What is the significance of isolated elevated levels of a specific substance, such as enzymes or hormones, in the blood?

From the Guidelines

Isolated elevated liver function tests should be evaluated with a comprehensive approach, considering the patient's clinical history, physical examination, and additional diagnostic tests, as the majority of abnormal results do not indicate significant liver disease 1. When evaluating isolated elevated liver function tests, it is essential to consider the patient's overall clinical presentation, as most abnormal results are not indicative of significant liver disease. According to the guidelines on the management of abnormal liver blood tests, the next step is to determine the likelihood of liver fibrosis using non-invasive tests such as FIB-4 or NAFLD fibrosis score 1.

Key Considerations

• The severity of abnormal aminotransferase can be classified as mild, moderate, or severe, with moderate and severe categories having significant clinical overlap 1.
• Pathologically increased levels of ALP may occur in cholestatic liver disease, and concomitantly elevated GGT can help confirm that an elevated ALP originates from the liver 1.
• Isolated elevated ALP of hepatic origin that persists over time suggests a chronic cholestatic process, such as partial bile duct obstruction, primary biliary cholangitis, or drug-induced cholestasis 1.

Diagnostic Approach

• Initial assessment includes calculation of a FIB-4 or NAFLD fibrosis score, with values <1.3 and ≤1.455, respectively, signifying a low risk of advanced fibrosis 1.
• Second-line tests that should be considered include serum markers such as ELF and imaging modalities such as ARFI elastography/FibroScan 1.
• Measurements of GGT can indicate whether pathologically elevated ALP is of hepatic or nonhepatic origin 1.

Management

• Referral to a hepatology clinic is recommended for assessment of liver disease, management of advanced fibrosis, screening and treatment of portal hypertension, and HCC screening and management 1.
• Lifestyle modifications, such as reducing alcohol consumption, maintaining a healthy weight, and following a balanced diet, can help manage liver disease and prevent progression 1.

From the FDA Drug Label

During all clinical studies in the U. S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values ≥ 3 times the upper limit of normal during treatment. If serum transaminase levels are increased (ALT > 2. 5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2. 5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation.

Isolated elevated liver enzymes (ALT) may occur in patients taking pioglitazone.

• The incidence of ALT values ≥ 3 times the upper limit of normal is approximately 0.30% in patients treated with ACTOS.
• Patients with mildly elevated liver enzymes should be evaluated to determine the cause of the elevation, and initiation or continuation of therapy with ACTOS should proceed with caution and include appropriate clinical follow-up.
• If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible, and ACTOS therapy should be discontinued if the levels remain elevated or if the patient is jaundiced 2 2.

From the Research

Isolated Elevated Liver Enzymes

• Isolated elevated liver enzymes can be caused by various factors, including non-alcoholic fatty liver disease (NAFLD), alcohol intake, and hepatitis C virus infection 3.
• A study found that the most common cause of transaminase elevation was NAFLD (40%), followed by alcohol intake (17%), and hepatitis C virus infection (13%) 3.
• Elevated gamma-glutamyl transpeptidase (GGT) levels were most commonly related to NAFLD (30%), closely followed by alcohol intake (27%), and hepatotoxicity (8%) 3.

Diagnostic Approach

• A rational approach to the differential diagnosis of elevated liver enzymes is necessary to avoid overdiagnosis while not missing rare causes of liver disease 4.
• The evaluation of patients with elevated liver enzymes should be guided by both the clinical presentation and the pattern of injury 5.
• Clinicians can use either an extensive testing strategy or a focused testing strategy, with the choice depending on the patient's history and physical exam 6.
• Focused testing becomes the most cost-effective strategy when accounting for pre-test probabilities and prior evaluations performed 6.

Evaluation of Abnormal Liver Chemistries

• The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin 7.
• Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels, while cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels 7.
• The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, and screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency 7.