Liver function tests: defining what's normal

[Guest guest]

BMJ 2004;328:987 (24 April), doi:10.1136/bmj.328.7446.987

Commentary

Liver function tests: defining what's normal

Roderick, senior lecturer in public health1

1 Community Clinical Sciences Research Division, University of Southampton,

B Floor, South Academic Block, Southampton General Hospital, Southampton

SO16 6YD

Correspondence to: P Roderick pjr@...

Chronic liver disease and hepatocellular carcinoma are major worldwide

public health problems in countries with endemically high levels of viral

hepatitis (B and C).1 However, even in western countries chronic liver

disease is an emerging problem, due not only to viral hepatitis but also to

the effects of lifestyle factors such as heavy alcohol consumption and

obesity.2 3

Liver function tests are widely performed blood tests used in patients with

suspected liver disease or unexplained illness and in some specific

situations such as screening of blood donors. The most widely used tests are

those used to detect the aminotransferases—alanine and aspartate—which are

associated with hepatocellular injury. Raised concentrations may indicate

serious underlying chronic liver disease, recognition of which is important

for guiding interventions to modify lifestyle and use of specific therapies

such as interferon for hepatitis C to prevent the risk of progression to

cirrhosis.

The sensitivity, specificity, and predictive values are important in

assessing the clinical utility of such tests. Normal ranges have been based

on distributions from healthy volunteers with two SD above the mean (that

is, top 2.5% cut-off) being considered the upper normal range.

Aminotransferase concentrations maybe within the normal range in people with

chronic liver disease.4 5 There is ongoing debate about whether to lower the

normal range to take account of changing lifestyle factors that influence

aminotransferase concentrations, particularly obesity, which in Western

countries would increase the detection of hepatitis C and alcoholic and

non-alcoholic fatty liver disease (NAFLD).6 7

Kim and colleagues have analysed the association between aminotransferase

concentrations and mortality from liver disease in a large prospective

cohort in Korea.1 They found that there was a graded increase in risk of

mortality from liver disease even within the normal range (20-40 IU/l)

compared with the lowest concentrations (< 20 IU/l) for both sexes. The

performance of the test in identifying future risk of mortality from liver

disease was maximised by lowering the threshold to about 30 IU/l. They

propose identifying a borderline level of aminotransferase of 30-39 IU/l,

suggesting that patients in this category should be further investigated

with more specific diagnostic tests for chronic liver disease.

What are the implications for countries with lower levels of chronic liver

disease than Korea? Test utility is affected by disease prevalence. In

countries with lower prevalence the negative predictive value (that is, the

ability of a negative test to exclude disease) will be higher and the

positive predictive value (that is, the ability of a positive test to

predict disease) will be lower. Lowering the upper normal range for

aminotransferase or including borderline cases will increase sensitivity at

the expense of specificity, so detecting more cases of chronic liver disease

but with a lower positive predictive value. These effects would be less

marked in those with suspected liver disease compared with the population as

whole. The cost effectiveness of further investigation of borderline cases

is not known but requires evaluation. A crucial diagnostic issue is how to

identify severe chronic liver disease (indicated by inflammation and

fibrosis), which is associated with high risk of progressing to cirrhosis.

Definitive evaluation currently relies on liver biopsy. Research is needed

to evaluate combinations of non-invasive measures to predict severe liver

disease; this could include patients with borderline concentrations of

aminotransferase.

--------------------------------------------------------------------------------

Competing interests: Research collaboration with Bayer Health-Care.

References

Kim HC, Nam CM, Jee SH, Han KH, Oh DY, Suh I. Normal serum aminotransferase

concentration and risk of mortality from liver disease: prospective cohort

study. BMJ 2004 doi/10.1136/bmj.38050.593634.63

JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated

aminotransferase levels in the United States. Am J Gastroenterol 2003;98:

960-7.[CrossRef][iSI][Medline]

Department of Health. On the state of the public health. The annual report

of the chief medical officer. London: Department of Health: 2002.

Kyrlagkitsis I, Portmann B, H, O'Grady J, Cramp ME. Liver histology

and progression of fibrosis in individuals with chronic hepatitis C and

normal elevated ALT. Am J Gastroenterol 2003;98: 1588-93.[iSI][Medline]

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in

asymptomatic patients. N Engl J Med 2000;342: 1266-71.[Free Full Text]

Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, del Vecchio E, et

al. Updated definitions of healthy ranges for serum alanine aminotransferase

levels. Ann Intern Med 2002;137: 1-9.[Abstract/Free Full Text]

Kaplan MM. Alanine transferase levels: what's normal. Ann Intern Med

2002;137: 49-50.[Free Full Text]

[Guest guest]

BMJ 2004;328:987 (24 April), doi:10.1136/bmj.328.7446.987

Commentary

Liver function tests: defining what's normal

Roderick, senior lecturer in public health1

1 Community Clinical Sciences Research Division, University of Southampton,

B Floor, South Academic Block, Southampton General Hospital, Southampton

SO16 6YD

Correspondence to: P Roderick pjr@...

