Abnormal Liver Enzymes: A Guide to Interpreting Test Results

Educational Objectives

The goal of this program is to improve diagnosis of liver disease. After hearing and assimilating this program, the clinicians will be able to:

1. Explain the components of a liver panel and their significance.
2. Devise an algorithm for evaluation and workup of mild, moderate, and severe elevations of aminotransferase levels and elevations in alkaline phosphatase and bilirubin levels.
3. Analyze liver enzymes to diagnose common chronic and hereditary liver diseases and autoimmune conditions.

Summary

Liver panel: includes 7 components, ie, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBR), direct BR, albumin, and total protein; the comprehensive metabolic panel (CMP) is a combination of liver (excluding direct BR) and renal panels; liver injury (LI) is suggested by abnormal AST, ALT, and ALP levels; synthetic function of the liver is described by BR, albumin, and coagulation factors (eg, prothrombin time [PT], international normalized ratio [INR]); to assess liver status, a trend or repeat testing is superior to use of isolated test results

AST and ALT: released in response to hepatocyte injury; AST is present in skeletal, cardiac, and smooth muscle, while ALT is more specific to the liver; types of LI — zone 1 injury (closest to the periportal area; eg, viral hepatitis, autoimmune hepatitis [AIH]) leads to higher ALT levels; zone 3 injury (farthest from the periportal area; eg, ischemic or toxic insults) causes elevation of AST levels

AST:ALT ratio (AAR; De Ritis ratio): helpful in differentiating etiology; an AAR of 2:1 is seen in alcohol-related liver disease (ARLD); in chronic liver disease (CLD), an AAR >1 suggests advanced fibrosis

Alkaline phosphatase: primarily produced by hepatocytes on the canalicular membrane; also found in bones, intestine, kidneys, and white blood cells; ALP levels are elevated during pregnancy and childhood (secondary to bone development); for isolated elevation of ALP, check γ-glutamyl-transferase (GGT) level; GGT is primarily present in kidneys, intestines, prostrate, and pancreas, as well as the liver (not in bone); ALP level is elevated when bile flow is disrupted

Bilirubin: exists in 2 forms, ie, unconjugated BR (ucBR; indirect) and conjugated BR (cBR; direct); insoluble ucBR is transported to the liver and converted to soluble cBR for excretion; elevations in ucBR level typically relate to excess formation (eg, hemolysis) or impaired conjugation of BR; conjugated hyperbilirubinemia (cHBR) typically results from CLD or obstruction of the biliary system; in patients with elevated TBR and normal ALT, AST, and ALP levels, fractionation of TBR is recommended

Albumin: exclusively produced by the liver (half-life, 3 wk); reduction suggests LD with duration ≥3 wk

PT and INR: more sensitive markers of synthetic function of the liver than albumin; INR may be elevated in severe acute LI (≈70% hepatocyte loss), CLD, vitamin K deficiency, chronic cholestasis, or malabsorptive disorders

Normal ALT levels: ≤2 SD of the mean; may occur in asymptomatic patients with CLD (eg, nonalcoholic fatty LD [NAFLD]); the upper limit of normal (ULN) suggested by the American Association for the Study of Liver Diseases for men and women is <30 IU/L and <19 IU/L, respectively, whereas those suggested by the American College of Gastroenterology are 29 to 33 IU/L for men and 19 to 25 IU/L for women

Initial approach to abnormal liver enzyme levels: repeat the test; if still abnormal, perform confirmatory tests to determine the source, ie, hepatic vs nonhepatic

Assess pattern of injury: if the enzymes remain persistently abnormal (ie, hepatocellular injury [elevated aminotransferases], cholestatic pattern of injury [elevated ALP and BR levels], or mixed injury); R factor — a ratio in which the numerator is ALT divided by the ULN for ALT, and the denominator is ALP divided by the ULN for ALP; ratios >5 suggest hepatocellular injury, <2, a cholestatic pattern, and 2 to 5, mixed

