The Liver Function Test "Panic": A Diagnostic Pathway

The Liver Function Test "Panic": A Diagnostic Pathway for the Internist

A structured approach to interpreting abnormal LFTs in the clinic or on the wards

Dr Neeraj Manikath  , claude.ai

Abstract

Abnormal liver function tests (LFTs) are among the most common laboratory findings encountered by internists, yet their interpretation often generates diagnostic uncertainty. This review provides a systematic, pattern-based approach to evaluating LFT abnormalities, emphasizing the crucial distinction between hepatocellular and cholestatic injury patterns. We discuss evidence-based algorithms for investigating asymptomatic isolated elevations, review drug-induced liver injury (DILI), and provide practical guidance on the appropriate use of non-invasive fibrosis assessment versus liver biopsy. Our goal is to equip postgraduate trainees and practicing internists with a rational framework that minimizes unnecessary testing while ensuring timely diagnosis of serious liver disease.

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Introduction

The term "liver function tests" is something of a misnomer—most LFTs actually measure hepatocellular injury or cholestasis rather than synthetic liver function. Nevertheless, these tests remain the cornerstone of hepatic evaluation. Abnormal LFTs are discovered in approximately 9% of the general population and up to 20% of hospitalized patients.^1,2 The challenge for the internist lies not in the detection of abnormalities but in their systematic interpretation and appropriate investigation.

Pearl: True tests of hepatic synthetic function include albumin, prothrombin time/INR, and bilirubin (conjugation capacity). Aminotransferases and alkaline phosphatase are markers of injury, not function.

The consequences of misinterpreting LFTs range from unnecessary anxiety and testing to missed diagnoses of cirrhosis, malignancy, or treatable metabolic liver diseases. This review presents a structured approach grounded in pattern recognition, emphasizing practical decision-making for the busy clinician.

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Hepatocellular vs. Cholestatic: The First Critical Step

Understanding the Pattern

The initial and most critical step in evaluating abnormal LFTs is determining whether the pattern suggests hepatocellular injury or cholestasis. This distinction immediately narrows the differential diagnosis and guides subsequent testing.^3,4

Hepatocellular Pattern:

• Predominant elevation of aminotransferases (ALT and AST)
• ALT/AST typically >5× upper limit of normal (ULN)
• Alkaline phosphatase (ALP) <2× ULN
• R-value >5 (where R = [ALT/ULN] ÷ [ALP/ULN])

Cholestatic Pattern:

• Predominant elevation of ALP
• ALP typically >2× ULN
• ALT/AST <2× ULN
• R-value <2

Mixed Pattern:

• R-value 2-5
• Both hepatocellular and cholestatic features present
• Often seen in prolonged or severe liver injury

Hack: Calculate the R-value when the pattern isn't immediately obvious. This single calculation, endorsed by international consensus for DILI assessment, can clarify ambiguous cases.⁵

The Role of GGT and 5'-Nucleotidase

When ALP is elevated, confirming its hepatic origin is essential, as ALP is present in bone, intestine, kidney, and placenta.

Oyster: An isolated ALP elevation in a young person after a fracture or in a child during a growth spurt is likely of bone origin. In pregnancy, ALP can be 2-4× ULN from placental production—this is physiologic.

Pearl: GGT (gamma-glutamyl transferase) and 5'-nucleotidase are hepatobiliary-specific. An elevated ALP with normal GGT suggests bone disease (Paget's disease, osteomalacia, bone metastases) or pregnancy. An elevated ALP with elevated GGT confirms hepatic origin.⁶

Bilirubin: Conjugated vs. Unconjugated

Total bilirubin elevation requires fractionation into direct (conjugated) and indirect (unconjugated) components.

Unconjugated Hyperbilirubinemia:

• Hemolysis (check LDH, haptoglobin, reticulocyte count)
• Gilbert's syndrome (benign, affects 3-7% of population)
• Crigler-Najjar syndrome (rare)

Conjugated Hyperbilirubinemia:

• Suggests hepatocellular dysfunction or biliary obstruction
• Always pathologic and warrants investigation

Pearl: In Gilbert's syndrome, bilirubin is typically <5 mg/dL (usually 1-3 mg/dL), rises with fasting or illness, and all other LFTs are normal. Genetic testing (UGT1A1 polymorphism) is available but rarely necessary—clinical context suffices.⁷

