Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease†

This document presents the official position of the American Association for the Study of Liver Diseases (AASLD) on the application of serum alanine aminotransferase (ALT) activity, based upon an analysis of the currently available scientific data. Its authorship was selected by the Public Policy Committee. The document is fully endorsed by the AASLD Governing Board. Physicians caring for patients with liver disease, predominantly hepatologists and gastroenterologists, have long been aware that measurements of liver enzyme activities (serum aminotransferases, including ALT alanine aminotransferase and AST asparate amniotransferase) are critical in the diagnosis and assessment of liver disease. These enzymes were formerly referred to as SGPT and SGOT, respectively. The serum ALT activity (hereafter termed ALT) has been regarded as a reliable and sensitive marker of liver disease. ALT may also be a good indicator of overall health, particularly in the context of obesity, the metabolic syndrome, and presence of cardiovascular disease, as many patients affected by these conditions also are at risk of having non-alcoholic fatty liver disease. Despite all these considerations, abnormal ALT activity is often ignored or minimized by practitioners as most patients are asymptomatic. Minor elevations are often construed to be clinically insignificant, in part because of lack of a longitudinal perspective about the impact of abnormal ALT on long-term outcome such as end-stage liver disease or premature mortality. This document summarizes the position of the American Association for the Study of Liver Disease regarding ALT and includes review of its physiology, its distribution in health and disease, and its role as a screening and diagnostic test and clinical tool. Specifically, the significance of ALT measurements for determining general health, liver health and liver disease is addressed. The purpose of this document is to reinforce that the significance and etiology of a persistently elevated ALT must be evaluated regardless of the degree of elevation and to examine ALT as a population screening tool for early detection of liver disease. Alanine aminotransferase (ALT) is an enzyme that catalyzes the transfer of amino groups to form the hepatic metabolite oxaloacetate.1 It is composed of 496 amino acids, which are encoded by a gene located in the long arm of chromosome 8.2, 3 ALT is found abundantly in the cytosol of the hepatocyte. ALT activity in the liver is about 3000 times that of serum activity. Thus, in the case of hepatocellular injury or death, release of ALT from damaged liver cells increases measured ALT activity in the serum. Although it is generally thought to be specific to the liver, it is also found in the kidney, and, in much smaller quantities, in heart and skeletal muscle cells. ALT released in the blood is catabolized in the liver with a resulting plasma half life of 47 ± 10 hours, which is considerably longer than that of AST (17 ± 5 hours).1 ALT activity varies day to day, by 10% to 30%. Within a given day, there is a significant diurnal variation, with ALT activities being up to 45% higher in the afternoon than in the early morning.4, 5 In acute hepatocellular injury, serum AST levels usually rise immediately, reaching a higher level than ALT initially, due to the higher activity of AST in hepatocytes and its release with liver injury. Within 24 to 48 hours, particularly if ongoing damage occurs, ALT will become higher than AST, because of its longer plasma half-life. In chronic hepatocellular injury, ALT is more commonly elevated than AST; however, as fibrosis progresses, ALT activities typically decline, and the ratio of AST to ALT gradually increases, so that by the time cirrhosis is present, AST is often higher than ALT.6, 7 One notable exception to the predominance of serum ALT activity in chronic liver disease is alcoholic liver disease where AST activity is generally higher than ALT levels. AIH, autoimmune hepatitis; ALD, alcoholic liver disease; ALT, alanine aminotransferase; ANA, antinuclear antibofy; AST, aspartate aminotransferase; BMI, body mass index; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HDL, high-density lipoprotein; MAST, Michigan alcoholism screening test; NAFLD, non-alcoholic fatty liver disease; SMA, smooth muscle actin; SMR, standardized mortality ratio; ULN, upper limit of normal. ALT measurement affords a readily available, low-cost blood test that is utilized throughout the United States as a tool for detection of liver disease. ALT is a valuable screening test to detect otherwise inapparent liver disease, such as asymptomatic viral hepatitis and non-alcoholic fatty liver disease, both of which represent an epidemic that remains largely undiagnosed in the United States. Apart from liver disease, however, serum ALT activity may be affected by a number of factors not associated with hepatic necrosis. ALT levels differ with gender, with higher values in men than in women.8 Additional factors that affect serum ALT levels include body mass index (BMI) and triglyceride levels, regardless of gender.9-11 Total cholesterol levels and alcohol consumption among men have a positive correlation, whereas smoking, physical activity and age have a negative correlation with ALT levels.11-13 Glucose levels, in women, have a positive correlation with ALT activities, whereas use of oral contraceptives tends to lower ALT values. Some of these correlations (such as BMI) may be explained by ALT being higher in people with fatty liver disease. Similarly, patients with hyperlipidemia or hyperglycemia may also have fatty liver