# Approach to Abnormal Liver Tests in the Outpatient Setting

## Introduction

Abnormal liver tests are among the most common laboratory findings encountered in outpatient internal medicine, affecting up to 10% of the US population. A systematic approach to interpretation, categorization of the pattern of injury, and targeted workup can efficiently narrow the differential and guide management. The terminology "liver tests" is preferred over "liver function tests" since aminotransferases reflect hepatocellular injury, not synthetic function.

## Understanding the Tests

### Markers of Hepatocellular Injury

- **ALT (alanine aminotransferase)**: most specific marker for hepatocyte injury; found primarily in hepatocytes
- **AST (aspartate aminotransferase)**: present in liver, cardiac muscle, skeletal muscle, kidneys, and red blood cells; less liver-specific
- **AST:ALT ratio > 2**: suggests alcohol-related liver disease (De Ritis ratio); also seen in cirrhosis of any etiology
- Mild elevations (< 5x ULN) are the most common pattern encountered in practice

### Markers of Cholestasis

- **Alkaline phosphatase (ALP)**: present in liver, bone, intestine, placenta; confirm hepatic origin with **GGT** or **5'-nucleotidase**
- **GGT (gamma-glutamyl transferase)**: sensitive but non-specific; elevated by alcohol, medications, obesity
- **Direct (conjugated) bilirubin**: elevation indicates impaired biliary excretion

### Markers of Synthetic Function

- **Albumin**: half-life of 21 days; reflects chronic synthetic capacity (also affected by inflammation, nephrotic syndrome, malnutrition)
- **Prothrombin time / INR**: reflects hepatic synthesis of clotting factors (II, V, VII, X); earliest marker of acute synthetic failure
- **Platelet count**: thrombocytopenia may suggest portal hypertension and advanced fibrosis/cirrhosis

## Pattern-Based Approach

| Pattern | R-value | Key Elevations | Common Causes |
|---------|---------|---------------|---------------|
| Hepatocellular | > 5 | ALT/AST predominant | MASLD, viral hepatitis, drugs, autoimmune hepatitis |
| Cholestatic | < 2 | ALP/GGT predominant | Obstruction, PBC, PSC, drugs |
| Mixed | 2-5 | Both elevated | Drug-induced, infiltrative disease |

### Hepatocellular Pattern (Elevated ALT/AST, Normal or Mildly Elevated ALP)

- Calculate the **R-value**: (ALT / ALT ULN) divided by (ALP / ALP ULN)
- R > 5: hepatocellular; R < 2: cholestatic; R 2-5: mixed

### Initial Workup for Hepatocellular Injury

- **Metabolic dysfunction-associated steatotic liver disease (MASLD)**: most common cause; assess BMI, metabolic syndrome, obtain hepatic steatosis index or ultrasound
- **Alcohol-associated liver disease**: detailed alcohol history; AST:ALT > 2, elevated GGT
- **Viral hepatitis**: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), hepatitis C antibody (anti-HCV) with reflex RNA
- **Medications/supplements**: review all prescription drugs, OTC medications, and herbal supplements (acetaminophen, statins, NSAIDs, antibiotics, supplements)
- **Hemochromatosis**: transferrin saturation (> 45% warrants HFE gene testing), ferritin
- **Autoimmune hepatitis**: ANA, ASMA, IgG levels; consider anti-LKM-1 in younger patients
- **Wilson disease**: ceruloplasmin (screen in patients < 40 years with unexplained liver disease)
- **Alpha-1 antitrypsin deficiency**: alpha-1 antitrypsin level and phenotyping
- **Celiac disease**: tissue transglutaminase IgA (often overlooked cause)
- **Thyroid disease**: TSH

![Diagnostic algorithm for elevated aminotransferases](images/alt-ast-workup-algorithm.png)

### Cholestatic Pattern (Elevated ALP with or without Elevated Bilirubin)

- Confirm hepatic origin of ALP with GGT
- **Imaging first**: right upper quadrant ultrasound to assess for biliary dilation
  - **Dilated ducts**: extrahepatic obstruction (choledocholithiasis, pancreatic mass, cholangiocarcinoma) -- proceed to MRCP or ERCP
  - **Non-dilated ducts**: intrahepatic cholestasis