Common Patterns and Their Differential Diagnoses

Table 1: LFT Patterns and Associated Conditions

Pattern	ALT/AST	ALP	Bilirubin	Common Causes
Hepatocellular	↑↑↑	↑ or N	↑ or N	Viral hepatitis, DILI, autoimmune hepatitis, ischemic hepatitis
Cholestatic	N or ↑	↑↑↑	↑↑	Bile duct obstruction, PBC, PSC, drug-induced cholestasis
Infiltrative	↑	↑↑↑	N or ↑	Malignancy, granulomatous disease, amyloidosis
Cirrhotic	↑ or N	↑ or N	↑↑	All causes of chronic liver disease, synthetic dysfunction

Hack: In acute hepatocellular injury with ALT >1,000 IU/L (massive elevation), think of viral hepatitis (HAV, HBV), toxin/drug (acetaminophen, Amanita), ischemic hepatitis ("shock liver"), autoimmune hepatitis (rarely this acute), or acute Budd-Chiari syndrome.⁸

Oyster: Ischemic hepatitis ("shock liver") presents with ALT often >1,000 IU/L, but the aminotransferases typically peak within 24-72 hours and fall rapidly—much faster than in viral or drug-induced hepatitis. Look for recent hypotension, cardiac arrest, or severe heart failure.⁹

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The Asymptomatic Patient with Isolated Elevations

Asymptomatic patients with mild-to-moderate LFT abnormalities (<5× ULN) discovered on routine testing present a common diagnostic challenge. The key is systematic evaluation based on the predominant pattern.

Isolated Aminotransferase Elevation (Hepatocellular Pattern)

The most common scenario in primary care and general internal medicine is the asymptomatic patient with ALT elevation in the 1-3× ULN range.

Initial Assessment

Step 1: Exclude Common Causes

• Alcohol use: Detailed history (AST:ALT ratio >2 suggests alcohol)
• Medications: Review ALL medications and supplements
• Metabolic syndrome: Check BMI, waist circumference, fasting glucose, lipids
• Viral hepatitis: HBsAg, anti-HCV antibody

Pearl: In alcoholic liver disease, AST is typically higher than ALT (ratio >2), AST rarely exceeds 300 IU/L, and GGT is often markedly elevated. This contrasts with most other causes where ALT > AST.¹⁰

Hack: Before embarking on extensive evaluation, repeat the LFTs in 2-4 weeks. Transient elevations from acute illness, intense exercise, or hemolysis may resolve, avoiding unnecessary testing.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Formerly known as non-alcoholic fatty liver disease (NAFLD), MASLD is now the leading cause of chronic liver disease globally, affecting 25-30% of the general population.¹¹

Diagnostic Criteria (2023 nomenclature):

• Hepatic steatosis (by imaging or histology)
• At least one of five cardiometabolic risk factors:
  • BMI ≥25 kg/m² (≥23 in Asian populations) or waist circumference above thresholds
  • Fasting glucose ≥100 mg/dL or diabetes or on treatment
  • Blood pressure ≥130/85 or on treatment
  • Triglycerides ≥150 mg/dL or on treatment
  • HDL-C <40 mg/dL (men) or <50 mg/dL (women) or on treatment

Pearl: Most patients with MASLD have normal or only mildly elevated aminotransferases (1-2× ULN). Normal LFTs do not exclude MASLD or even advanced fibrosis.¹²

Workup for MASLD:

1. Ultrasound abdomen (identifies steatosis in 60-95% of cases with >30% fat)
2. Rule out other causes (viral hepatitis, alcohol, hemochromatosis, Wilson's, autoimmune hepatitis, medications)
3. Assess fibrosis risk (see FibroScan section below)

Oyster: A "bright liver" on ultrasound is suggestive but not diagnostic of steatosis. Up to 30% hepatic fat is required for reliable ultrasound detection. MRI-PDFF (proton density fat fraction) is the gold standard for quantifying steatosis non-invasively but is expensive and not routinely necessary.¹³

Hemochromatosis

Hereditary hemochromatosis (HH) is among the most common genetic disorders in populations of Northern European descent (prevalence 1 in 200-300) and can present with isolated aminotransferase elevation.¹⁴

Screening Tests:

• Fasting transferrin saturation (TS): TS >45% is abnormal (sensitivity 90-95%)
• Ferritin: Elevated (often >1,000 ng/mL in symptomatic patients)

Pearl: Transferrin saturation is the most sensitive screening test and should be checked fasting. Ferritin alone is insufficient as it's an acute-phase reactant and can be elevated in inflammation, infection, or malignancy.¹⁵

When to Test for HFE Mutations:

• TS >45% on two separate occasions
• Ferritin >300 ng/mL (men) or >200 ng/mL (women) with TS >45%

C282Y/C282Y homozygotes account for 80-90% of clinical hemochromatosis in Northern European populations. Penetrance is incomplete; only 25-30% develop iron overload-related disease.

