people with clotting disorders who have received clotting factors, people with history of chronic liver disease in whom co-infection with hepatitis a can lead to fulminant hepatitis, and intravenous drug users (rare). hepatitis b main article: hepatitis b hbv replication hepatitis b is the most common cause of viral hepatitis in the world with more than 240 million chronic carriers of the virus, 1 million of whom are in the united states. in approximately two-thirds of patients who develop acute hepatitis b infection, no identifiable exposure is evident. of those acutely infected, 25% become lifetime carriers of the virus. risk of infection is highest among intravenous drug users, people with high-risk sexual behaviors, healthcare workers, people who had multiple transfusions, organ transplant patients, dialysis patients and newborns infected during the birthing process. close to 780,000 deaths in the world are attributed to hepatitis b. the most endemic regions are in sub-saharan africa and east asia, where as many as 10% of adults are chronic carriers. carrier rates in developed nations are significantly lower, encompassing less than 1% of the population. in endemic regions, transmission is thought to be associated with exposure during birth and close contact between young infants. hepatitis c main article: hepatitis c hepc replication chronic hepatitis c is a major cause of liver cirrhosis and hepatocellular carcinoma. it is a common medical reason for liver transplantation due to its severe complications. it is estimated that 130–180 million people in the world are affected by this disease representing a little more than 3% of the world population. in the developing regions of africa, asia and south america, prevalence can be as high as 10% of the population. in egypt, rates of hepatitis c infection as high as 20% have been documented and are associated with iatrogenic contamination related to schistosomiasis treatment in the 1950s–1980s. currently in the united states, approximately 3.5 million adults are estimated to be infected. 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. most chronic carriers of hepatitis c are unaware of their infection status. the most common mode of transmission of hepatitis c virus is exposure to blood products via blood transfusions (prior to 1992) and intravenous drug injection. a history of intravenous drug injection is the most important risk factor for chronic hepatitis c. other susceptible populations include those engaged in high-risk sexual behavior, infants of infected mothers, and healthcare workers. hepatitis d main article: hepatitis d the hepatitis d virus causes chronic and fulminant hepatitis in the context of co-infection with the hepatitis b virus. it is primarily transmitted via non-sexual contact and via needles. susceptibility to hepatitis d differs by geographic region. in the united states and northern europe, populations at risk are intravenous drug users and people who receive multiple transfusions. in the mediterranean, hepatitis d is predominant among hepatitis b virus co-infected people. hepatitis e main article: hepatitis e similar to hepatitis a, hepatitis e manifests as large outbreaks and epidemics associated with fecal contamination of water sources. it accounts for more than 55,000 deaths annually with approximately 20 million people worldwide thought to be infected with the virus. it affects predominantly young adults, causing acute hepatitis. in infected pregnant women, hepatitis e infection can lead to fulminant hepatitis with third trimester mortality rates as high as 30%. those with weakened immune systems, such as organ transplant recipients, are also susceptible. infection is rare in the united states but rates are high in the developing world (africa, asia, central america, middle east). many genotypes exist and are differentially distributed around the world. there is some evidence of hepatitis e infection of animals, serving as a reservoir for human infection. alcoholic hepatitis alcoholic hepatitis (ah) in its severe form has a one-month mortality as high as 50%. 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. other contributing factors include younger age <60, binge pattern drinking, poor nutritional status, obesity and hepatitis c co-infection. it is estimated that as much as 20% of people with ah are also infected with hepatitis c. 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. it is estimated that 70% of people who have ah will progress to cirrhosis. non-alcoholic steatohepatitis non-alcoholic steatohepatitis (nash) is projected to become the top reason for liver transplantation in the united states by 2020, supplanting chronic liver disease due to hepatitis c. about 20–45% of the u.s. population have nafld and 6% have nash. the estimated prevalence of nash in the world is 3–5%. of nash patients who develop cirrhosis, about 2% per year will likely progress to hepatocellular carcinoma. worldwide, the estimated prevalence of hepatocellular carcinoma related to nafld is 15–30%. 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 we now think is likely to be hepatitis begin 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". based on its association with the surface of the hepatitis b virus, the australia antigen was renamed to "hepatitis b surface antigen" or hbsag. blumberg continued to study the antigen, and eventually developed the first hepatitis b vaccine using plasma rich in hbsag, for which he received the nobel prize in medicine in 1976. 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. a 1997 report demonstrated that a single hospitalization related to hepatitis a cost an average of $6,900 and resulted in around $500 million in total annual healthcare costs. 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. a large majority of that sum was spent on treating disease symptoms and complications. chronic hepatitis b infections are not as endemic in the united states, but accounted for $357 million in hospitalization costs in the year 1990. that number grew to $1.5 billion in 2003, but remained stable as of 2006, which may be attributable to the introduction of effective drug therapies and vaccination campaigns. people infected with chronic hepatitis c tend to be frequent users of the health care system globally. it has been estimated that a person infected with hepatitis c in the united states will result in a monthly cost of $691. that number nearly doubles to $1,227 for people with compensated (stable) cirrhosis, while the monthly cost of people with decompensated (worsening) cirrhosis is almost five times as large at $3,682. the wide-ranging effects of hepatitis make it difficult to estimate indirect costs, but studies have speculated that the total cost is $6.5 billion annually in the united states. in canada, 56% of hcv related costs are attributable to cirrhosis and total expenditures related to the virus are expected to peak at cad$396 million in the year 2032. 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.