Normal Enzyme Levels May Hide Advanced Liver Fibrosis

[Guest guest]

http://www.medpagetoday.com/Gastroenterology/GeneralHepatology/tb/10846

Normal Enzyme Levels May Hide Advanced Liver Fibrosis

By Judith Groch, Contributing Writer, MedPage Today

Published: September 09, 2008

Reviewed by Zalman S. Agus, MD; Emeritus Professor

University of Pennsylvania School of Medicine.

MILAN, Italy, Sept. 9 -- Patients with nonalcoholic fatty liver disease but

normal alanine aminotransferase (ALT) levels are still at risk of severe hepatic

disease, researchers found. Action Points

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

Explain to interested patients that among patients with nonalcoholic fatty liver

disease, the risk of developing severe disease persists despite normal liver

enzyme levels.

Explain that in the absence of a biopsy or a simple test to identify those at

risk, patients require careful follow-up and lifestyle changes to reduce

metabolic syndrome risks.

More than half of such patients had advanced fibrosis, as well as altered

glucose metabolism and insulin resistance, Silvia Fargion, M.D., of the

University of Milan, and colleagues reported in the September issue of

Hepatology.

Nonalcoholic fatty liver disease is now considered the hepatic expression of

metabolic syndrome -- obesity, type 2 diabetes, and dyslipidemia account for the

risk of advanced liver disease, in addition to the well-established

cardiovascular risk, the researchers wrote.

However, the most common criterion for referral to a liver unit is the presence

of elevated liver enzymes, and only individuals with increased ALT levels have

been enrolled in most nonalcoholic fatty liver disease studies.

So, the researchers said, it is uncertain whether patients with normal ALT have

a milder disease and whether they should undergo liver biopsy.

To shed some light on the subject, the researchers reviewed the histological

data of 458 patients with nonalcoholic fatty liver disease who underwent liver

biopsy from January 2003 through June 2006.

Of these, 395 (86%) had altered liver enzymes; 63 with persistently elevated

ferritin or long-lasting severe steatosis had normal ALT levels.

Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis( ™2)

were identified by multivariate analysis. Patients with normal ALT were

significantly older, had lower body mass index, fasting triglycerides, insulin

resistance, ALT, and gamma-glutamyltransferase, but a higher prevalence of

hypertension.

Nonalcoholic steatohepatitis was diagnosed in 59% of patients with normal ALT

and in 74% of those with increased ALT (P=0.01).

In the overall series of patients, nonalcoholic fatty liver was independently

predicted by ALT (odds 1.11, 95% confidence interval 1.04 to 1.19 per 10-IU/mL

increase) and diabetes (OR 1.5, 95% CI 1.1 to 2.0).

The same variables were selected in patients with increased ALT, whereas in

those with normal ALT, homeostasis model assessment (HOMA-IR), and ALT were

independent predictors.

Severe fibrosis was independently predicted by serum ferritin (OR 1.04, 95% CI

1.001 to 1.08 per 50-ng/mL increase), ALT (OR 1.07, 95% CI 1.02 to 1.14), and

diabetes (OR 1.8, 95% CI 1.4 to 2.3) in the overall series; serum ferritin and

diabetes in those with increased ALT.

However, only homeostasis model assessment (HOMA-IR) predicted more severe

fibrosis in patients with normal ALT (OR 1.97, 95% CI 1.2 to 3.7).

The evidence suggests that liver biopsy might be mandatory in most cases unless

sensitive and specific noninvasive tests currently unavailable prove their

efficacy. However, the investigators said, this raises the question of the

feasibility and cost-effectiveness of liver biopsy in an extremely large at-risk

population.

At present, biopsy is rarely indicated for patients with normal ALT. For this

reason there were only 63 cases with normal ALT for this study, a definite

limitation, the researchers noted.

A recently proposed scoring system (NASH score) to identify patients with

advanced fibrosis potentially rendering liver biopsy unnecessary in 75% of

cases, found a positive predictive value of 100% and a negative predictive value

of 89.6% for identifying patients with and without advanced fibrosis,

respectively.

The findings from the present study suggest that the score could also be used in

the general population, including in persons with normal ALT.

Diabetes and insulin resistance were factors most closely associated with severe

liver disease in that population.

In addition, hypertension, a key feature of the metabolic syndrome, was

surprisingly more prevalent in patients with normal ALT.

This underlines the fact that the metabolic alterations related to steatosis and

to adipose tissue-related endocrine dysfunction occur independently of overt

liver damage.

Study limitations included the small number of patients with a normal ALT, and

the variability of liver biopsy in the sample. The large number of patients

referred to the liver units for hyperferritinemia means that this patient

population was not truly representative, the researchers said.

These data indicate that more than half of nonalcoholic liver disease patients

with normal ALT levels have a potentially progressive liver disease, they said.

In the absence of biopsy or of an adequate score to identify those at risk,

these patients could miss careful follow-up and might not be motivated to adopt

lifestyle changes that might cure their liver disease and the extrahepatic

manifestations of the metabolic syndrome.

Clinicians should be aware of the importance of a complete clinical evaluation

for early diagnosis and treatment of liver disease, as well as the different

manifestations of the metabolic syndrome, they concluded.

The study was supported by grants from FIRST 2005-2006, Ricerca Corrente IRCCS

2004-2006, and Centro Universitario per lo Studio delle Malattie Metaboliche del

Fegato.

No conflicts of interest were reported.

Additional source: Hepatology

Source reference:

Fracanzani AL, et al " Risk of Severe Liver Disease in Nonalcoholic Fatty Liver

Disease with Normal Aminotransferase levels: A Role for Insulin Resistance and

Diabetes " Hepatology 2008; 48: 792-798.