Hack: If TS and ferritin are both elevated, order HFE gene testing before referring to hepatology. If C282Y homozygous, the diagnosis is confirmed. If heterozygous or wild-type, consider secondary iron overload or other causes and refer for further evaluation.

Oyster: H63D homozygosity or C282Y/H63D compound heterozygosity rarely causes significant iron overload. If ferritin is markedly elevated in these genotypes, look for other contributing factors (alcohol, MASLD, chronic hemolysis).

Wilson Disease

Wilson disease is rare (prevalence ~1 in 30,000) but must not be missed, as it is treatable and potentially fatal if undiagnosed. Consider in any patient <40 years with unexplained liver disease, neuropsychiatric symptoms, or hemolytic anemia.¹⁶

Screening Tests:

• Serum ceruloplasmin: Low (<20 mg/dL) in 95% of cases
• 24-hour urine copper: Elevated (>100 µg/24h is abnormal; >40 µg is suspicious)
• Slit-lamp examination: Kayser-Fleischer rings (brownish corneal deposits)

Pearl: A low ceruloplasmin is not specific; it can be low in protein-losing states, malnutrition, or heterozygote carriers. The diagnosis requires multiple supporting features. Serum copper is often low (bound to ceruloplasmin), but free (non-ceruloplasmin-bound) copper is elevated.¹⁷

Wilson Disease Scoring (Leipzig Criteria): The diagnosis is unlikely if score <0, possible if 2-3, and likely if ≥4. Parameters include Kayser-Fleischer rings, neurologic symptoms, Coombs-negative hemolytic anemia, ceruloplasmin, urine copper, and genetic testing.

Oyster: Acute Wilson disease can present as fulminant hepatic failure with high bilirubin, low aminotransferases (reflecting massive hepatocyte loss), low alkaline phosphatase, hemolytic anemia, and renal failure. The AST:ALT ratio is often >4 and ALP:bilirubin ratio <4—a unique pattern. This is a transplant emergency.¹⁸

Hack: In patients <40 with unexplained hepatitis, check ceruloplasmin first. If low or borderline, refer promptly to hepatology for 24-hour urine copper and slit-lamp examination.

Autoimmune Hepatitis (AIH)

Autoimmune hepatitis predominantly affects women (70-80%) and can present at any age, though peaks occur in adolescence/early adulthood and perimenopausal years. It may be asymptomatic or present with acute hepatitis.¹⁹

Screening Tests:

• Antinuclear antibody (ANA)
• Anti-smooth muscle antibody (ASMA)
• Anti-liver kidney microsomal antibody (anti-LKM1) for Type 2 AIH
• Serum IgG levels (typically elevated)

Pearl: AIH is a diagnosis of exclusion requiring (1) interface hepatitis on histology, (2) elevated serum IgG or positive autoantibodies, (3) exclusion of viral hepatitis and other causes, and (4) response to immunosuppression. Simplified diagnostic criteria can assist but liver biopsy is typically required for definitive diagnosis.²⁰

Oyster: Up to 10-20% of AIH patients are autoantibody-negative at presentation. If clinical suspicion is high (young woman, elevated IgG, no other cause), biopsy may still reveal characteristic interface hepatitis and plasma cell infiltration.

Hack: Check ANA, ASMA, and IgG as a screen in patients <50 with unexplained hepatitis, particularly women. If ANA ≥1:80 or ASMA ≥1:40 with elevated IgG (>1.1× ULN) and no other explanation, refer to hepatology for consideration of biopsy and treatment.

Alpha-1 Antitrypsin Deficiency

A1AT deficiency (genotype PiZZ) affects 1 in 2,000-5,000 and can cause both liver disease and emphysema. Liver disease presentation ranges from neonatal cholestasis to adult cirrhosis.²¹

Screening:

• Serum alpha-1 antitrypsin level
• Pi phenotype or genotype if level is low

Pearl: Suspect A1AT deficiency in patients with early-onset emphysema (especially basilar), family history, or cryptogenic cirrhosis. Liver disease is less common than lung disease but can be severe.

Isolated Alkaline Phosphatase Elevation (Cholestatic Pattern)

Isolated ALP elevation (without aminotransferase elevation) requires confirmation of hepatic origin (check GGT) followed by evaluation for cholestatic liver diseases.

