare infection of infants. Infection rates are highest in low resource countries with inadequate public sanitation and large concentrated populations. In such regions, as much as 90% of children younger than 10 years old have been infected and are immune, corresponding both to lower rates of clinically symptomatic disease and outbreaks. The availability of a childhood vaccine has significantly reduced infections in the United States, with incidence declining by more than 95% as of 2013. Paradoxically, the highest rates of new infection now occur in young adults and adults who present with worse clinical illness. It is a common medical reason for liver transplantation due to its severe complications. Hepatitis C is particularly prevalent among people born between 1945 and 1965, a group of about 800,000 people, with prevalence as high as 3.2% versus 1.6% in the general U.S. population. but is frequently compared to or used as an example of viroids (in relation to humans). It is primarily transmitted via non-sexual contact and via needles. In infected pregnant women, Hepatitis E infection can lead to fulminant hepatitis with third trimester mortality rates as high as 30%. Most people who develop AH are men but women are at higher risk of developing AH and its complications likely secondary to high body fat and differences in alcohol metabolism. In this population, the presence of hepatitis C virus leads to more severe disease with faster progression to cirrhosis, hepatocellular carcinoma and increased mortality. Obesity increases the likelihood of progression to cirrhosis in cases of alcoholic hepatitis. About 20–45% of the U.S. population have NAFLD and 6% have NASH. Of NASH patients who develop cirrhosis, about 2% per year will likely progress to hepatocellular carcinoma. NASH is thought to be the primary cause of cirrhosis in approximately 25% of patients in the United States, representing 1–2% of the general population. == History ==

Early observations Initial accounts of a syndrome that is now considered to be hepatitis began to occur around 3000 B.C. Clay tablets that served as medical handbooks for the ancient Sumerians described the first observations of jaundice. The Sumerians believed that the liver was the home of the soul, and attributed the findings of jaundice to the attack of the liver by a devil named Ahhazu. Around 400 B.C., Hippocrates recorded the first documentation of an epidemic jaundice, in particular noting the uniquely fulminant course of a cohort of patients who all died within two weeks. He wrote, "The bile contained in the liver is full of phlegm and blood, and erupts...After such an eruption, the patient soon raves, becomes angry, talks nonsense and barks like a dog." Given the poor sanitary conditions of war, infectious jaundice played a large role as a major cause of mortality among troops in the Napoleonic Wars, the American Revolutionary War, and both World Wars. During World War II, estimates of soldiers affected by hepatitis were upwards of 10 million. During World War II, soldiers received vaccines against diseases such as yellow fever, but these vaccines were stabilized with human serum, presumably contaminated with hepatitis viruses, which often created epidemics of hepatitis. It was suspected these epidemics were due to a separate infectious agent, and not due to the yellow fever virus itself, after noting 89 cases of jaundice in the months after vaccination out of a total 3,100 patients that were vaccinated. After changing the seed virus strain, no cases of jaundice were observed in the subsequent 8,000 vaccinations. Willowbrook State School experiments A New York University researcher named Saul Krugman continued this research into the 1950s and 1960s, most infamously with his experiments on mentally disabled children at the Willowbrook State School in New York, a crowded urban facility where hepatitis infections were highly endemic to the student body. Krugman injected students with gamma globulin, a type of antibody. After observing the temporary protection against infection this antibody provided, he then tried injected live hepatitis virus into students. Krugman also controversially took feces from infected students, blended it into milkshakes, and fed it to newly admitted children. His research was received with much controversy, as people protested the questionable ethics surrounding the chosen target population. Henry Beecher was one of the foremost critics in an article in the New England Journal of Medicine in 1966, arguing that parents were unaware to the risks of consent and that the research was done to benefit others at the expense of children. Moreover, he argued that poor families with mentally disabled children often felt pressured to join the research project to gain admission to the school, with all of the educational and support resources that would come along with it. Others in the medical community spoke out in support of Krugman's research in terms of its widespread benefits and understanding of the hepatitis virus, and Willowbrook continues to be a commonly cited example in debates about medical ethics. Australia antigen The next insight regarding hepatitis B was a serendipitous one by Dr. Baruch Blumberg, a researcher at the NIH who did not set out to research hepatitis, but rather studied lipoprotein genetics. He travelled across the globe collecting blood samples, investigating the interplay between disease, environment, and genetics with the goal of designing targeted interventions for at-risk people that could prevent them from getting sick. He noticed an unexpected interaction between the blood of a patient with hemophilia that had received multiple transfusions and a protein found in the blood of an indigenous Australian person. He named the protein the "Australia antigen" and made it the focus of his research. He found a higher prevalence of the protein in the blood of patients from developing countries, compared to those from developed ones, and noted associations of the antigen with other diseases like leukemia and Down Syndrome. Eventually, he came to the unifying conclusion that the Australia antigen was associated with viral hepatitis. In 1970, David Dane first isolated the hepatitis B virion at London's Middlesex Hospital, and named the virion the 42-nm "Dane particle". == Society and culture ==

