The work-up for abnormal aminotransferases differs according to the degree of alteration, since different etiologies are considered for mild elevations compared to moderate–severe elevations. However, as mentioned earlier, the degree of elevation does not necessarily reflect the extent of liver damage. Moderate–severe elevations are more suggestive of an acute liver injury, whereas when mild elevations in aminotransferases are encountered, chronic liver diseases should also be considered in addition to acute liver injury.

Mild alterations are commonly encountered by primary care physicians. Though some expert recommendations include repeating transaminases 6 months before initiating a work-up, the clinical scenario will likely dictate the urgency of further clinical evaluation. However, if repeat transaminases are normal, this does not entirely exclude liver diseases since aminotransferases fluctuate in liver disease. The importance of a thorough history cannot be overstated. Also, there should be a focus on identifying risk factors, family history, and possible exposures to over-the-counter medications, supplements, and alcohol. If there is clear exposure such as a medication and/or the pattern of aminotransferases is typical of alcohol use (AST:ALT >2), then it is reasonable to repeat transaminases after discontinuing the exposure. Initial testing for anti-HCV and HBsAg testing should be considered, especially in patients with IV drug use, exposure to nonsterile needles, or sexual exposure to an infected person with further consideration of anti-HCV testing in the age-based cohort of persons born between 1945 and 1965 and HBsAg testing in those of Asian descent.

Additional testing includes acquisition of ferritin, iron, and total iron-binding capacity (TIBC) to screen for hereditary hemochromatosis, and if both ferritin and transferrin saturation (iron/TIBC × 100) are increased, then it is reasonable to test for HFE gene mutation. Furthermore, it is reasonable to test for antinuclear antibodies (ANA), antismooth body antibodies (ASMA), immunoglobulin levels, and occasionally anti-LKM (liver–kidney microsomes) to rule out autoimmune hepatitis, especially in young or middle-aged women with concomitant autoimmune diseases. If the earlier tests are unrevealing, further serologic work-up to consider include alpha-1 antitrypsin levels to rule out alpha-1 antitrypsin deficiency, tissue transglutaminase antibodies to rule out celiac disease, and serum ceruloplasmin levels in patients under the age of 50 to evaluate for Wilson’s disease. In the absence of serological findings and a history of alcohol abuse, one shoulder consider the presence of nonalcoholic fatty liver disease (NAFLD), particularly in patients with conditions linked to metabolic syndrome and insulin resistance (i.e., increased BMI, diabetes, hyperlipidemia, hypertension). However, lack of the above-mentioned risk factors does not exclude the possibility of NAFLD. Despite the commonality and increasing prevalence of fatty liver disease [13], the lack of disease-specific serology can make the diagnosis challenging in the absence of histology.

Moderate-to-marked elevations in aminotransferases are usually more typical of acute compared to chronic liver disease. A moderate increase in aminotransferase levels has a higher sensitivity and specificity for identifying acute injury compared to mild elevations in aminotransferases. Studies have shown a sensitivity of 91 % and specificity of 95 % with an AST ≥ 200 IU/L while ALT levels ≥ 300 IU/L offer sensitivity of 96 % and specificity of 94 % [14]. Although there are certain liver injuries that are associated with markedly elevated aminotransferases, these same etiologies should be considered in mild elevations as well.

Certain patterns of liver injury are indicative of specific disease etiologies. For example, aminotransferases levels >75 times the upper limit of normal (ULN) are indicative of ischemic or toxic liver injury [15] with a subsequent rise in bilirubin levels 3–5 days after the insult. Acute viral hepatitis usually present with a more modest elevation of aminotransferases. Patients with moderate-to-marked increases (>10–20 × ULN) in aminotransferases should be tested for IgM antibodies to hepatitis A, IgM to hepatitis B core antigen, hepatitis B surface antigen, and hepatitis C antibody. If these are negative, it is reasonable to test for HCV RNA particularly in the setting of risk factors. Other considerations include acetaminophen-induced hepatic damage as it causes 54 and 16 % of acute liver failure in the United Kingdom and United States [16].

Another etiology of moderate elevations is alcohol-induced acute hepatitis damage. This can present as both acute and acute-on-chronic liver injury. The increase in AST levels is reported to be less than six to seven times the ULN in 98 % of the patients with alcoholic liver disease, and the AST:ALT ratio >1 in 92 % and >2 in 70 % of patients [17]. After these common causes have been excluded, other less common causes such as nonhepatotropic viruses such as Epstein–Barr virus , cytomegalovirus, and herpes simplex virus, as well as other infiltrative, autoimmune, extrahepatic, and congenital causes should be considered. Imaging modalities can point to extrahepatic causes by demonstrating a dilated biliary system particularly in the setting of biliary colic and/or known gallstones (Fig. 1.1).

Despite being produced predominantly in the liver and bone, alkaline phosphatase isoenzymes can be found in renal, intestinal, placental tissue, or within leukocytes. In the liver, alkaline phosphatase is located on the canalicular membrane of hepatocytes and an increase in serum levels usually indicates osseous or hepatobiliary pathology. With a half-life of approximately 6 days, an increase in alkaline phosphatase levels occurs secondary to increased synthesis with leakage of the serum and not due to decreased clearance.

GGT is a microsomal enzyme located throughout the body, including hepatocytes and cholangiocytes in the liver, kidney, pancreas, spleen, heart, brain, and seminal vesicles. It has a high sensitivity for hepatobiliary disease but lacks specificity. Levels can become elevated in patients taking certain classes of medications, including anticonvulsants, oral contraceptives, barbiturates, antiretroviral therapy, as well as patients with comorbidities, such as chronic obstructive pulmonary disease, renal failure, and acute myocardial infarctions. GGT is clinically useful to identify the etiology of an isolated increase in alkaline phosphatase, as it is not elevated in bone disease. Elevated GGT levels also occur in alcohol-related liver disease, even in patients with normal alkaline phosphatase levels. Because of its high sensitivity, some physicians advocate acquisition of GGT levels as an indirect marker of current alcohol consumption [18]. Beyond alcohol liver disease, GGT levels may also be two to three times greater in more than 50 % of patients with NAFLD [19]. Because elevated GGT levels are frequently elevated in most forms of liver disease, it is most useful when evaluating patients with an elevated alkaline phosphatase levels with otherwise normal liver enzymes and bilirubin levels.

There is some physiologic variation of serum alkaline phosphatase levels in certain populations, including certain physiologic circumstance in which the intestinal alkaline phosphatase can be proportionately elevated and result in elevated serum levels. For instance, because patients with blood type O and B have increased intestinal alkaline phosphatase after a fatty meal [20], some physicians recommend obtaining fasting alkaline phosphatase levels. Also, elevated intestinal alkaline phosphatase can be indicative of certain benign familial conditions, including familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis, which are typically characterized by elevations in the alkaline phosphatase despite a normal GGT with occasional elevations in the bilirubin level. The age of the individual also has an impact on the serum alkaline phosphatase levels with levels being twice as high in adolescents compared with adults due to increased bone growth. In addition, there is an unexplained increase in levels after age 30 years old, but the increase is greater in women compared to men [21].

Patients with Wilson’s disease may have a low serum alkaline phosphatase, especially when the patient presents with fulminant hepatitis and hemolysis. It is thought that this is due to reduced activity of the enzyme, owing to displacement of the cofactor zinc by copper.

Table 1.2 lists the common causes of elevated levels [12]. When patients have an isolated elevated alkaline phosphatase or if the alkaline phosphatase is elevated out of proportion to the other liver enzymes, one should consider cholestatic disorders.