Teachable Moment
August 14, 2023
Mild Transaminase Elevation With Rapid Diagnostic Escalation: A Teachable Moment
Priyal Gandhi, Niloofar Latifi
JAMA Intern Med. Published online August 14, 2023. doi:10.1001/jamainternmed.2023.3884
Story From the Front Lines
A33-year-old woman with well-controlled hypertension and body mass index of 21 (calculated as weight in kilograms divided by height in meters squared) presented to primary care for follow-up. Routine laboratory tests showed a newly elevated aspartate aminotransferase (AST) level of 168 U/L and alanine aminotransferase (ALT) level of 78 U/L (to convert AST and ALT to μkat/L, multiply by 0.0167). Tests 4 days later showed an AST level of 97 U/L, ALT level of 62 U/L, low-density lipoprotein cholesterol level of 99 mg/dL (to convert to mmol/L, multiply by 0.0259), and hemoglobin A1c value of 4.7% (to convert to proportion of total hemoglobin, multiply by 0.01). She reported drinking 2 alcoholic beverages per month and denied new medications or supplements. Further evaluation over 2 weeks was negative for hemochromatosis and viral and autoimmune causes. Ultrasonography showed fatty infiltration. Elastography demonstrated minimal to no fibrosis with severe hepatic steatosis. She underwent a liver biopsy for diagnostic clarity 1 week later, which was complicated by intrahepatic arterial bleeding requiring embolization with multiple follow-up visits for pain and infections. Pathology was consistent with nonalcoholic fatty liver disease (NAFLD). Further history-taking revealed polycystic ovary syndrome as a risk factor for NAFLD.
Teachable Moment
The diagnosis of NAFLD in a patient with normal body mass index is nuanced. While there are different perspectives on evaluation of mildly elevated transaminase levels, this scenario serves as an opportunity to review a reasonable stepwise diagnostic approach based on current guidelines and evidence.
Mild AST and ALT elevation is defined as levels 2 to 5 times the upper limit of normal. Clinical practice guidelines recommend stepwise evaluation with an emphasis on disease prevalence (Figure).1-4 History and physical examination may identify signs warranting specific testing, such as skin bronzing seen in hemochromatosis. Given the high prevalence of NAFLD and alcohol-related liver disease in people with elevated transaminase levels,2 an appropriate strategy for most patients is to evaluate for NAFLD risk factors; promote lifestyle modification with weight loss, physical activity, and alcohol abstinence; and discontinue hepatotoxic medications prior to further diagnostic workup.1,2 After a 1-month trial of these interventions, repeated transaminase testing can be obtained to assess for persistent elevation.5
If transaminase levels remain elevated despite initial interventions, the workup can be expanded. However, if there is significant concern for patient loss to follow-up, it would be reasonable to pursue further workup on the initial encounter. First-pass evaluation for the most prevalent causes of mild liver injury includes universal hepatitis B and C testing, iron studies, screening for diabetes and metabolic syndrome, and abdominal ultrasonography.1-5 Patients without a likely diagnosis based on this evaluation should receive treatment for identifiable risk factors and continue a trial of lifestyle modifications for an additional 3 months.
Patients without a likely diagnosis and with persistently elevated transaminase levels after 3 months may benefit from specialist referral for evaluation of autoimmune, genetic, and other uncommon diseases, along with consideration of liver biopsy.1-4 Liver biopsy is recommended when noninvasive testing is unrevealing or when multiple diagnoses are possible (strong recommendation, very low level of evidence).1 Calculated scores such as the Fibrosis-4 Index and advances in imaging with high sensitivity and specificity for ruling out advanced fibrosis have further reduced the need for liver biopsy for staging purposes.1-4
The recommendation for stepwise evaluation of mildly elevated transaminase levels over time is supported by a 2-year prospective study of 1290 primary care patients with abnormal transaminase levels.5 After excluding those with fatty liver disease (38% of patients), less than 5% of patients were found to have a liver-specific disease, and only 1.3% required immediate therapy. Therefore, extensive up-front workup may not be valuable for most patients.
The current patient had decreasing transaminase levels on repeated testing, an identifiable risk factor for fatty liver disease (polycystic ovary syndrome), and imaging findings consistent with NAFLD without advanced fibrosis. She would have benefited from at least a 3-month trial of lifestyle modifications including alcohol cessation. However, within weeks, she underwent a liver biopsy, which provided a definitive diagnosis without altering management and at the expense of significant morbidity. Though her biopsy complications are uncommon, it reminds us of the importance of careful history-taking and the role of stepwise management over time, as there may be a high price for rapid diagnostic escalation to address discomfort with diagnostic uncertainty.