Primary Biliary Cholangitis (PBC)

PBC is a chronic cholestatic autoimmune disease predominantly affecting middle-aged women (90% female, peak age 40-60 years). Many patients are asymptomatic at diagnosis.²²

Diagnosis:

• Elevated ALP (>1.5× ULN)
• Positive anti-mitochondrial antibody (AMA) at ≥1:40 (present in 95% of cases)
• Liver biopsy showing characteristic findings (if AMA negative)

Pearl: The combination of cholestatic LFTs and positive AMA is sufficient for diagnosis in most cases—biopsy is not required if both criteria are met. PBC-specific ANA (anti-gp210, anti-sp100) may be positive in AMA-negative PBC.

Oyster: Despite being a "primary biliary" disease, PBC does not cause biliary obstruction visible on imaging. Ultrasound or MRCP is normal. The disease affects small intrahepatic bile ducts not visible on imaging.

Hack: In any middle-aged woman with elevated ALP and normal GGT-confirmed hepatic origin, check AMA. If positive, diagnose PBC and refer to hepatology for ursodeoxycholic acid (UDCA) therapy, which can slow progression.²³

Primary Sclerosing Cholangitis (PSC)

PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to strictures and cholestasis. It has strong association with inflammatory bowel disease (IBD), particularly ulcerative colitis (60-80% of PSC patients have IBD).²⁴

Diagnosis:

• Cholestatic LFTs
• MRCP showing multifocal bile duct strictures and dilations ("beading")
• Liver biopsy showing "onion-skin" periductal fibrosis (not always necessary)

Pearl: Unlike PBC, PSC affects both large and small bile ducts. MRCP is the diagnostic imaging modality of choice. ERCP is reserved for therapeutic intervention or when small-duct PSC (normal MRCP) is suspected and biopsy is needed.

Oyster: PSC patients have increased risk of cholangiocarcinoma (lifetime risk 10-20%). CA 19-9 can be used for surveillance but has limited sensitivity and specificity. Dominant strictures should raise concern for malignancy.²⁵

Hack: In any patient with IBD (especially UC) and elevated ALP, order MRCP to screen for PSC even if asymptomatic. Early detection allows surveillance and management planning.

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Don't Forget the Drugs: A Review of Drug-Induced Liver Injury (DILI)

Drug-induced liver injury is responsible for approximately 10% of acute hepatitis cases and up to 50% of acute liver failure cases in developed countries. More than 1,000 medications and herbal products have been implicated.^26,27

Mechanisms and Patterns

DILI can manifest as hepatocellular, cholestatic, or mixed injury patterns:

Hepatocellular DILI (R >5):

• Acetaminophen (predictable, dose-dependent)
• NSAIDs (idiosyncratic)
• Isoniazid, pyrazinamide
• Antiretrovirals (especially NRTIs)
• Statins (rare)
• Antifungals (ketoconazole, terbinafine)

Cholestatic/Mixed DILI (R <2):

• Anabolic steroids
• Oral contraceptives
• Antibiotics (amoxicillin-clavulanate, macrolides, trimethoprim-sulfamethoxazole)
• Chlorpromazine
• Azathioprine

Pearl: Acetaminophen is the only truly dose-dependent hepatotoxin—toxicity occurs at >4g/day (>3g with alcohol use) due to depletion of glutathione and NAPQI accumulation. All other DILI is idiosyncratic and unpredictable.²⁸

The RUCAM Score

The Roussel Uclaf Causality Assessment Method (RUCAM) is a structured tool for assessing DILI likelihood based on:

• Time to onset and recovery
• Risk factors
• Exclusion of other causes
• Previous reports
• Response to rechallenge (rarely done)

Scores: ≤0 = excluded, 1-2 = unlikely, 3-5 = possible, 6-8 = probable, ≥9 = highly probable.²⁹

Hack: Practically, suspect DILI if (1) medication started within 3 months of LFT elevation (some drugs like amoxicillin-clavulanate can cause delayed cholestatic injury up to 6 weeks after stopping), (2) other causes excluded, and (3) LFTs improve after drug discontinuation. Rechallenge is rarely justified given risk.

High-Risk Medications

Antibiotics are the most common class causing DILI (45% of cases):

• Amoxicillin-clavulanate (most common single agent)
• Fluoroquinolones
• Macrolides (especially azithromycin)
• Trimethoprim-sulfamethoxazole
• Isoniazid (10-20% hepatotoxicity, higher in rapid acetylators)³⁰

Oyster: Amoxicillin-clavulanate DILI classically presents as cholestatic injury 1-6 weeks AFTER completing therapy. Many patients (and physicians) don't make the connection because the drug has been stopped.