Define severity of injury: most useful when triaging hepatocellular injury; borderline elevation is 2 times ULN, mild, 2 to 5 times ULN, moderate, 5 to 15 times ULN, and severe, >15 times ULN; consider the duration, especially in borderline and mild elevations

Hepatocellular injury: the differential diagnosis has 3 components; AST predominant — eg, zone 3 injuries, cirrhosis; ALT predominant — typically seen in NAFLD, acute or chronic viral hepatitis, drug-induced liver injuries, and CLD, but also seen in celiac disease, acute bile duct obstruction (BDO), and veno-occlusive disease; nonhepatic sources — include rhabdomyolysis, cardiac injuries, thyroid disorders, hemolysis, adrenal insufficiency, and macro-AST syndrome

Approach to mild elevations: history — assess for recent symptoms, viral illness, recent medication changes, and recent use of antibiotics; review all comorbidities, with a focus on risk factors for LD; elicit family history; physical examination (PE) — assess all patients for CLD and manifestations of portal hypertension; rare disorders with classic findings include hemochromatosis (bronzing of the skin), Wilson disease (WD; neurologic symptoms), and α₁-antitrypsin disease (AATD; pulmonary symptoms); initial workup — includes hemogram and complete blood count (to assess platelets), CMP, PT or INR, hepatitis C antibody test (and reflex polymerase chain reaction testing with a genotype for patients with positive results), hepatitis B test (includes hepatitis B surface antigen [HBsAg], HB core antibody [HBcAb], and HBsAb), and an iron panel (ie, ferritin, iron, and total iron binding capacity); assess liver parenchyma via abdominal ultrasonography (US)

Autoimmune conditions: rule out if enzymes remain persistently abnormal (eg, antinuclear antibody, anti-smooth muscle antibody, immunoglobulins, ceruloplasmin [for WD], AAT phenotype [for AATD]); if negative and enzymes remain abnormal for >3 mo, a liver biopsy (LB) may be considered

Approach to moderate elevations: after history, PE, and initial workup, a more thorough evaluation is recommended (eg, immunoglobulin [Ig] M and IgG, HBc IgM, exclusion of autoimmune conditions); acute liver failure — rare; characterized by rapid deterioration of liver function, multiorgan failure, and death; patients often present with coagulopathy (INR >1.5) and hepatic encephalopathy (crucial for diagnosis; occurs in the absence of CLD); prompts urgent consultation and referral

Approach to severe elevations: history and PE often reveal etiology; assess for acetaminophen toxicity, vascular or cardiac insufficiency, and acute liver failure; risk for acute decompensation is high; comprehensive testing should be performed; rule out vascular issues via Doppler imaging; test for herpes simplex virus, Epstein-Barr virus, and cytomegalovirus; tests for chronic and autoimmune conditions should include liver-kidney microsomal antibody; assess for illicit drug use; maintain a low threshold for initiation of N-acetylcysteine for acetaminophen toxicity; LB — provider discretion is recommended in cases of severe or massive elevations (may have no diagnostic utility)

Elevated ALP level: hepatic etiologies — BDO; also seen in primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), benign intrahepatic recurrent cholestasis, drug-induced LI, and infiltrative diseases of the liver (less common); nonhepatic etiologies — include bone disease, pregnancy, chronic renal failure, and malignancies (less common)

Approach to isolated elevation of ALP: extrahepatic sources — check GGT; alternative tests include ALP isoenzyme or 5’-nucleosidase; hepatic sources — assess BD via imaging; perform serologic tests for PBC (antimitochondrial antibodies [AMA]) and AIH); magnetic resonance cholangiopancreatography (MRCP) is specific for extrahepatic and intrahepatic BD; if investigations are unrevealing and ALP is >2 times ULN on 2 separate tests, LB may be considered

Approach to elevated ALP and TBR: imaging is key; if US is normal, perform further serologic tests; BD abnormalities warrant MRCP

Elevated TBR: ucHBR — etiologies include Gilbert syndrome, Crigler-Najjar syndrome, hemolysis, ineffective erythropoiesis, resorption of large hematomas, hyperthyroidism, and post-blood transfusion syndromes; cHBR — etiologies include CLD, BDO, viral and toxic hepatitis, acute alcohol-related hepatitis, and autoimmune diseases