Economic burden Overall, hepatitis accounts for a significant portion of healthcare expenditures in both developing and developed nations, and is expected to rise in several developing countries. While hepatitis A infections are self-limited events, they are associated with significant costs in the United States. It has been estimated that direct and indirect costs are approximately $1817 and $2459 respectively per case, and that an average of 27 work days is lost per infected adult. Cost effectiveness studies have found widespread vaccination of adults to not be feasible, but have stated that a combination hepatitis A and B vaccination of children and at risk groups (people from endemic areas, healthcare workers) may be. Hepatitis B accounts for a much larger percentage of health care spending in endemic regions like Asia. In 1997 it accounted for 3.2% of South Korea's total health care expenditures and resulted in $696 million in direct costs. Chronic hepatitis B infections are not as endemic in the United States, but accounted for $357 million in hospitalization costs in the year 1990. It has been estimated that a person infected with hepatitis C in the United States will result in a monthly cost of $691. 2003 Monaca outbreak The largest outbreak of hepatitis A virus in United States history occurred among people who ate at a now-defunct Mexican food restaurant located in Monaca, Pennsylvania in late 2003. Over 550 people who visited the restaurant between September and October 2003 were infected with the virus, three of whom died as a direct result. After conducting its investigation, the CDC attributed the source of the outbreak to the use of contaminated raw green onion. The restaurant was purchasing its green onion stock from farms in Mexico at the time. It is believed that the green onions may have been contaminated through the use of contaminated water for crop irrigation, rinsing, or icing or by handling of the vegetables by infected people. Green onion had caused similar outbreaks of hepatitis A in the southern United States prior to this, but not to the same magnitude. The CDC believes that the restaurant's use of a large communal bucket for chopped raw green onion allowed non-contaminated plants to be mixed with contaminated ones, increasing the number of vectors of infection and amplifying the outbreak. The restaurant was closed once it was discovered to be the source, and over 9,000 people were given hepatitis A immune globulin because they had either eaten at the restaurant or had been in close contact with someone who had. == Special populations ==

HIV co-infection Persons infected with HIV have a particularly high burden of HIV-HCV co-infection. In a recent study by the WHO, the likelihood of being infected with hepatitis C virus was six times greater in those who also had HIV. Vertical transmission occurs largely via a neonate's exposure to maternal blood and vaginal secretions during birth. The risk of viral transmission is approximately 10–20% when maternal blood is positive for HBsAg, and up to 90% when also positive for HBeAg. It is safe for non-immune pregnant women to receive the HBV vaccine. A growing body of evidence shows that antiviral therapy initiated in the third trimester significantly reduces transmission to the neonate. A 2010 systematic review and meta-analysis found that Lamivudine initiated early in the third trimester also significantly reduced mother-to-child transmission of HBV, without any known adverse effects. The ACOG states that the evidence available does not suggest any particular mode of delivery (i.e. vaginal vs. cesarean) is better at reducing vertical transmission in mothers with HBV. The same study found the risk of vertical transmission to be 10.8% in HCV-positive, HIV-positive women. Hepatitis E Pregnant women who contract HEV are at significant risk of developing fulminant hepatitis with maternal mortality rates as high as 20–30%, most commonly in the third trimester . == Vaccine ==

An essential defense against hepatitis infections, especially those caused by Hepatitis A and B, is the hepatitis vaccination. The Hepatitis B vaccination is quite effective and frequently used. The frequency of hepatitis-related liver illnesses and fatalities has been considerably decreased by the immunization campaigns. == See also ==