Herbal and Dietary Supplements (HDS):

• Responsible for 20% of DILI cases in the US
• Often not disclosed by patients unless specifically asked
• Common culprits: green tea extract, anabolic steroids, multi-ingredient bodybuilding supplements, kava, Garcinia cambogia³¹

Pearl: ALWAYS ask about supplements, teas, energy drinks, weight-loss products, and bodybuilding supplements. Patients often don't consider these "drugs" and won't mention them unless specifically queried.

Statins:

• Mild ALT elevation (1-3× ULN) occurs in 1-3% of patients, usually transient
• Clinically significant hepatotoxicity is rare (1 in 100,000)
• Routine LFT monitoring is no longer recommended by guidelines³²
• ALT up to 3× ULN can be monitored; statin continuation is often safe

Hack: If a patient on a statin has ALT 1-3× ULN and no symptoms, check for other causes (MASLD is much more common). If no other cause and patient is tolerating the statin well, monitoring may be reasonable as benefit often outweighs risk.

Management of Suspected DILI

1. Stop the offending agent (if identified and safe to discontinue)
2. Exclude other causes (viral hepatitis, autoimmune, biliary obstruction)
3. Monitor LFTs weekly initially until downtrending
4. N-acetylcysteine for acetaminophen toxicity within 24 hours (or later if acute liver failure)
5. Corticosteroids for select cases (drug hypersensitivity with rash/eosinophilia, autoimmune-like DILI)
6. Consider transplant referral if acute liver failure develops (INR >1.5, encephalopathy)

Oyster: Hy's Law predicts high mortality risk in DILI: aminotransferases >3× ULN + total bilirubin >2× ULN + no cholestasis (ALP <2× ULN). This pattern has 10-50% mortality or need for transplant.³³

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When to Order a FibroScan vs. When to Refer for Biopsy

Assessing hepatic fibrosis is crucial for prognosis and treatment decisions in chronic liver disease. Non-invasive methods have largely supplanted biopsy for routine staging, but biopsy retains important diagnostic roles.

Non-Invasive Fibrosis Assessment

Serum Biomarkers

FIB-4 Index:

• Calculation: (Age × AST) ÷ (Platelet count × √ALT)
• FIB-4 <1.3: Low probability of advanced fibrosis
• FIB-4 1.3-2.67: Indeterminate
• FIB-4 >2.67: High probability of advanced fibrosis
• Readily available, no cost, excellent negative predictive value³⁴

APRI Score:

• Calculation: (AST/ULN) × 100 ÷ Platelet count
• APRI <0.5: Low probability of fibrosis
• APRI >1.5: High probability of cirrhosis

Pearl: FIB-4 and APRI are simple, validated scores that should be calculated for ALL patients with chronic liver disease. FIB-4 <1.3 has >90% negative predictive value for excluding advanced fibrosis in MASLD.³⁵

Enhanced Liver Fibrosis (ELF) Test:

• Proprietary panel (TIMP-1, PIIINP, hyaluronic acid)
• ELF <7.7: F0-F1, ELF 7.7-9.8: F2, ELF 9.8-11.3: F3, ELF >11.3: F4
• More expensive but excellent performance

Vibration-Controlled Transient Elastography (VCTE/FibroScan)

FibroScan measures liver stiffness (in kPa) as a surrogate for fibrosis. It has become the standard non-invasive assessment tool.³⁶

Interpretation (MASLD):

• <8 kPa: F0-F1 (no/minimal fibrosis)
• 8-10 kPa: F2 (significant fibrosis)
• 10-14 kPa: F3 (advanced fibrosis)

• 14 kPa: F4 (cirrhosis)

Advantages:

• Point-of-care, rapid (5-10 minutes)
• Highly reproducible
• Can be repeated for longitudinal monitoring
• CAP (controlled attenuation parameter) quantifies steatosis

Limitations:

• Unreliable in obesity (BMI >35), ascites, narrow intercostal spaces
• Overestimates fibrosis in acute inflammation, cholestasis, congestion
• Requires specialized equipment and trained operators
• Cutoffs vary by liver disease etiology

Oyster: Liver stiffness can be falsely elevated by recent food intake, acute hepatitis (ALT >5× ULN), extrahepatic cholestasis, right heart failure, and infiltrative disease. For best results, the patient should be fasting for 3-4 hours.³⁷

Hack: Use a two-step approach in primary care: (1) Calculate FIB-4. If <1.3, reassure and follow. If ≥1.3, (2) order FibroScan or refer to hepatology. This algorithm reduces unnecessary referrals while capturing patients needing advanced care.

