for consumers to track all known prescription and non-prescription compounds associated with liver injury. 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 main article: 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. over time, non-alcoholic fatty liver disease can progress to non-alcoholic steatohepatitis, which additionally involves liver cell death, liver inflammation and possible fibrosis. factors accelerating progression from nafld to nash are obesity, older age, non-african american ethnicity, female gender, diabetes mellitus, hypertension, higher alt or ast level, higher ast/alt ratio, low platelet count, and an ultrasound steatosis score. in the early stages (as with nafld and early nash), most patients are asymptomatic or have mild right upper quadrant pain, and diagnosis is suspected on the basis of abnormal liver function tests. as the disease progresses, symptoms typical of chronic hepatitis may develop. 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. nash is recognized as the third most common cause of liver disease in the united states. autoimmune main article: autoimmune hepatitis autoimmune hepatitis is a chronic disease caused by an abnormal immune response against liver cells. 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). other autoantibodies that are less common but more specific to autoimmune hepatitis are the antibodies against liver kidney microsome 1 (lkm1) and soluble liver antigen (sla). autoimmune hepatitis can also be triggered by drugs (such as nitrofurantoin, hydralazine, and methyldopa), after liver transplant, or by viruses (such as hepatitis a, epstein-barr virus, or measles). autoimmune hepatitis can present anywhere within the spectrum from asymptomatic to acute or chronic hepatitis to fulminant liver failure. patients are asymptomatic 25–34% of the time, and the diagnosis is suspected on the basis of abnormal liver function tests. some studies show between 25% and 75% of cases present with signs and symptoms of acute hepatitis. 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 increases the risk for cirrhosis, and the risk for liver cancer is increased by about 1% for each year of the disease. many people with autoimmune hepatitis have other autoimmune diseases. 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. genetic genetic causes of hepatitis include alpha-1-antitrypsin deficiency, hemochromatosis, and wilson's disease. in alpha-1-antitrypsin deficiency, a co-dominant mutation in the gene for alpha-1-antitrypsin results in the abnormal accumulation of the mutant aat protein within liver cells, leading to liver disease. hemochromatosis and wilson's disease are both autosomal recessive diseases involving abnormal storage of minerals. in hemochromatosis, excess amounts of iron accumulate in multiple body sites, including the liver, which can lead to cirrhosis. in wilson's disease, excess amounts of copper accumulate in the liver and brain, causing cirrhosis and dementia. when the liver is involved, alpha-1-antitrypsin deficiency and wilson's disease tend to present as hepatitis in the neonatal period or in childhood. hemochromatosis typically presents in adulthood, with the onset of clinical disease usually after age 50. ischemic hepatitis main article: ischemic hepatitis ischemic hepatitis (also known as shock liver) results from reduced blood flow to the liver as in shock, heart failure, or vascular insufficiency. 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 main article: neonatal hepatitis 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. structural abnormalities such as biliary atresia and choledochal cysts can lead to cholestatic liver injury leading to neonatal hepatitis. metabolic diseases such as glycogen storage disorders and lysosomal storage disorders are also implicated. neonatal hepatitis can be idiopathic, and in such cases, biopsy often shows large multinucleated cells in the liver tissue. 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. viral hepatitis stages of liver disease the pathway by which hepatic viruses cause viral hepatitis is best understood in the case of hepatitis b and c. the viruses do not directly activate apoptosis (cell death). 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. the chronic presence of the virus within liver cells results in multiple waves of inflammation, injury and wound healing that over time lead to scarring or fibrosis and culminate in hepatocellular carcinoma. people with impaired immune response are at greater risk of developing chronic infection. natural killer cells are the primary drivers of the initial innate response and create a cytokine environment that results in the recruitment of cd4 t-helper and cd8 cytotoxic t-cells. type i interferons are the cytokines that drive the antiviral response. in chronic hepatitis b and c, natural killer cell function is impaired. steatohepatitis steatohepatitis is seen in both alcoholic and non-alcoholic liver disease and is the culmination of a cascade of events that began with injury. in the case of non-alcoholic steatohepatitis, this cascade is initiated by changes in metabolism associated with obesity, insulin resistance, and lipid dysregulation. in alcoholic hepatitis, chronic excess alcohol use is the culprit. though the inciting event may differ, the progression of events is similar and begins with accumulation of free fatty acids (ffa) and their breakdown products in the liver cells in a process called steatosis. this initially reversible process overwhelms the hepatocyte's ability to maintain lipid homeostasis leading to a toxic effect as fat molecules accumulate and are broken down in the setting of an oxidative stress response. over time, this abnormal lipid deposition triggers the immune system via toll-like receptor 4 (tlr4) resulting in the production of inflammatory cytokines such as tnf that cause liver cell injury and death. these events mark the transition to steatohepatitis and in the setting of chronic injury, fibrosis eventually develops setting up events that lead to cirrhosis and hepatocellular carcinoma. microscopically, changes that can be seen include steatosis with large and swollen hepatocytes (ballooning), evidence of cellular injury and cell death (apoptosis, necrosis), evidence of inflammation in particular in zone 3 of the liver, variable degrees of fibrosis and mallory bodies. diagnosis most elevated aminotransferase cause alt chronic hepatitis b, c, and d nonalcoholic liver disease acute viral hepatitis medications/toxins autoimmune hepatitis wilson's disease alpha-1-antitrypsin deficiency hemochromatosis ischemic hepatitis (severe elevation up to thousands) ast alcoholic liver disease cirrhosis histopathology of acute hepatitis with lobular disarray and associated lymphocytic inflammation, acidophil body formation (arrow) and bilirubinostasis. 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. in general, for viral hepatitis and other acute causes of hepatitis, the person's blood tests and clinical picture are sufficient for diagnosis. for other causes of hepatitis, especially chronic causes, blood tests may not be useful. in this case, liver biopsy is the gold standard for establishing the diagnosis: histopathologic analysis is able to reveal the precise extent and pattern of inflammation and fibrosis. biopsy is typically not the initial diagnostic test because it is invasive and is associated with a small but significant risk of bleeding that is increased in people with liver injury and cirrhosis. 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. characteristic patterns of liver enzyme abnormalities can point to certain causes or stages of hepatitis. generally, ast and alt are elevated in most cases of hepatitis regardless of whether the person shows any symptoms. the degree of elevation (i.e. levels in the hundreds vs. in the thousands), the predominance for ast vs. alt elevation, and the ratio between ast and alt are informative of the diagnosis. ultrasound, ct, and mri can all identify steatosis (fatty changes) of the liver tissue and nodularity of the liver surface suggestive of cirrhosis. 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. liver biopsy is the only definitive diagnostic test that is able to assess inflammation and fibrosis of the liver. viral hepatitis main article: viral hepatitis viral hepatitis is primarily diagnosed through blood tests for levels of viral antigens (such as the hepatitis b surface or core antigen), anti-viral antibodies (such as the anti-hepatitis b surface antibody or anti-hepatitis a antibody), or viral dna/rna. in early infection (i.e. within 1 week), igm antibodies are found in the blood. in late infection and after recovery, igg antibodies are present and remain in the body for up to years. therefore, when a patient is positive for igg antibody but negative for igm antibody, he is considered immune from the virus via either prior infection and recovery or prior vaccination. in the case of hepatitis b, blood tests exist for multiple virus antigens (which are different components of the virion particle) and antibodies. 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. alcoholic versus non-alcoholic the most apparent distinguishing factor between alcoholic steatohepatitis (ash) and nonalcoholic steatohepatitis (nash) is a history of excessive alcohol use. 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