disease, as a part of the metabolic syndrome. In light of the increasing prevalence of obesity in Americans, the distribution of ALT in the apparently healthy population has changed such that some patients with non-alcoholic fatty liver disease may have ALTs in the normal range as determined by the mean ± 2 standard deviations.9 In response, some physicians have advocated lowering the normal range.8 To the extent that there is a rough correlation between ALT and degree of hepatic inflammation in general, patients with high ALT levels tend to have more severe inflammation in the liver than those with normal ALT values. In contrast, the correlation between ALT and degree of hepatic fibrosis, the parameter that is most relevant to the prognosis of the patient, is not very strong, as exemplified by the common observation that a cirrhotic patient may have normal or only mildly elevated ALT. Since serum ALT levels rise in disease states that cause hepatocellular injury, serum ALT levels can effectively identify an ongoing liver disease process. The probability of clinically significant liver disease increases, particularly if the elevated ALT is associated with symptoms such as fatigue, anorexia or pruritus. The utility of additional evaluation of a patient with asymptomatic elevation of ALT depends upon the findings of history and physical examination, the length of time that ALT has been elevated and the level of ALT elevation. Whereas one study suggested that the majority of asymptomatic people with elevated ALT do not have significant liver disease, a Scandinavian study of 151 consecutive patients with mild to moderate elevations of serum aminotransferase levels for at least 6 months revealed that liver disease was common.14, 15 Diagnoses included non-alcoholic steatohepatitis and hepatic steatosis (noted in 42%), chronic HCV (15%), alcoholic liver disease (8%) and autoimmune hepatitis, primary biliary cirrhosis and alpha1 antitrypsin deficiency in smaller numbers. The level of ALT also guides the urgency and extent of further investigation. A serum ALT level less than 5 times the upper limit of the normal range should be rechecked before an extensive work-up is undertaken. If elevated ALT levels are confirmed and if they remain persistently elevated, additional work-up is indicated. ALT levels greater than 5 times the upper limit of the normal range suggest a potentially serious, active liver disease process and work-up should be initiated without waiting to confirm the persistence of abnormal ALT. ALT levels greater than 15 times the normal range indicate severe acute liver cell injury and evaluation should be initiated immediately. The differential diagnosis for patients with severe acute liver injury (ALT levels >15 times the normal range) is relatively limited. Acute viral hepatitis (A-E), ischemic hepatitis or other vascular disorders such as acute venous outflow occlusion (Budd-Chiari), or toxin-mediated hepatitis should be considered. Acute autoimmune hepatitis, hepatic lymphoma or acute biliary occlusion may also present with highly elevated ALT activity. The diagnosis may be made upon historical grounds ischemic episode, risk factors of acquisition of viral hepatitis, medication or hepatotoxin exposure (e.g., isoniazid) or overdose (e.g., acetaminophen). Blood testing (hepatitis and autoimmune serologies) may be helpful where applicable, whereas abdominal imaging may be helpful in other settings (e.g., venous outflow obstruction, biliary obstruction or abnormal lymphadenopathy). NAFLD is probably the most common cause of abnormal ALT values among US adults and may affect up to 3% of the US population.16, 17 Risk factors for NAFLD include obesity, diabetes and hyperlipidemia.18 Elevated ALT may be a component of the metabolic syndrome, the hallmark of which is insulin resistance, manifested by hyperglycemia, hyperlipidemia, abdominal obesity and hypertension. The role of NAFLD as an increasing threat to public health is highlighted by the well-publicized trend in the proportion of overweight or obese Americans.19 Similarly, the prevalence of the metabolic syndrome is also increasing rapidly.20 In these patients, testing for ALT will facilitate timely diagnosis of NAFLD before irreversible fibrosis of the liver is established. Elevated ALT activities may be the only clue to this entity since there are no definitive blood tests to confirm the diagnosis. Furthermore, patients with high ALT among those with the metabolic syndrome may represent a subgroup with a propensity for systemic inflammation that may, in turn, increase the risk of atherosclerosis, leading to coronary artery or cerebrovascular disease.21 Elevated ALT levels may correlate with the severity of NAFLD. In a study in which 233 morbidly obese women were examined, 60% had some degree of hepatic fibrosis, and the majority of these patients had an elevated ALT value. Twenty-eight percent of patients with mild fibrosis and 68% of patients with advanced fibrosis had raised ALT activity. ALT levels were elevated in only 17% of patients without fibrosis.22 These observations are helpful in correlating elevated ALT with severity of liver damage. Therefore, ALT represents an excellent screening test to detect significant NAFLD.23 ALD remains the most common cause of liver-related morbidity and mortality in the United States.24 In alcoholic liver injury, AST activity is characteristically elevated in comparison to ALT activity, although mild elevation of ALT level is common.25 This is thought to be due to the longer half-life of mitochondrial AST released in response to alcohol and the coexistence of deficiency of pyridoxal-6-phosphate in alcoholics, which is a