Magnetic Resonance Elastography (MRE)

MRE is the most accurate non-invasive fibrosis assessment method (AUROC >0.90 for advanced fibrosis) and performs well in obesity where FibroScan fails. However, it is expensive, not widely available, and typically reserved for cases where FibroScan is inadequate.³⁸

Liver Biopsy: When Is It Still Needed?

Despite advances in non-invasive testing, biopsy remains the gold standard and is necessary in specific scenarios:

Indications for Liver Biopsy:

1. Diagnostic uncertainty

   • Multiple potential etiologies (e.g., AIH vs. DILI vs. viral)
   • Suspected autoimmune hepatitis (required for diagnosis)
   • Suspected infiltrative disease (sarcoidosis, amyloidosis, malignancy)

2. Discordant non-invasive tests

   • FIB-4 high but FibroScan low (or vice versa)
   • Clinical findings inconsistent with staging

3. Clinical trial enrollment

   • Most NASH treatment trials require biopsy confirmation

4. Prognostic information in specific diseases

   • MASLD/MASH: Distinguishing steatosis from steatohepatitis, assessing inflammation
   • AIH: Assessing response to therapy, determining treatment endpoints

5. Drug-induced liver injury with unusual features

   • Atypical pattern, consideration of rechallenge

Pearl: Liver biopsy samples only 1/50,000th of the liver (sampling error) and has interobserver variability in staging (κ = 0.5-0.6). A biopsy showing F2 fibrosis could represent F1-F3 disease. Non-invasive tests sample the entire liver.³⁹

Contraindications (relative):

• INR >1.5 (correct with FFP or use transjugular approach)
• Platelets <50,000/µL (transjugular route preferred)
• Ascites (use transjugular or ultrasound-guided approach)
• Uncooperative patient
• Suspected vascular lesion or echinococcal cyst

Hack: Transjugular liver biopsy allows simultaneous measurement of hepatic venous pressure gradient (HVPG), which is the gold standard for portal hypertension assessment. Consider this route in patients with thrombocytopenia, ascites, or when HVPG measurement would alter management.

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Practical Algorithms and Decision Trees

Algorithm 1: Initial Approach to Abnormal LFTs

1. Repeat LFTs to confirm abnormality (unless severely elevated or symptomatic)
2. Determine pattern (hepatocellular vs. cholestatic vs. mixed)
3. Review medications and alcohol use
4. Order initial panel:
   • Hepatocellular: HBsAg, anti-HCV, ferritin, transferrin saturation, ANA, ASMA, IgG
   • Cholestatic: Ultrasound abdomen, AMA, GGT (if ALP elevated)
5. Calculate FIB-4 if chronic elevation

Algorithm 2: Hepatocellular Pattern (ALT/AST Predominant)

• ALT >1,000 IU/L: Acetaminophen level, viral hepatitis panel, ultrasound with Doppler (rule out Budd-Chiari), consider ischemic hepatitis
• ALT 100-1,000 IU/L: Viral hepatitis, DILI (stop suspect drugs), autoimmune workup if young/female
• ALT <100 IU/L (chronic): MASLD (assess metabolic risk factors), hemochromatosis screen (TS, ferritin), Wilson disease if age <40 (ceruloplasmin), alcohol use

Algorithm 3: Cholestatic Pattern (ALP Predominant)

• Confirm hepatic origin (GGT, 5'-nucleotidase)
• Imaging: Ultrasound first-line → MRCP if dilated ducts or PSC suspected
• If imaging shows obstruction: ERCP or surgical consultation
• If imaging normal:
  • AMA → PBC (refer to hepatology for UDCA)
  • MRCP if IBD or PSC suspected
  • Liver biopsy if cause unclear

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Special Populations

Pregnancy

Pregnancy causes physiologic changes in LFTs:

• ALP rises 2-4× (placental production) in third trimester—normal
• Albumin decreases (hemodilution)—normal
• ALT/AST should remain normal

Pregnancy-specific liver diseases:

• Hyperemesis gravidarum: Mild ALT elevation (<300 IU/L), first trimester
• Intrahepatic cholestasis of pregnancy (ICP): Pruritus, elevated bile acids (>10 µmol/L diagnostic), elevated ALP/bilirubin, third trimester
• HELLP syndrome: Hemolysis, elevated liver enzymes, low platelets; preeclampsia spectrum, third trimester
• Acute fatty liver of pregnancy (AFLP): Rare, life-threatening, microvesicular steatosis, third trimester⁴⁰

Pearl: In pregnant patients with pruritus and cholestatic LFTs, measure serum bile acids. ICP increases risk of preterm delivery and stillbirth; ursodeoxycholic acid treatment reduces bile acids and may improve outcomes.