Chronic liver disease and hepatocellular carcinoma are major worldwide

public health problems in countries with endemically high levels of viral

hepatitis (B and C).1 However, even in western countries chronic liver

disease is an emerging problem, due not only to viral hepatitis but also to

the effects of lifestyle factors such as heavy alcohol consumption and

obesity.2 3

Liver function tests are widely performed blood tests used in patients with

suspected liver disease or unexplained illness and in some specific

situations such as screening of blood donors. The most widely used tests are

those used to detect the aminotransferases—alanine and aspartate—which are

associated with hepatocellular injury. Raised concentrations may indicate

serious underlying chronic liver disease, recognition of which is important

for guiding interventions to modify lifestyle and use of specific therapies

such as interferon for hepatitis C to prevent the risk of progression to

cirrhosis.

The sensitivity, specificity, and predictive values are important in

assessing the clinical utility of such tests. Normal ranges have been based

on distributions from healthy volunteers with two SD above the mean (that

is, top 2.5% cut-off) being considered the upper normal range.

Aminotransferase concentrations maybe within the normal range in people with

chronic liver disease.4 5 There is ongoing debate about whether to lower the

normal range to take account of changing lifestyle factors that influence

aminotransferase concentrations, particularly obesity, which in Western

countries would increase the detection of hepatitis C and alcoholic and

non-alcoholic fatty liver disease (NAFLD).6 7

Kim and colleagues have analysed the association between aminotransferase

concentrations and mortality from liver disease in a large prospective

cohort in Korea.1 They found that there was a graded increase in risk of

mortality from liver disease even within the normal range (20-40 IU/l)

compared with the lowest concentrations (< 20 IU/l) for both sexes. The

performance of the test in identifying future risk of mortality from liver

disease was maximised by lowering the threshold to about 30 IU/l. They

propose identifying a borderline level of aminotransferase of 30-39 IU/l,

suggesting that patients in this category should be further investigated

with more specific diagnostic tests for chronic liver disease.

What are the implications for countries with lower levels of chronic liver

disease than Korea? Test utility is affected by disease prevalence. In

countries with lower prevalence the negative predictive value (that is, the

ability of a negative test to exclude disease) will be higher and the

positive predictive value (that is, the ability of a positive test to

predict disease) will be lower. Lowering the upper normal range for

aminotransferase or including borderline cases will increase sensitivity at

the expense of specificity, so detecting more cases of chronic liver disease

but with a lower positive predictive value. These effects would be less

marked in those with suspected liver disease compared with the population as

whole. The cost effectiveness of further investigation of borderline cases

is not known but requires evaluation. A crucial diagnostic issue is how to

identify severe chronic liver disease (indicated by inflammation and

fibrosis), which is associated with high risk of progressing to cirrhosis.

Definitive evaluation currently relies on liver biopsy. Research is needed

to evaluate combinations of non-invasive measures to predict severe liver

disease; this could include patients with borderline concentrations of

aminotransferase.

--------------------------------------------------------------------------------

Competing interests: Research collaboration with Bayer Health-Care.

References

Kim HC, Nam CM, Jee SH, Han KH, Oh DY, Suh I. Normal serum aminotransferase

concentration and risk of mortality from liver disease: prospective cohort

study. BMJ 2004 doi/10.1136/bmj.38050.593634.63

JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated

aminotransferase levels in the United States. Am J Gastroenterol 2003;98:

960-7.[CrossRef][iSI][Medline]

Department of Health. On the state of the public health. The annual report

of the chief medical officer. London: Department of Health: 2002.

Kyrlagkitsis I, Portmann B, H, O'Grady J, Cramp ME. Liver histology

and progression of fibrosis in individuals with chronic hepatitis C and

normal elevated ALT. Am J Gastroenterol 2003;98: 1588-93.[iSI][Medline]

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in

asymptomatic patients. N Engl J Med 2000;342: 1266-71.[Free Full Text]

Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, del Vecchio E, et

al. Updated definitions of healthy ranges for serum alanine aminotransferase

levels. Ann Intern Med 2002;137: 1-9.[Abstract/Free Full Text]

Kaplan MM. Alanine transferase levels: what's normal. Ann Intern Med

2002;137: 49-50.[Free Full Text]

[Guest guest]

BMJ 2004;328:987 (24 April), doi:10.1136/bmj.328.7446.987

Commentary

Liver function tests: defining what's normal

Roderick, senior lecturer in public health1

1 Community Clinical Sciences Research Division, University of Southampton,

B Floor, South Academic Block, Southampton General Hospital, Southampton

SO16 6YD

Correspondence to: P Roderick pjr@...