[Guest guest]

http://www.medpagetoday.com/Gastroenterology/GeneralHepatology/tb/10846

Normal Enzyme Levels May Hide Advanced Liver Fibrosis

By Judith Groch, Contributing Writer, MedPage Today

Published: September 09, 2008

Reviewed by Zalman S. Agus, MD; Emeritus Professor

University of Pennsylvania School of Medicine.

MILAN, Italy, Sept. 9 -- Patients with nonalcoholic fatty liver disease but

normal alanine aminotransferase (ALT) levels are still at risk of severe hepatic

disease, researchers found. Action Points

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

Explain to interested patients that among patients with nonalcoholic fatty liver

disease, the risk of developing severe disease persists despite normal liver

enzyme levels.

Explain that in the absence of a biopsy or a simple test to identify those at

risk, patients require careful follow-up and lifestyle changes to reduce

metabolic syndrome risks.

More than half of such patients had advanced fibrosis, as well as altered

glucose metabolism and insulin resistance, Silvia Fargion, M.D., of the

University of Milan, and colleagues reported in the September issue of

Hepatology.

Nonalcoholic fatty liver disease is now considered the hepatic expression of

metabolic syndrome -- obesity, type 2 diabetes, and dyslipidemia account for the

risk of advanced liver disease, in addition to the well-established

cardiovascular risk, the researchers wrote.

However, the most common criterion for referral to a liver unit is the presence

of elevated liver enzymes, and only individuals with increased ALT levels have

been enrolled in most nonalcoholic fatty liver disease studies.

So, the researchers said, it is uncertain whether patients with normal ALT have

a milder disease and whether they should undergo liver biopsy.

To shed some light on the subject, the researchers reviewed the histological

data of 458 patients with nonalcoholic fatty liver disease who underwent liver

biopsy from January 2003 through June 2006.

Of these, 395 (86%) had altered liver enzymes; 63 with persistently elevated

ferritin or long-lasting severe steatosis had normal ALT levels.

Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis( ™2)

were identified by multivariate analysis. Patients with normal ALT were

significantly older, had lower body mass index, fasting triglycerides, insulin

resistance, ALT, and gamma-glutamyltransferase, but a higher prevalence of

hypertension.

Nonalcoholic steatohepatitis was diagnosed in 59% of patients with normal ALT

and in 74% of those with increased ALT (P=0.01).

In the overall series of patients, nonalcoholic fatty liver was independently

predicted by ALT (odds 1.11, 95% confidence interval 1.04 to 1.19 per 10-IU/mL

increase) and diabetes (OR 1.5, 95% CI 1.1 to 2.0).

The same variables were selected in patients with increased ALT, whereas in

those with normal ALT, homeostasis model assessment (HOMA-IR), and ALT were

independent predictors.

Severe fibrosis was independently predicted by serum ferritin (OR 1.04, 95% CI

1.001 to 1.08 per 50-ng/mL increase), ALT (OR 1.07, 95% CI 1.02 to 1.14), and

diabetes (OR 1.8, 95% CI 1.4 to 2.3) in the overall series; serum ferritin and

diabetes in those with increased ALT.

However, only homeostasis model assessment (HOMA-IR) predicted more severe

fibrosis in patients with normal ALT (OR 1.97, 95% CI 1.2 to 3.7).

The evidence suggests that liver biopsy might be mandatory in most cases unless

sensitive and specific noninvasive tests currently unavailable prove their

efficacy. However, the investigators said, this raises the question of the

feasibility and cost-effectiveness of liver biopsy in an extremely large at-risk

population.

At present, biopsy is rarely indicated for patients with normal ALT. For this

reason there were only 63 cases with normal ALT for this study, a definite

limitation, the researchers noted.

A recently proposed scoring system (NASH score) to identify patients with

advanced fibrosis potentially rendering liver biopsy unnecessary in 75% of

cases, found a positive predictive value of 100% and a negative predictive value

of 89.6% for identifying patients with and without advanced fibrosis,

respectively.

The findings from the present study suggest that the score could also be used in

the general population, including in persons with normal ALT.

Diabetes and insulin resistance were factors most closely associated with severe

liver disease in that population.

In addition, hypertension, a key feature of the metabolic syndrome, was

surprisingly more prevalent in patients with normal ALT.

This underlines the fact that the metabolic alterations related to steatosis and

to adipose tissue-related endocrine dysfunction occur independently of overt

liver damage.

Study limitations included the small number of patients with a normal ALT, and

the variability of liver biopsy in the sample. The large number of patients

referred to the liver units for hyperferritinemia means that this patient

population was not truly representative, the researchers said.

These data indicate that more than half of nonalcoholic liver disease patients

with normal ALT levels have a potentially progressive liver disease, they said.

In the absence of biopsy or of an adequate score to identify those at risk,

these patients could miss careful follow-up and might not be motivated to adopt

lifestyle changes that might cure their liver disease and the extrahepatic

manifestations of the metabolic syndrome.

Clinicians should be aware of the importance of a complete clinical evaluation

for early diagnosis and treatment of liver disease, as well as the different

manifestations of the metabolic syndrome, they concluded.

The study was supported by grants from FIRST 2005-2006, Ricerca Corrente IRCCS

2004-2006, and Centro Universitario per lo Studio delle Malattie Metaboliche del

Fegato.

No conflicts of interest were reported.

Additional source: Hepatology

Source reference:

Fracanzani AL, et al " Risk of Severe Liver Disease in Nonalcoholic Fatty Liver

Disease with Normal Aminotransferase levels: A Role for Insulin Resistance and

Diabetes " Hepatology 2008; 48: 792-798.