Hospitalized Patients

Mild transaminase elevation (ALT/AST <500 IU/L) is common in hospitalized patients and often multifactorial (medications, sepsis, hypotension, parenteral nutrition).⁴¹

Ischemic hepatitis ("shock liver"):

• Requires significant hypotension or hypoxia
• ALT/AST often >1,000 IU/L (peak at 24-72h)
• LDH markedly elevated
• Rapid improvement with restored perfusion
• Mortality relates to underlying cause, not liver injury

Oyster: "Shock liver" doesn't always require documented hypotension. Severe heart failure with poor cardiac output can cause ischemic hepatitis even with blood pressures that seem adequate.

Post-Transplant Patients

Abnormal LFTs in solid organ transplant recipients (any organ) require consideration of:

• Viral hepatitis (HBV, HCV, CMV, EBV)
• Drug hepatotoxicity (azathioprine, calcineurin inhibitors)
• PTLD (post-transplant lymphoproliferative disorder)
• Graft-versus-host disease (after HSCT)
• In liver transplant: rejection, recurrent disease, vascular complications

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Pearls, Oysters, and Hacks: A Summary

Top 10 Pearls:

1. Calculate the R-value ([ALT/ULN] ÷ [ALP/ULN]) to definitively categorize ambiguous LFT patterns
2. AST:ALT ratio >2 strongly suggests alcohol-related liver disease
3. Transferrin saturation (fasting) is the most sensitive screen for hemochromatosis
4. Wilson disease must be excluded in any patient <40 with unexplained liver disease
5. AMA positivity with cholestatic LFTs is diagnostic of PBC—biopsy not required
6. Amoxicillin-clavulanate can cause cholestatic injury weeks after stopping therapy
7. FIB-4 <1.3 has >90% NPV for excluding advanced fibrosis in MASLD
8. Liver stiffness by FibroScan can be falsely elevated by non-fasting state, acute inflammation, and heart failure
9. Most patients with MASLD have normal or near-normal aminotransferases
10. Hy's Law (ALT >3× ULN + bilirubin >2× ULN without ALP elevation) predicts 10-50% mortality in DILI

Top 10 Oysters (Pitfalls/Surprises):

1. Gilbert's syndrome causes isolated unconjugated hyperbilirubinemia—it's benign and common (3-7% of population)
2. Ischemic hepatitis causes massive aminotransferase elevation but resolves rapidly (unlike viral or drug hepatitis)
3. Up to 20% of AIH patients are seronegative (ANA/ASMA negative) at presentation
4. PSC affects large ducts (visible on MRCP) unlike PBC which affects microscopic ducts
5. Acute Wilson disease presents with high bilirubin, LOW ALT/AST, low ALP—a unique pattern indicating massive necrosis
6. H63D homozygosity rarely causes significant iron overload; look for cofactors
7. Normal LFTs do not exclude cirrhosis or advanced fibrosis
8. Bone disease and pregnancy cause isolated ALP elevation—check GGT to confirm hepatic origin
9. Herbal supplements and bodybuilding products are a leading cause of DILI but often not disclosed
10. Liver biopsy samples only 1/50,000th of the organ—sampling error is real

Top 10 Hacks (Time-Savers/Practical Tips):

1. Repeat LFTs in 2-4 weeks before extensive workup if mildly elevated and patient asymptomatic
2. Always ask specifically about supplements, teas, and weight-loss products—patients don't volunteer this
3. Use two-step approach: FIB-4 first (free), then FibroScan if ≥1.3
4. If HFE testing shows C282Y homozygosity with elevated iron studies, diagnosis confirmed—refer for phlebotomy
5. Check ceruloplasmin in any patient <40 with unexplained hepatitis—Wilson disease is treatable but catastrophic if missed
6. In cholestatic pattern with normal imaging, check AMA first (easiest test for most common cause: PBC)
7. Calculate FIB-4 in ALL chronic liver disease patients at every visit—it's prognostic and guides referral
8. For suspected DILI, focus on drugs started in prior 1-3 months; cholestatic DILI can lag 6 weeks post-drug
9. Don't stop statins for ALT <3× ULN unless symptomatic—benefit usually outweighs risk
10. If liver biopsy is needed but platelets <50K or INR >1.5, request transjugular approach (safer + allows HVPG measurement)

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When to Refer to Hepatology

Urgent Referral (<1 week):