Chronic liver disease and hepatocellular carcinoma are major worldwide

public health problems in countries with endemically high levels of viral

hepatitis (B and C).1 However, even in western countries chronic liver

disease is an emerging problem, due not only to viral hepatitis but also to

the effects of lifestyle factors such as heavy alcohol consumption and

obesity.2 3

Liver function tests are widely performed blood tests used in patients with

suspected liver disease or unexplained illness and in some specific

situations such as screening of blood donors. The most widely used tests are

those used to detect the aminotransferases—alanine and aspartate—which are

associated with hepatocellular injury. Raised concentrations may indicate

serious underlying chronic liver disease, recognition of which is important

for guiding interventions to modify lifestyle and use of specific therapies

such as interferon for hepatitis C to prevent the risk of progression to

cirrhosis.

The sensitivity, specificity, and predictive values are important in

assessing the clinical utility of such tests. Normal ranges have been based

on distributions from healthy volunteers with two SD above the mean (that

is, top 2.5% cut-off) being considered the upper normal range.

Aminotransferase concentrations maybe within the normal range in people with

chronic liver disease.4 5 There is ongoing debate about whether to lower the

normal range to take account of changing lifestyle factors that influence

aminotransferase concentrations, particularly obesity, which in Western

countries would increase the detection of hepatitis C and alcoholic and

non-alcoholic fatty liver disease (NAFLD).6 7

Kim and colleagues have analysed the association between aminotransferase

concentrations and mortality from liver disease in a large prospective

cohort in Korea.1 They found that there was a graded increase in risk of

mortality from liver disease even within the normal range (20-40 IU/l)

compared with the lowest concentrations (< 20 IU/l) for both sexes. The

performance of the test in identifying future risk of mortality from liver

disease was maximised by lowering the threshold to about 30 IU/l. They

propose identifying a borderline level of aminotransferase of 30-39 IU/l,

suggesting that patients in this category should be further investigated

with more specific diagnostic tests for chronic liver disease.

What are the implications for countries with lower levels of chronic liver

disease than Korea? Test utility is affected by disease prevalence. In

countries with lower prevalence the negative predictive value (that is, the

ability of a negative test to exclude disease) will be higher and the

positive predictive value (that is, the ability of a positive test to

predict disease) will be lower. Lowering the upper normal range for

aminotransferase or including borderline cases will increase sensitivity at

the expense of specificity, so detecting more cases of chronic liver disease

but with a lower positive predictive value. These effects would be less

marked in those with suspected liver disease compared with the population as

whole. The cost effectiveness of further investigation of borderline cases

is not known but requires evaluation. A crucial diagnostic issue is how to

identify severe chronic liver disease (indicated by inflammation and

fibrosis), which is associated with high risk of progressing to cirrhosis.

Definitive evaluation currently relies on liver biopsy. Research is needed

to evaluate combinations of non-invasive measures to predict severe liver

disease; this could include patients with borderline concentrations of

aminotransferase.

--------------------------------------------------------------------------------

Competing interests: Research collaboration with Bayer Health-Care.

References

Kim HC, Nam CM, Jee SH, Han KH, Oh DY, Suh I. Normal serum aminotransferase

concentration and risk of mortality from liver disease: prospective cohort

study. BMJ 2004 doi/10.1136/bmj.38050.593634.63

JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated

aminotransferase levels in the United States. Am J Gastroenterol 2003;98:

960-7.[CrossRef][iSI][Medline]

Department of Health. On the state of the public health. The annual report

of the chief medical officer. London: Department of Health: 2002.

Kyrlagkitsis I, Portmann B, H, O'Grady J, Cramp ME. Liver histology

and progression of fibrosis in individuals with chronic hepatitis C and

normal elevated ALT. Am J Gastroenterol 2003;98: 1588-93.[iSI][Medline]

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in

asymptomatic patients. N Engl J Med 2000;342: 1266-71.[Free Full Text]

Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, del Vecchio E, et

al. Updated definitions of healthy ranges for serum alanine aminotransferase

levels. Ann Intern Med 2002;137: 1-9.[Abstract/Free Full Text]

Kaplan MM. Alanine transferase levels: what's normal. Ann Intern Med

2002;137: 49-50.[Free Full Text]

[Guest guest]

BMJ 2004;328:987 (24 April), doi:10.1136/bmj.328.7446.987

Commentary

Liver function tests: defining what's normal

Roderick, senior lecturer in public health1

1 Community Clinical Sciences Research Division, University of Southampton,

B Floor, South Academic Block, Southampton General Hospital, Southampton

SO16 6YD

Correspondence to: P Roderick pjr@...

