II. Epidemiology
- Mild asymptomatic transaminase elevations (<5x normal) are common
- U.S. Prevalence may be as high as 10%
- However, serious liver disease is found in only 5% of these cases
III. Approach: Focus of evaluation
- Iatrogenic or Treatable disease
- Communicable or Inheritable disease
- True abnormality versus False Positive testing
IV. History
- Non-Alcoholic Fatty Liver risk factors
- Medications
- Aminotransferase Elevations (ALT, AST)
- See Hepatotoxin
- Cholestatic Elevations (Alkaline Phosphatase, GGT)
- Aminotransferase Elevations (ALT, AST)
- Alcohol Abuse (Alcoholic Hepatitis)
- Contagious Contacts (Viral Hepatitis)
V. Symptoms (mild elevations are usually asymptomatic)
VI. Signs
- Weight loss
- Stigmata of Chronic Liver Disease or Cirrhosis
- Gynecomastia
- Testicular atrophy
- Spider Nevi
- Finger nail Clubbing
- Asterixis
- Abdominal exam
VII. Differential Diagnosis (Transaminase elevation, Transaminitis)
- Common hepatic causes
- Alcoholic Liver Disease (27%)
- AST/ALT ration >2
- GGT increased
- Nonalcoholic Fatty Liver Disease (25-51%)
- Metabolic Syndrome
- Increased Serum Triglycerides and Serum Glucose and low HDL Cholesterol
- Alcoholic Liver Disease (27%)
- Uncommon hepatic causes
- Hepatitis B or Hepatitis C (18%)
- Hemochromatosis (3%)
- Serum Iron and Ferritin levels increased
- Hepatotoxins (medications)
- Rare hepatic causes
- Autoimmune Hepatitis (1%)
- More common in young women with autoimmune disorders
- Evaluation includes SPEP, ANA, SMA, LKM-1
- Alpha-1 Antitrypsin Deficiency (1%)
- Associated with premature COPD
- Primary Biliary Cirrhosis (0.3%)
- Wilson Disease
- Consider in liver disease at a young age (e.g. <30 years old)
- Serum ceruplasmin abnormal
- Autoimmune Hepatitis (1%)
- Extrahepatic causes
- Celiac Disease
- Hemolysis
- Causes include G6PD, Sickle Cell Anemia, infection
- Muscular disorders (e.g. Polymyositis)
- Increased CPK and aldolase
- Hypothyroidism or Hyperthyroidism
VIII. Labs
- See Liver Function Test
- Markers of hepatocyte injury
- Precautions
- Liver transaminases (ALT, AST) true normal ranges are <25 IU/L in women, <33 IU/L in men
- For those with liver disease risk factors, the lab cut-offs (50-60 IU/L) are abnormal (not simply borderline)
- Transaminase elevations are considered mild if <5 times normal
- Elevations >5 times normal require extensive evaluation for cause
- Alanine transaminase (ALT)
- Most specific for hepatocyte injury
- Aspartate transaminase (AST)
- Less specific than ALT (present outside liver)
- Non-liver causes include Celiac Sprue, Hemolysis, Dermatomyositis, tissue infarction, Hyperthyroidism
- AST to ALT Ratio
- AST/ALT ratio <1 in Non-Alcoholic Fatty Liver Disease (LR+ 80, LR- 0.2)
- AST/ALT ratio >2 in Alcoholism (LR+ 17, LR- 0.49)
- AST/ALT ratio >4 in Wilson's Disease
- Lactate Dehydrogenase (LDH)
- Least specific for hepatocyte injury
- Dramatically increased in ischemic hepatitis
- Increased with alk phos in liver metastases
- Precautions
- Markers of cholestasis
- Marker of liver function and Protein synthesis
- Markers of advanced fibrosis
IX. Imaging
-
Abdominal Ultrasound right upper quadrant
- Preferred cost-effective evaluation
-
Abdominal CT
- Consider if Ultrasound is non-diagnostic
X. Management: Increased serum transaminases (ALT, AST)
- Criteria
- Indicated in mild, asymptomatic liver transaminase (ALT, AST) elevations <5 times normal
- Symptomatic or elevations >5 times normal should prompt more urgent, thorough evaluation
- See Alkaline Phosphatase for cholestasis causes
- Step 0: History and Physical
- Lab and diagnostic evaluation as directed by history and physical
- Avoid Hepatotoxins including Alcohol
- Consider Fasting lipid profile and Serum Glucose (or complete in step 1)
- Plan repeat evaluation and labs in 2-4 weeks (see Step 2)
- Step 1: Obtain initial lab work
- Hepatic panel (as above)
- Prothrombin Time (INR)
- Serum Albumin
- Complete Blood Count with Platelet Count
- Viral Hepatitis Serology
- Consider Hepatitis A Serology
- Hepatitis B Serology (HBsAg)
- Hepatitis C Serology
- Consider Monospot
- Serum Ferritin, Serum Iron and TIBC (Hemochromatosis)
- Fasting lipid profile and Fasting Glucose (or Hemoglobin A1C)
- Step 2: Evaluate labs, history and examination
- Treat specific causes
- Consider Non-Alcoholic Fatty Liver disease (NAFLD) - most common
- Step 3: General measures if no cause identified
- Avoid Hepatotoxins
- Withdraw suspected medications
- Abstain from Alcohol use
- Reduce hepatic Steatosis risks
- Weight loss if Overweight
- Improve Blood Sugar control in Diabetes Mellitus
- Treat Hyperlipidemia (esp. Serum Triglycerides)
- Repeat Liver Function Tests in 2-6 months
- Obtain imaging as above if elevations persist
- Liver Function Tests often remain elevated on follow-up for longer than 2 years
- Lilford (2013) Health Technol Assess 17(28): 1-307 [PubMed]
- Avoid Hepatotoxins
- Step 4: Abnormal transaminases persist on recheck
- Obtain Ultrasound of right upper quadrant
- Obtain disease specific markers
- Complete initial labs in Step 1 if not done
- Ceruloplasmin (Wilson's Disease)
- Antinuclear Antibody
- Anti-Smooth Muscle Antibody
- Alpha-1-antitrypsin
- Anti-tissue transglutaminase Antibody: Celiac Sprue
- Consider non-hepatic transaminase elevations
- Peripheral Smear, Coombs test (Hemolysis)
- Rhabdomyolysis or Polymyositis (Creatine Kinase, aldolase)
- If testing as above is negative for specific cause
- Obese patient: See Steatosis
- Non-obese Patient
- Aminotransferases exceed twice normal
- Refer to Gastroenterology for biopsy
- Aminotransferases mildly elevated
- Follow serial Aminotransferases (AST, ALT)
- Aminotransferases exceed twice normal
XI. Management: Increased Alkaline Phosphatase (marked) with normal transaminases
- Confirm increase is due to gastrointestinal cause (e.g. as opposed to bone) with a fractionated Alkaline Phosphatase
- Cholestatic Liver Disease
- Infiltrative Conditions
- Malignancy
- Amyloidosis
- Sarcoidosis
- Infectious disease
- References
- Loftus (2012) Mayo POIM Conference, Rochester