cofactor for the enzymatic activity of ALT.26 History of alcohol use should be ascertained by accurate questioning such as with the CAGE questionnaire27 or the MAST (Michigan alcoholism screening test)28 in all patients with serum aminotransferase elevations. Random blood alcohol level is sometimes useful in distinguishing ALD from NAFLD. The histology of ALD may be indistinguishable from that of NAFLD.29 Chronic HCV infection is the most common chronic blood-borne infection in the United States, affecting approximately 2% of the population.30, 31 However, ALT levels fluctuate in HCV and values may occasionally fall into the normal range.32 Since HCV infection is frequently asymptomatic, ALT elevations noted upon routine blood testing often stimulate the work-up whereby HCV infection is diagnosed. Sixty-nine percent of 248 asymptomatic blood donors who tested positive for HCV antibody had elevated ALT activity.33 Sixty-eight percent of patients positive for HCV RNA had elevated ALT levels, compared with 17% of those without detectable RNA. Patients with severe liver damage on liver biopsy in this cohort had at least 1 elevated ALT determination. Twenty-nine percent of HCV-infected patients with initially normal ALT values, when followed, will develop persistently elevated ALT levels, and 57% will develop transient elevation in ALT activities within 5 years.34 HCV patients with persistently normal ALT levels (at least 2 normal ALT values within 6 months) are more likely to be females35 and tend to have lower necroinflammatory and fibrosis scores on liver biopsy when compared to similar patients with elevated ALT activities.36, 37 Significant fibrosis was found in 8% to 20% of patients with normal ALT levels compared to 60% of patients with elevated ALT activities. While ALT analysis alone may fail to detect a minority of persons infected with HCV, it is most effective in detecting those persons whose liver disease is more severe. Such a characteristic enhances the value of ALT as a screening tool for detection of clinically important liver disease. Moreover, the sensitivity of ALT analysis can be improved with serial measurements and long-term follow-up. Chronic HBV infection, a common etiology of elevated ALT values worldwide, afflicts at least 1.3 million individuals in the United States.38 Certain risk groups, such as individuals born in endemic countries, with a history of injection drug use, or on hemodialysis, may be identified in whom prevalence of HBV infection is particularly high in the United States.39 Chronic HBV infection is also frequently asymptomatic and is sometimes discovered because of an elevated ALT level identified upon routine blood testing. Among HBV patients, the level of ALT is associated with progression of liver disease and development of morbidity. The cumulative risk of development of complications is in patients with ALT values at least 1 to 2 times the upper of normal Among patients who are hepatitis B e ALT is also of the of Thus, in HBV patients, ALT is useful not only in determining the presence of significant liver disease and for also in the in the history of the The use of many has been associated with elevated ALT and are also If elevated ALT levels are should be and ALT levels should be If ALT activity remains elevated, other should be If the medication must be for clinical ALT activity should be If ALT values to increase or are associated with development of symptoms or of hepatic the medication must be hepatitis may also be identified by of mild to moderate elevations of ALT Patients may be asymptomatic or have symptoms such as and the diagnosis is confirmed with testing such as antinuclear antibody and smooth muscle antibody and a liver may be considered. activity an important role in determining and also response in those who Although AST activity has been in these ALT activity is important in these ALT levels may also be elevated in hepatic such as primary biliary cirrhosis or primary elevations in ALT level may be noted in a relatively common of in people of Elevated and serum levels are usually of the gene the although a liver biopsy with remains a useful diagnostic to the extent of liver injury and of Liver biopsy is in patients with elevated ALT levels, elevated serum and gene of the disease are not usually noted the or in men and the or in It is particularly important to identify patients with early in because liver injury can be with of disease can be if before complications elevations in ALT activity may also identify other less common disorders such as disease and Furthermore, mild elevations of ALT levels are also in the of While ALT is useful as an test in detecting liver disease, its value as a of overall health and is a between ALT activity and when the process not from the The to the between elevated ALT values and mortality risk was based on a cohort of of a health in In this there were individuals of between and in whom and between and were This cohort was up to when were to and of 1 summarizes the impact of levels of ALT on mortality. In of the had ALT whereas only of women had ALT ALT activity, in with higher mortality from all and liver disease. the of ALT was much on mortality. compared to those with ALT men with ALT had times the risk of from liver disease. In women, a similar trend was the number of and in the ALT was the risk in this Risk of to ALT. risk from all of and from liver disease in men and women is In the ALT activity with the risk of cardiovascular mortality as with those with ALT men with ALT had 3 times the risk of from cardiovascular A similar trend was suggested in women, the of cardiovascular was of the in women more A similar analysis