Mild, Asymptomatic Elevations of ALT and AST

gathered from : https://www.aafp.org/pubs/afp/issues/2017/1201/p709.html

Prevalence

• Estimated prevalence of elevated transaminase levels in primary care: ~10%
• Less than 5% of these patients have serious liver disease

General Guidelines

• Mild elevations: Less than five times the upper limit of normal (ULN)
• Immediate evaluation warranted for elevations greater than five times ULN

Causes of Elevated Liver Transaminase Levels

• Hepatocellular Damage:
  • ALT and AST released during hepatocellular damage
  • ALT elevations more specific for liver injury
  • AST elevations can be caused by extrahepatic disorders (e.g., thyroid disorders, celiac sprue, hemolysis, muscle disorders)

Normal ALT Levels

• Males: 29 to 33 IU/L (0.48 to 0.55 μkat/L)
• Females: 19 to 25 IU/L (0.32 to 0.42 μkat/L)

AST Ratio

• Alcoholic Liver Disease:
  • AST ratio > 2
  • Mean AST values: 152:70
  • Positive likelihood ratio (LR+): 17
  • Negative likelihood ratio (LR–): 0.49
• Nonalcoholic Fatty Liver Disease (NAFLD):
  • ASTratio < 1
  • Mean ASTvalues: 66:91
  • LR+: 80
  • LR–: 0.2

Categorization of Causes for Mild, Asymptomatic Elevation of Transaminase Levels

• Common Causes:
  • Nonalcoholic fatty liver disease (NAFLD)
  • Chronic hepatitis B and C
  • Alcoholic liver disease
  • Medications (e.g., statins, NSAIDs, acetaminophen)
  • Metabolic syndrome
• Uncommon Causes:
  • Hemochromatosis
  • Wilson disease
  • Alpha-1 antitrypsin deficiency
  • Autoimmune hepatitis
  • Celiac disease
• Rare Causes:
  • Hemolysis
  • Muscle disorders (e.g., polymyositis, muscular dystrophy)
  • Thyroid disorders (e.g., hypothyroidism, hyperthyroidism)
  • Adrenal insufficiency

Nonalcoholic Fatty Liver Disease (NAFLD):

• Prevalence: Most common cause of asymptomatic transaminase elevation (25% to 51%).
• Subtypes:
  • Nonalcoholic Fatty Liver (NAFL): Hepatic steatosis without inflammation.
    • Treatment: Lifestyle modifications (weight loss, diet, exercise).
  • Nonalcoholic Steatohepatitis (NASH): Hepatocyte injury with ballooning, inflammation, potential fibrosis.
    • Risk: Progression to cirrhosis and hepatocellular carcinoma.
    • Prevalence: 3% to 5% of the adult population.

• Risk Factors:
  • Metabolic syndrome (waist circumference, elevated BP, high triglycerides, low HDL, insulin resistance).
  • Type 2 diabetes mellitus.
• Diagnosis:
  • Imaging: Ultrasonography preferred; does not differentiate NAFL and NASH.
  • NAFLD Fibrosis Score: Assesses risk of liver-related complications using clinical data (age, BMI, AST/ALT ratio, platelets, albumin, presence of diabetes).
  • Vibration-Controlled Transient Elastography: Noninvasive assessment of hepatic fibrosis, limited by operator experience and high BMI.
• Clinical Management:
  • High-risk patients or those with coexisting liver diseases should be referred to a gastroenterologist.

Alcoholic Liver Disease:

• Primary Cause: Liver-related mortality in Western countries.
• Overlap with NAFLD: Similar disease spectrum and histopathology.
• Diagnostic Tool: Alcoholic liver disease/NAFLD index (ALT level, AST level, height, MCV, sex, weight).
  • Validation: Positive likelihood ratio (LR+) = 12, negative likelihood ratio (LR–) = 0.07.