• ALT/AST >10× ULN (especially if bilirubin rising or INR elevated)
• Any hepatitis with INR >1.5 or encephalopathy
• Acute liver failure
• Suspected acute Wilson disease
• Suspected autoimmune hepatitis with severe presentation

Routine Referral (4-8 weeks):

• Unexplained LFT elevation after initial workup
• Confirmed cirrhosis or advanced fibrosis (FIB-4 >2.67, FibroScan >10 kPa)
• Chronic viral hepatitis (HBV, HCV) for treatment consideration
• PBC or PSC diagnosis
• Hemochromatosis with ferritin >1,000 ng/mL or evidence of organ damage
• Wilson disease (any suspicion)
• Autoimmune hepatitis

Consider Referral:

• MASLD with FIB-4 1.3-2.67 or FibroScan 8-10 kPa
• Persistently elevated LFTs (>6 months) without clear cause
• Patient request for specialist evaluation

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Conclusion

Abnormal liver function tests are a daily challenge for the internist, but a systematic, pattern-based approach can efficiently narrow the differential diagnosis and guide appropriate investigation. The key steps—distinguishing hepatocellular from cholestatic patterns, excluding common causes (alcohol, drugs, metabolic syndrome, viral hepatitis), screening for treatable genetic diseases (hemochromatosis, Wilson disease), and assessing fibrosis risk non-invasively—form the backbone of rational LFT evaluation.

The era of reflexive liver biopsy has passed; serum biomarkers and elastography now provide excellent fibrosis staging for most patients. However, biopsy retains crucial diagnostic roles, particularly for autoimmune hepatitis and infiltrative diseases. The internist's role is to complete an evidence-based initial evaluation, stratify risk, and refer appropriately to hepatology when specialized care is indicated.

As metabolic dysfunction-associated steatotic liver disease continues to rise in prevalence globally, internists will increasingly encounter patients with mildly elevated aminotransferases. Efficient identification of the minority with advanced fibrosis—while avoiding overinvestigation of the majority with benign disease—is the modern challenge. The algorithms and principles outlined here provide a roadmap for meeting that challenge.

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References

1. Ioannou GN, Boyko EJ, Lee SP. The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-2002. Am J Gastroenterol. 2006;101(1):76-82.

2. Krier M, Ahmed A. The asymptomatic outpatient with abnormal liver function tests. Clin Liver Dis. 2009;13(2):167-177.

3. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172(3):367-379.

4. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6-19.

5. Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2015;17(1):14.

6. Kaplan MM, Righetti A. Induction of rat liver alkaline phosphatase: the mechanism of the serum elevation in bile duct obstruction. J Clin Invest. 1970;49(3):508-516.

7. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333(18):1171-1175.

8. Kaplowitz N. Acute liver failure. N Engl J Med. 2021;385(21):2001-2012.

9. Tapper EB, Sengupta N, Bonder A. The incidence and outcomes of ischemic hepatitis: a systematic review with meta-analysis. Am J Med. 2015;128(12):1314-1321.

10. Cohen JA, Kaplan MM. The SGOT/SGPT ratio--an indicator of alcoholic liver disease. Dig Dis Sci. 1979;24(11):835-838.

11. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79(6):1542-1556.

12. Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48(3):792-798.

13. Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging. 2011;34(4):729-749.

14. European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22.

15. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352(17):1769-1778.

16. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012;56(3):671-685.

17. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111.

18. Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48(4):1167-1174.

19. Mack CL, Adams D, Assis DN, et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722.

20. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169-176.

21. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900.

22. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419.

23. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877.

24. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660-678.

25. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383(9935):2168-2179.

26. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419-1425.

27. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148(7):1340-1352.e7.

28. Lee WM. Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away? J Hepatol. 2017;67(6):1324-1331.

29. Danan G, Benichou C. Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323-1330.

30. Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966.

31. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60(4):1399-1408.

32. Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39(2):e38-e81.

33. Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15(4):241-243.

34. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325.

35. Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104-1112.

36. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156(5):1264-1281.e4.

37. Petta S, Wong VW, Cammà C, et al. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values. Hepatology. 2017;65(4):1145-1155.

38. Loomba R, Wolfson T, Ang B, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology. 2014;60(6):1920-1928.

39. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898-1906.

40. Westbrook RH, Dusheiko G, Williamson C. Pregnancy and liver disease. J Hepatol. 2016;64(4):933-945.

41. Lowe D, John S. Alkaline phosphatase. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024.

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Author Declaration: This review represents current evidence-based practice as of early 2025. Guidelines and recommendations evolve; readers should consult current society guidelines for the most up-to-date recommendations.

Conflicts of Interest: None declared.

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