has been in on a all who had ALT determined in the were identified and who had in had ALT had within normal and The standardized mortality ratio associated with ALT between 1 and 2 times the was whereas ALT greater than 2 times the was the other ALT less than the was associated with lower risk of than The of ALT being a marker of cardiovascular health has been evaluated by and who the and to correlate ALT activity and risk of coronary artery disease in the general US in the the for the which of lack of or heart and including ALT activity at least of not have hepatitis B or or history of alcohol These included whose ALT was within normal and who had elevated ALT activities. these 2 groups were compared to those with elevated ALT activity had higher cholesterol lower high-density and higher blood and were more likely to be These and other risk factors for coronary artery disease were in a Risk to the risk of coronary artery disease. with elevated ALT levels were to have increase in the risk of coronary artery disease within 10 In women, there was a increase in These that ALT activity is of mortality in the general While mortality may be due to liver disease, it may also be to other risk factors for ALT elevation including obesity, serum and plasma in to alcohol which are to health The cardiovascular mortality risk associated with ALT activity may in part be explained by the metabolic syndrome commonly present in patients with non-alcoholic fatty liver disease. ALT may as a marker of a that is associated with higher cardiovascular risk among individuals with the metabolic The clinical and so suggest that ALT may be useful as a screening test for early detection of asymptomatic liver disease and for other of premature mortality. is as the of disease by or other which can be and A screening test is not to be it is to individuals with a high probability of disease from those with a In a screening test or the most is the by and The the 10 of the to ALT as a screening test for early detection of liver disease in the The primary for which ALT is to is chronic liver disease, which may to liver end-stage liver disease hepatocellular Chronic liver disease is the leading cause of in the United In hepatocellular which in patients with chronic liver disease, is one of the most common the It is that the of and mortality from in the United States has been increasing in the further the of chronic liver disease as a public health of chronic liver disease is with of hepatic fibrosis, leading to although the at which this progression varies by the specific liver disease and by use diagnostic tests to the degree of fibrosis, which has most commonly been a liver although for this assessment are being These the progression of disease in In most chronic liver disease, the disease between the of disease and end-stage liver disease is measured in and This for screening with ALT to detect liver disease in a is as an irreversible Chronic liver disease to effective may be at an early to progression to In such as chronic hepatitis patients with advanced fibrosis have response to than in those with disease. ALT is a test to identify with chronic liver disease in an asymptomatic if not chronic liver disease a component of hepatic inflammation and hepatocellular which ALT is thought to Although high to the diagnostic of ALT in the detection of liver disease in the general population are by or by suggest of ALT as a test to detect chronic liver disease in its early a blood ALT is as as many other such as screening and serum cholesterol Patients with chronic liver disease are commonly in age or and ALT testing before the of life may identify most asymptomatic patients with liver disease. However, further are to at ALT screening must be or to the of a of screening ALT. elevated serum aminotransferase activities 1 of the most common for or study is available to to that may if screening of ALT were to be A diagnostic to identify patients with chronic liver disease that may most from may clinical from such a screening These 2 the and of ALT as a screening its and in general of for morbidity and mortality associated with abnormal ALT, the physical and and of an screening likely the of early diagnosis of chronic liver disease. However, the and of population screening ALT have not been ALT is an part of the evaluation of patients with liver disease. Its as a screening test for liver disease is highlighted by the that most patients with common liver such as viral hepatitis B and and non-alcoholic fatty liver disease have elevated ALT, they remain without symptoms to a Thus, although the and use of ALT analysis may differ specific liver disease ALT is a sensitive test to detect individuals with liver disease. The of ALT activity as an indicator of liver disease has been in which a between ALT and mortality from liver disease. Furthermore, suggest that ALT has a role as a of mortality of liver disease. This is generally construed to NAFLD as a component of the metabolic of insulin resistance, which the development of cardiovascular disease. ALT activity may be important not only as a marker of liver also as an indicator of general although measurement of ALT is commonly as a part of the hepatic the significance of this test may have been In ALT as a screening tool for the found that ALT most of the for a screening However, additional will the and of ALT These include of the for ALT screening and assessment of the impact of its as as its While for these that ALT is an excellent screening test in individuals at risk of liver disease. an abnormal ALT as determined by a normal must an clinical The the Public Policy of AASLD for the to to this document on its The of