### Intrahepatic Cholestasis Workup

- **Primary biliary cholangitis (PBC)**: anti-mitochondrial antibody (AMA), IgM elevation; predominantly affects middle-aged women
- **Primary sclerosing cholangitis (PSC)**: MRCP showing multifocal biliary strictures; associated with IBD (especially ulcerative colitis); pANCA may be positive
- **Drug-induced cholestasis**: amoxicillin-clavulanate, anabolic steroids, oral contraceptives
- **Infiltrative disease**: sarcoidosis, lymphoma, amyloidosis

### Isolated Hyperbilirubinemia

| Type | Mechanism | Common Causes |
|------|-----------|---------------|
| Unconjugated (indirect) | Overproduction or impaired conjugation | Gilbert syndrome, hemolysis, ineffective erythropoiesis |
| Conjugated (direct) | Impaired excretion | Dubin-Johnson, Rotor syndrome, hepatocellular/cholestatic disease |

- **Unconjugated (indirect)**: Gilbert syndrome (most common, benign, affects 5-10% of population), hemolysis, ineffective erythropoiesis
- **Conjugated (direct)**: Dubin-Johnson syndrome, Rotor syndrome, hepatocellular or cholestatic disease

## MASLD and MASH: The Epidemic

- **MASLD** (formerly NAFLD): hepatic steatosis with at least one cardiometabolic risk factor
- **MASH** (formerly NASH): steatosis with inflammation and hepatocyte ballooning +/- fibrosis
- Prevalence: 25-30% of adults; leading cause of chronic liver disease globally
- **FIB-4 index**: non-invasive fibrosis score using age, AST, ALT, and platelet count
  - FIB-4 < 1.3: low risk (negative predictive value > 90%)
  - FIB-4 >= 1.3: consider transient elastography (FibroScan) or enhanced liver fibrosis (ELF) test
- **Resmetirom** (Rezdiffra): first FDA-approved therapy for MASH with moderate-to-advanced fibrosis (thyroid hormone receptor-beta agonist)
- Weight loss of >= 7-10% can achieve histologic improvement; GLP-1 RAs show promise

![MASLD fibrosis risk stratification pathway](images/masld-fibrosis-pathway.png)

## When to Refer to Hepatology

- ALT/AST > 10x ULN (acute liver injury) or signs of acute liver failure
- Suspected autoimmune hepatitis, PBC, PSC, or Wilson disease
- Advanced fibrosis on non-invasive testing (FIB-4 >= 2.67 or liver stiffness >= 9.7 kPa)
- Need for liver biopsy
- Cirrhosis and its complications
- Unexplained liver test abnormalities persisting beyond 6 months of workup

## Drug-Induced Liver Injury (DILI)

- Consider DILI in any patient with new liver test abnormalities
- **Intrinsic DILI**: dose-dependent, predictable (e.g., acetaminophen)
- **Idiosyncratic DILI**: unpredictable, not dose-dependent; latency weeks to months
- **LiverTox database** (NIH): essential resource for evaluating suspected DILI
- Common culprits: antibiotics (amoxicillin-clavulanate #1), NSAIDs, antiepileptics, statins, herbal/dietary supplements (especially green tea extract, turmeric)

![Approach to suspected drug-induced liver injury](images/dili-approach.png)

## Key Clinical Pearls

- MASLD is now the most common cause of mildly elevated aminotransferases; use FIB-4 as the first-line non-invasive fibrosis assessment
- An AST:ALT ratio > 2 strongly suggests alcohol-related liver disease but can also be seen in cirrhosis of any cause
- Always check hepatitis B and C serologies in any patient with unexplained transaminase elevation; both are treatable
- Statins are safe in patients with chronic liver disease and MASLD; they are only contraindicated in acute liver injury or decompensated cirrhosis

## References

1. Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. *Am J Gastroenterol*. 2017;112(1):18-35.
2. Rinella ME, Lazarus JV, Ratziu V, et al. A Multi-Society Delphi Consensus Statement on New Fatty Liver Disease Nomenclature (MASLD). *Hepatology*. 2023;78(6):1966-1986.
3. Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis (MAESTRO-NASH). *N Engl J Med*. 2024;390(6):497-509.
4. Chalasani N, Bonkovsky HL, Fontana RJ, et al. Features and Outcomes of 899 Patients with Drug-Induced Liver Injury (DILIN). *Gastroenterology*. 2015;148(7):1340-1352.