Chronic liver disease and hepatocellular carcinoma are major worldwide

public health problems in countries with endemically high levels of viral

hepatitis (B and C).1 However, even in western countries chronic liver

disease is an emerging problem, due not only to viral hepatitis but also to

the effects of lifestyle factors such as heavy alcohol consumption and

obesity.2 3

Liver function tests are widely performed blood tests used in patients with

suspected liver disease or unexplained illness and in some specific

situations such as screening of blood donors. The most widely used tests are

those used to detect the aminotransferases—alanine and aspartate—which are

associated with hepatocellular injury. Raised concentrations may indicate

serious underlying chronic liver disease, recognition of which is important

for guiding interventions to modify lifestyle and use of specific therapies

such as interferon for hepatitis C to prevent the risk of progression to

cirrhosis.

The sensitivity, specificity, and predictive values are important in

assessing the clinical utility of such tests. Normal ranges have been based

on distributions from healthy volunteers with two SD above the mean (that

is, top 2.5% cut-off) being considered the upper normal range.

Aminotransferase concentrations maybe within the normal range in people with

chronic liver disease.4 5 There is ongoing debate about whether to lower the

normal range to take account of changing lifestyle factors that influence

aminotransferase concentrations, particularly obesity, which in Western

countries would increase the detection of hepatitis C and alcoholic and

non-alcoholic fatty liver disease (NAFLD).6 7

Kim and colleagues have analysed the association between aminotransferase

concentrations and mortality from liver disease in a large prospective

cohort in Korea.1 They found that there was a graded increase in risk of

mortality from liver disease even within the normal range (20-40 IU/l)

compared with the lowest concentrations (< 20 IU/l) for both sexes. The

performance of the test in identifying future risk of mortality from liver

disease was maximised by lowering the threshold to about 30 IU/l. They

propose identifying a borderline level of aminotransferase of 30-39 IU/l,

suggesting that patients in this category should be further investigated

with more specific diagnostic tests for chronic liver disease.

What are the implications for countries with lower levels of chronic liver

disease than Korea? Test utility is affected by disease prevalence. In

countries with lower prevalence the negative predictive value (that is, the

ability of a negative test to exclude disease) will be higher and the

positive predictive value (that is, the ability of a positive test to

predict disease) will be lower. Lowering the upper normal range for

aminotransferase or including borderline cases will increase sensitivity at

the expense of specificity, so detecting more cases of chronic liver disease

but with a lower positive predictive value. These effects would be less

marked in those with suspected liver disease compared with the population as

whole. The cost effectiveness of further investigation of borderline cases

is not known but requires evaluation. A crucial diagnostic issue is how to

identify severe chronic liver disease (indicated by inflammation and

fibrosis), which is associated with high risk of progressing to cirrhosis.

Definitive evaluation currently relies on liver biopsy. Research is needed

to evaluate combinations of non-invasive measures to predict severe liver

disease; this could include patients with borderline concentrations of

aminotransferase.

--------------------------------------------------------------------------------

Competing interests: Research collaboration with Bayer Health-Care.

References

Kim HC, Nam CM, Jee SH, Han KH, Oh DY, Suh I. Normal serum aminotransferase

concentration and risk of mortality from liver disease: prospective cohort

study. BMJ 2004 doi/10.1136/bmj.38050.593634.63

JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated

aminotransferase levels in the United States. Am J Gastroenterol 2003;98:

960-7.[CrossRef][iSI][Medline]

Department of Health. On the state of the public health. The annual report

of the chief medical officer. London: Department of Health: 2002.

Kyrlagkitsis I, Portmann B, H, O'Grady J, Cramp ME. Liver histology

and progression of fibrosis in individuals with chronic hepatitis C and

normal elevated ALT. Am J Gastroenterol 2003;98: 1588-93.[iSI][Medline]

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in

asymptomatic patients. N Engl J Med 2000;342: 1266-71.[Free Full Text]

Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, del Vecchio E, et

al. Updated definitions of healthy ranges for serum alanine aminotransferase

levels. Ann Intern Med 2002;137: 1-9.[Abstract/Free Full Text]

Kaplan MM. Alanine transferase levels: what's normal. Ann Intern Med

2002;137: 49-50.[Free Full Text]