Drug-Induced Liver Injury (DILI):

• Incidence: Estimated at 19.1 cases per 100,000 persons annually.
• Identification: Detailed history of prescription, over-the-counter medications, and supplements.
• Common Drugs:
  • Acetaminophen, statins, antibiotics (tetracyclines, fluoroquinolones), NSAIDs, anti-seizure drugs (valproic acid, phenytoin), anti-tuberculosis drugs (isoniazid, rifampin).
  • Herbal supplements also contribute to DILI (9% of cases).
• Resources: Liver-Tox for clinical information on DILI.
• Statins: Safe in stable chronic liver diseases like NAFLD and hepatitis C; FDA recommends only baseline ALT/AST before initiation

Viral Hepatitis:

• Prevalence in the US:
  • Hepatitis C: ~3.5 million persons.
  • Hepatitis B: Up to 2.2 million persons.
• Screening: Hepatitis B surface antigen and hepatitis C virus antibody testing for high-risk patients (USPSTF guidelines).

Hereditary Hemochromatosis:

• Genetics: Autosomal recessive; common in Northern European Caucasians (1 in 150 to 250 persons).
• Phenotypic Expression: Severe iron overload in ~10% of those with genotype.
• Diagnosis:
  • Initial Tests: Transferrin saturation (>45%) and serum ferritin (>250-300 ng/mL in men, >200 ng/mL in women).
  • Genetic Testing: HFE mutations (C282Y, H63D).
  • Higher Predictive Thresholds: Transferrin saturation >60% in men, >50% in women for 95% predictive accuracy.

Alpha1-Antitrypsin Deficiency (AATD):

• Prevalence: 1 in 3,000 to 5,000 persons; only 10% diagnosed.
• Clinical Presentation: Early-onset emphysema, unexplained liver enzyme elevation, advanced liver disease.
• Diagnosis:
  • Initial Test: Serum alpha1-antitrypsin levels.
  • Follow-Up: Protein phenotyping or genotyping for PiZZ variant if levels are low.

Autoimmune Hepatitis:

• Prevalence: 11 to 17 per 100,000 persons.
• Demographics: More common in young women; associated with other autoimmune disorders.
• Diagnosis:
  • Tests: Hypergammaglobulinemia (IgG levels), serum protein electrophoresis, antinuclear antibody (ANA), smooth muscle antibody (SMA), liver/kidney microsome type 1 antibody (anti-LKM1).

Wilson Disease:

• Prevalence: 1 in 30,000 persons; autosomal recessive.
• Clinical Clues: Kayser-Fleischer rings, neuropsychiatric symptoms.
• Diagnosis:
  • Initial Test: Serum ceruloplasmin.
  • Further Testing: 24-hour urine copper levels, genetic testing, liver biopsy if ceruloplasmin is low.

Extrahepatic Causes

• Thyroid Disorders:
  • Patterns: Both hypo- and hyperthyroidism can cause elevated transaminase levels.
  • Screening: Thyroid-stimulating hormone (TSH), free T4, free/total T3.
• Celiac Disease:
  • Association: Modest elevations in transaminase levels.
  • Screening: Tissue transglutaminase IgA, serum IgA level, anti-deamidated gliadin peptide IgG.
• Other Considerations:
  • Hemolysis: Consider if clinical picture suggests.
  • Strenuous Exercise: Temporary elevation in transaminase levels.
  • Rhabdomyolysis and Polymyositis: Creatine kinase or aldolase measurements in patients with significant myalgias.

Suggested Diagnostic Evaluation

• Large Prospective Study (UK):
  • Evaluated nearly 1,300 primary care patients with abnormal transaminase levels.
  • Findings:
    • 38% had fatty liver disease.
    • Less than 5% had significant liver disease.
    • Serious liver disease in 1.3% (viral hepatitis, hereditary hemochromatosis).
    • 84% of abnormal liver enzyme results remained abnormal after one month, 75% after two years.
• Evaluation Recommendations:
  • Initial Assessment:
    • Thorough patient history and physical examination.
    • Consider common, uncommon, and rare causes.
  • Diagnostic Tools:
    • Imaging (ultrasonography, transient elastography).
    • Clinical scores (NAFLD fibrosis score).
    • Specific lab tests (autoantibodies, genetic testing).