Evaluation for ucHBR: in the absence of hemolysis and with normal ALP, AST, and ALT, suspect Gilbert syndrome (GS), which can be confirmed by UGT1A1 genotype testing; if negative, LB may be performed

Evaluation for cHBR: comprehensive evaluation includes imaging and assessment for all CLD; if imaging is abnormal, consider MRCP or endoscopic retrograde CP; for unexplained elevations in BR, consider LB

Liver biopsy: at present, performed infrequently, usually when the diagnosis is unclear (not for prognosis); however, LB is crucial for diagnosis and management of AIH

Acute vs chronic LD: acute insults (eg, viral illness, drug-induced LI, sepsis) tend to self-resolve, and most patients face no long-term sequelae; in CLD, seek reversible causes; in most CLDs, liver enzymes do not play a key role in outcomes (except AIH, where ALT is an important indicator of disease suppression); severity of fibrosis defines outcome, morbidity, and mortality; LB is not needed for assessing fibrosis

Common CLDs: NAFLD — most common; strongly associated with metabolic disorders; fibrosis defines outcome; liver enzymes are not prognostic; levels may be ≤10 times ULN; NAFLD is a diagnosis of exclusion; ARLD — history is essential; for men, heavy drinking is defined as >14 drinks per week, and for women, >7 drinks per week; enzyme levels are typically <10 times ULN; alcohol biomarkers are available to assess recent drinking

Hepatitis B virus (HBV): a blood-borne pathogen; patients with a competent immune system are less likely to develop chronic HBV infection; vertical transmission at birth leads to chronic hepatitis in 90% of cases; only 5% to 10% adults develop chronic HBV infection; presence of HBsAg for 6 mo (consecutively) is required for diagnosis of chronic HBV; presence of HBc IgM suggests acute infection

Hepatitis C virus (HCV): a blood-borne pathogen; cleared spontaneously by ≈20% of patients; the investigation of choice is HC antibody, with reflex viral quantification and genotype testing; treatment for 8 to 12 wk is effective

Autoimmune conditions: AIH — immune-mediated injury (often has a hepatocellular pattern); immunosuppression is effective

Cholestatic autoimmune conditions: PBC — typically affects small ducts; 95% of patients test positive for AMA; PSC — typically affects large ducts; diagnosis is by MRCP; often overlaps with inflammatory bowel disease; no curative treatment is available

Hereditary diseases: hereditary hemochromatosis — testing includes serum ferritin, iron, and transferrin saturation levels; serum ferritin is an acute phase reactant and may be elevated in other inflammatory diseases; confirmatory testing (HFE gene mutation analysis) is required if transferrin saturation is >45%; AATD — patients with persistently elevated AST or ALT should undergo screening; patients may present early with LD; WD — patients with persistently elevated AST and ALT and those <55 yr of age should undergo screening (ie, ceruloplasmin level; may be low in malnourished patients); confirm with 24-hr urinary copper and slit-lamp eye examination (to identify pathognomonic Kayser-Fleischer rings)

Readings

Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750-755. View Article; Dufour DR, Lott JA, Nolte FS, et al. Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem. 2000;46:2027-2049. View Article; Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis. 2011;43:89-95. View Article; Obika M, Noguchi H. Diagnosis and evaluation of nonalcoholic fatty liver disease. Exp Diabetes Res. 2011;2012. View Article; Sotil EU, Jensen DM. Serum enzymes associated with cholestasis. Clin Liver Dis. 2004;8:41-54. View Article; Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. Hepatology. 2017;66(1):84-95. doi:10.1002/hep.29113. View Article; Yokoda RT, Carey EJ. Primary biliary cholangitis and primary sclerosing cholangitis. J Am Coll Gastroenterol| ACG. 2019;114:1593-1605. View Article.

Disclosures

For this program, members of the faculty and the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Shetty was recorded exclusively for Audio Digest. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

FP712301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.